FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Equine Vet J / Investigating the pathogenesis of high-serum gamma-glutamyl ...
Equine veterinary journal2021; 54(1); 39-51; doi: 10.1111/evj.13435

Investigating the pathogenesis of high-serum gamma-glutamyl transferase activity in Thoroughbred racehorses: A series of case-control studies.

Abstract: High-serum γ-Glutamyl Transferase (GGT) activity has been associated with and thought to be a marker of maladaptation to training and possibly poor performance in racehorses, but the cause is unknown. Objective: To investigate possible metabolic and infectious causes for the high GGT syndrome. Methods: Pilot case-control study and nested case-control study. Methods: The case-control study in 2017 included 16 horses (8 cases and 8 controls with median [range] serum GGT 82 [74-148] and 22 [19-28] IU/L, respectively) from the same stable. In 2018, similar testing was performed in a nested case-control study that identified 27 case (serum GGT 50 ≥ IU/L)-control pairs from three stables for further testing. Serum liver chemistries, selenium measurements, viral PCR and metabolomics were performed. Results: No differences were found in frequency of detection of viral RNA/DNA or copy numbers for equine hepacivirus (EqHV) and parvovirus-hepatitis (EqPV-H) between cases and controls. Mild increases in hepatocellular injury and cholestatic markers in case vs control horses suggested a degree of liver disease in a subset of cases. Metabolomic and individual bile acid testing showed differences in cases compared with controls, including increased abundance of pyroglutamic acid and taurine-conjugated bile acids, and reduced abundance of Vitamin B6. Selenium concentrations, although within or above the reference intervals, were also lower in case horses in both studies. Conclusions: Observational study design did not allow us to make causal inferences. Conclusions: We conclude that high GGT syndrome is likely a complex metabolic disorder and that viral hepatitis was not identified as a cause for this syndrome in this cohort of racehorses. Our results support a contribution of oxidative stress and cholestasis in its pathophysiology.
© 2021 EVJ Ltd.
Get Full Text
Publication Date: 2021-03-08 PubMed ID: 33555643DOI: 10.1111/evj.13435Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Observational Study
  • Veterinary

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research study explores the unclear causes of high-serum γ-Glutamyl Transferase (GGT) activity in Thoroughbred racehorses. Despite viruses being suspected as potential causes, this study suggests that oxidative stress and cholestasis may play more significant roles in high GGT syndrome in racehorses, which has been linked to maladaptation to training and poor performance.

Study Details

  • The study was conducted over two years, 2017 and 2018, and consisted of a pilot case-control study and a nested case-control study.
  • In 2017, the data obtained from 16 horses from the same stable (8 cases and 8 controls) were analyzed. The horses exhibiting high serum GGT activity had concentrations in the range of 74-148 IU/L, while the controls showed values between 19-28 IU/L.
  • In 2018, a similar testing method was used for 27 case-control pairs sourced from three different stables, where ‘case’ horses had serum GGT activity greater than or equal to 50 IU/L.
  • Data collection included serum liver chemistries, selenium measurements, viral PCR, and metabolomics.

Results

  • The detection frequency and copy numbers for equine hepacivirus (EqHV) and parvovirus-hepatitis (EqPV-H) showed no significant difference between case and control groups.
  • Increased hepatocellular injury and cholestatic marker indications in ‘case’ horses hint at some level of liver disease.
  • Metabolomics and individual bile acid tests showed differences in ‘case’ and ‘control’ horses. The former exhibited increased abundance of pyroglutamic acid and taurine-conjugated bile acids and reduced Vitamin B6 levels.
  • Although within or above reference intervals, ‘case’ horses showed lower selenium concentrations in both studies.

Conclusion

  • Drawing causal inferences was not possible due to the observational study design.
  • The ‘High GGT Syndrome’ commonly observed in racehorses is likely a complex metabolic disorder.
  • Viral hepatitis was not identified as a cause of the syndrome in the particular cohort of racehorses studied.
  • The study findings suggest the involvement of oxidative stress and cholestasis in the pathophysiology of the disorder.

Cite This Article

APA
Mann S, Ramsay JD, Wakshlag JJ, Stokol T, Reed S, Divers TJ. (2021). Investigating the pathogenesis of high-serum gamma-glutamyl transferase activity in Thoroughbred racehorses: A series of case-control studies. Equine Vet J, 54(1), 39-51. https://doi.org/10.1111/evj.13435

Publication

Equine veterinary journal
ISSN: 2042-3306
NlmUniqueID: 0173320
Country: United States
Language: English
Volume: 54
Issue: 1
Pages: 39-51

Researcher Affiliations

Mann, Sabine
  • Department of Population Medicine and Diagnostic Sciences, Cornell College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Ramsay, Joshua D
  • Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, USA.
Wakshlag, Joseph J
  • Department of Clinical Sciences, Cornell College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Stokol, Tracy
  • Department of Population Medicine and Diagnostic Sciences, Cornell College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
Reed, Steven
  • Rood & Riddle Equine Hospital, Lexington, KY, USA.
Divers, Thomas J
  • Department of Clinical Sciences, Cornell College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

MeSH Terms

  • Animals
  • Case-Control Studies
  • Horse Diseases / blood
  • Horse Diseases / virology
  • Horses
  • Parvoviridae Infections / veterinary
  • Parvovirus
  • gamma-Glutamyltransferase / blood

Grant Funding

  • 84870-2017 / Grayson-Jockey Club Research Foundation

References

This article includes 50 references
  1. Tyler-McGowan CM, Golland LC, Evans DL, Hodgson DR, Rose RJ. Haematological and biochemical responses to training and overtraining.. Equine Vet J 1999;31(Suppl 30):621-5.
  2. Snow DH, Harris P. Enzymes as markers for the evaluation of physical fitness and training of racing horses.. Adv Clin Enzymol 1988;6:251-8.
  3. Mack SJ, Kirkby K, Malalana F, McGowan CM. Elevations in serum muscle enzyme activities in racehorses due to unaccustomed exercise and training.. Vet Rec 2014;174(6):145.
  4. Snow DH, Gash SP, Rice D. Field observations on selenium status, whole blood glutathione peroxidase and plasma gamma-glutamyl transferase activities in Thoroughbred racehorses.. Equine Exercise Physiology 2 1987; p. 494-505.
  5. Rivero JL, van Breda E, Rogers CW, Lindner A, Sloet van Oldruitenborgh-Oosterbaan MM. Unexplained underperformance syndrome in sport horses: classification, potential causes and recognition.. Equine Vet J 2008;40(6):611-8.
  6. DeNotta SL, Divers TJ. Clinical pathology in the adult sick horse: the gastrointestinal system and liver.. Vet Clin North Am Equine Pract 2020;36(1):105-20.
  7. Divers TJ, Tennant BC, Kumar A, McDonough S, Cullen J, Bhuva N. New parvovirus associated with serum hepatitis in horses after inoculation of common biological product.. Emerg Infect Dis 2018;24(2):303-10.
  8. Ramsay JD, Evanoff R, Wilkinson TE Jr, Divers TJ, Knowles DP, Mealey RH. Experimental transmission of equine hepacivirus in horses as a model for hepatitis C virus.. Hepatology 2015;61(5):1533-46.
  9. Blackmore DJ, Willett K, Agness D. Selenium and gamma-glutamyl transferase activity in the serum of thoroughbreds.. Res Vet Sci 1979;26(1):76-80.
  10. Williams CA. The effect of oxidative stress during exercise in the horse.. J Anim Sci 2016;94(10):4067-75.
  11. Margonis K, Fatouros IG, Jamurtas AZ, Nikolaidis MG, Douroudos I, Chatzinikolaou A. Oxidative stress biomarkers responses to physical overtraining: implications for diagnosis.. Free Radic Biol Med 2007;43(6):901-10.
  12. Radak Z, Chung HY, Koltai E, Taylor AW, Goto S. Exercise, oxidative stress and hormesis.. Ageing Res Rev 2008;7(1):34-42.
  13. Koenig G, Seneff S. Gamma-glutamyltransferase: a predictive biomarker of cellular antioxidant inadequacy and disease risk.. Dis Markers 2015;2015:818570.
  14. Liu X, Ser Z, Locasale JW. Development and quantitative evaluation of a high-resolution metabolomics technology.. Anal Chem 2014;86(4):2175-84.
  15. Goncalves MD, Hwang SK, Pauli C, Murphy CJ, Cheng Z, Hopkins BD. Fenofibrate prevents skeletal muscle loss in mice with lung cancer.. Proc Natl Acad Sci USA 2018;115(4):E743-E752.
  16. Chong J, Wishart DS, Xia J. Using MetaboAnalyst 4.0 for comprehensive and integrative metabolomics data analysis.. Curr Protoc Bioinformatics 2019;68(1):e86.
  17. Divers TJ. The poor performance horse.. Proceedings of Tenth Bain-Fallon Memorial Lectures. Equine Diagnostics and Therapeutics 1988.
  18. Rico AG, Braun JP, Benard P, El Hassan AA, Cazieux A. Tissue distribution and blood levels of gamma-glutamyl transferase in the horse.. Equine Vet J 1977;9(2):100-1.
  19. Nagel D, Siler D, Franz H, Jung K. Ultra-long-distance running and the liver.. Int J Sports Med 1990;11(6):441-5.
  20. Chemnitz G, Schmidt E, Schmidt FW, Lobers J. Diagnostische und prognostische Bedeutung massiv erhöhter Glutamat-Dehydrogenase-Aktivität im Serum.. Dtsch Med Wochenschr 1984;109(47):1789-93.
  21. Gemaque BS, de Souza AJ, Soares MD, Malheiros AP, Silva AL, Alves MM. Hepacivirus infection in domestic horses, Brazil, 2011-2013.. Emerg Infect Dis 2014;20(12):2180-2.
  22. Meister TL, Tegtmeyer B, Brüggemann Y, Sieme H, Feige K, Todt D. Characterization of equine parvovirus in thoroughbred breeding horses from Germany.. Viruses 2019;11(10):965.
  23. Tomlinson JE, Jager M, Struzyna A, Laverack M, Fortier LA, Dubovi E. Tropism, pathology, and transmission of equine parvovirus-hepatitis.. Emerg Microbes Infect 2020;9(1):651-63.
  24. Pfaender S, Walter S, Grabski E, Todt D, Bruening J, Romero-Brey I. Immune protection against reinfection with nonprimate hepacivirus.. Proc Natl Acad Sci USA 2017;114(12):E2430-E2439.
  25. Scheel TK, Kapoor A, Nishiuchi E, Brock KV, Yu Y, Andrus L. Characterization of nonprimate hepacivirus and construction of a functional molecular clone.. Proc Natl Acad Sci USA 2015;112(7):2192-7.
  26. Lyons S, Kapoor A, Schneider BS, Wolfe ND, Culshaw G, Corcoran B. Viraemic frequencies and seroprevalence of non-primate hepacivirus and equine pegiviruses in horses and other mammalian species.. J Gen Virol 2014;95(Pt 8):1701-11.
  27. McGowan CM, Golland LC, Evans DL, Hodgson DR, Rose RJ. Effects of prolonged training, overtraining and detraining on skeletal muscle metabolites and enzymes.. Equine Vet J 2002;34(Suppl 34):257-63.
  28. Leleu C, Haentjens F. Morphological, haemato-biochemical and endocrine changes in young Standardbreds with 'maladaptation' to early training.. Equine Vet J 2010;42(Suppl 38):171-8.
  29. Zeyner A, Harmeyer J. Metabolic functions of L-carnitine and its effects as feed additive in horses. A review.. Arch Tierernahr 1999;52(2):115-38.
  30. Rebouche CJ, Seim H. Carnitine metabolism and its regulation in microorganisms and mammals.. Annu Rev Nutr 1998;18(1):39-61.
  31. Foster CVL, Harris RC, Pouret EJM. Survey of plasma free carnitine levels in 74 Thoroughbred horses at stud and in training.. Equine Vet J 1989;21(2):139-41.
  32. van der Kolk JH, Thomas S, Mach N, Ramseyer A, Burger D, Gerber VN. Serum acylcarnitine profile in endurance horses with and without metabolic dysfunction.. Vet J 2020;255:105419.
  33. Lu SC. Regulation of glutathione synthesis.. Mol Aspects Med 2009;30(1-2):42-59.
  34. Lu SC. Glutathione synthesis.. Biochem Biophys Acta 2013;1830(5):3143-53.
  35. Leeuwenburgh C, Ji LL. Glutathione depletion in rested and exercised mice: biochemical consequence and adaptation.. Arch Biochem Biophys 1995;316(2):941-9.
  36. Lew H, Pyke S, Quintanilha A. Changes in the glutathione status of plasma, liver and muscle following exhaustive exercise in rats.. FEBS Lett 1985;185(2):262-6.
  37. Chamera T, Spieszny M, Klocek T, Kostrzewa-Nowak D, Nowak R, Lachowicz M. Could biochemical liver profile help to assess metabolic response to aerobic effort in athletes?. J Strength Cond Res 2014;28(8):2180-6.
  38. Emami A, Bazargani-Gilani B. Effect of oral CoQ10supplementation along with precooling strategy on cellular response to oxidative stress in elite swimmers.. Food Funct 2018;9(8):4384-93.
    doi: 10.1039/c8fo00960kgoogle scholar: lookup
  39. Kieliszek M, Błażejak S. Selenium: significance, and outlook for supplementation.. Nutrition 2013;29(5):713-8.
  40. Gamarra Y, Santiago FC, Molina-López J, Castaño J, Herrera-Quintana L, Domínguez A. Pyroglutamic acidosis by glutathione regeneration blockage in critical patients with septic shock.. Crit Care 2019;23(1):162.
  41. Kannan K, Jain SK. Effect of vitamin B6 on oxygen radicals, mitochondrial membrane potential, and lipid peroxidation in H2O2-treated U937 monocytes.. Free Radic Biol Med 2004;36(4):423-8.
  42. Hsu C-C, Cheng C-H, Hsu C-L, Lee W-J, Huang S-C, Huang Y-C. Role of vitamin B6 status on antioxidant defenses, glutathione, and related enzyme activities in mice with homocysteine-induced oxidative stress.. Food & Nutrition Research 2015;59.
    doi: 10.3402/fnr.v59.25702google scholar: lookup
  43. Roma MG, Sanchez Pozzi EJ. Oxidative stress: a radical way to stop making bile.. Ann Hepatol 2008;7(1):16-33.
  44. Villa JG, Almar MM, Collago PS, Llamazares E, González-Gallego J. Impairment of bile secretion induced by exhaustive exercise in the rat.. Int J Sports Med 1993;14(4):179-84.
  45. Beuers U, Denk GU, Soroka CJ, Wimmer R, Rust C, Paumgartner G. Taurolithocholic acid exerts cholestatic effects via phosphatidylinositol 3-kinase-dependent mechanisms in perfused rat livers and rat hepatocyte couplets.. J Biol Chem 2003;278(20):17810-8.
  46. Schwenk M, Schwarz LR, Greim H. Taurolithocholate inhibits taurocholate uptake by isolated hepatocytes at low concentrations.. Naunyn Schmiedebergs Arch Pharmacol 1977;298(2):175-9.
  47. Masubuchi N, Sugihara M, Sugita T, Amano K, Nakano M, Matsurra T. Oxidative stress markers, secondary bile acids and sulfated bile acids classify the clinical liver injury type: promising diagnostic biomarkers for cholestasis.. Chem Biol Interact 2016;255:83-91.
  48. Mills PC, Smith NC, Casas I, Harris P, Harris RC, Marlin DJ. Effects of exercise intensity and environmental stress on indices of oxidative stress and iron homeostasis during exercise in the horse.. Eur J Appl Physiol Occup Physiol 1996;74(1-2):60-6.
  49. Whitfield JB. Gamma glutamyl transferase.. Crit Rev Clin Lab Sci 2001;38(4):263-355.
  50. Wu N, Yang M, Gaur U, Xu H, Yao Y, Li D. Alpha-ketoglutarate: physiological functions and applications.. Biomol Ther 2016;24(1):1-8.

Citations

This article has been cited 12 times.
  1. Irving J, Pineau V, Shultz S, Ter Woort F, Julien F, Lambey S, van Erck-Westergren E. Impact of Low-Starch Dietary Modifications on Faecal Microbiota Composition and Gastric Disease Scores in Performance Horses. Animals (Basel) 2025 Jun 28;15(13).
    doi: 10.3390/ani15131908pubmed: 40646806google scholar: lookup
  2. Fortier C, El-Hage C, Normand C, Hue ES, Sutton G, Marcillaud-Pitel C, Jeffers K, Bamford N, Oden E, Paillot R, Hartley C, Gilkerson J, Pronost S. Detection of Equine Parvovirus-Hepatitis Virus and Equine Hepacivirus in Archived Sera from Horses in France and Australia. Viruses 2024 May 28;16(6).
    doi: 10.3390/v16060862pubmed: 38932156google scholar: lookup
  3. Filho HCM, Trindade KLG, Silva CJFL, Cruz RKS, Vilela CF, Coelho CS, Filho JDR, Manso HECCC. The Welfare of Horses Competing in Three-Barrel Race Events Is Shown to Be Not Inhibited by Short Intervals between Starts. Animals (Basel) 2024 Feb 9;14(4).
    doi: 10.3390/ani14040583pubmed: 38396551google scholar: lookup
  4. Jager MC, Choi E, Tomlinson JE, Van de Walle G. Naturally acquired equine parvovirus-hepatitis is associated with a wide range of hepatic lesions in horses. Vet Pathol 2024 May;61(3):442-452.
    doi: 10.1177/03009858231214024pubmed: 38018088google scholar: lookup
  5. Huertas RM, Arguedas M, Estrada JM, Moscoso E, Umaña D, Solano G, Vargas M, Segura Á, Sánchez A, Herrera M, Villalta M, Arroyo-Portilla C, Gutiérrez JM, León G. Clinical effects of immunization, bleeding, and albumin-based fluid therapy in horses used as immunoglobulin source to produce a polyspecific antivenom (Echitab-plus-ICP) towards venoms of African snakes. Toxicon X 2023 Jun;18:100158.
    doi: 10.1016/j.toxcx.2023.100158pubmed: 37180815google scholar: lookup
  6. Gołyński M, Metyk M, Ciszewska J, Szczepanik MP, Fitch G, Bęczkowski PM. Homocysteine-Potential Novel Diagnostic Indicator of Health and Disease in Horses. Animals (Basel) 2023 Apr 11;13(8).
    doi: 10.3390/ani13081311pubmed: 37106874google scholar: lookup
  7. Peng S, Magdesian KG, Dowd J, Blea J, Carpenter R, Ho W, Finno CJ. Investigation of high gamma-glutamyltransferase syndrome in California Thoroughbred racehorses. J Vet Intern Med 2022 Nov;36(6):2203-2212.
    doi: 10.1111/jvim.16582pubmed: 36377652google scholar: lookup
  8. Jager MC, Tomlinson JE, Henry CE, Fahey MJ, Van de Walle GR. Prevalence and pathology of equine parvovirus-hepatitis in racehorses from New York racetracks. Virol J 2022 Nov 1;19(1):175.
    doi: 10.1186/s12985-022-01901-3pubmed: 36320007google scholar: lookup
  9. Bazzano M, Arfuso F, Bonfili L, Eleuteri AM, McLean A, Serri E, Spaterna A, Laus F. Measuring Biochemical Variables and Serum Amyloid A (SAA) in Working Mules in Central Italy. Animals (Basel) 2022 Oct 16;12(20).
    doi: 10.3390/ani12202793pubmed: 36290179google scholar: lookup
  10. Ramadan MM, Dailey D. Trouble for Horses in Paradise: Toxicity and Fatality Resulting from the Consumption of Indigofera spicata (Fabaceae) on Oahu Island. Vet Sci 2022 Jun 4;9(6).
    doi: 10.3390/vetsci9060271pubmed: 35737323google scholar: lookup
  11. Gawor A, Ruszczyńska A, Konopka A, Wryk G, Czauderna M, Bulska E. Label-Free Mass Spectrometry-Based Proteomic Analysis in Lamb Tissues after Fish Oil, Carnosic Acid, and Inorganic Selenium Supplementation. Animals (Basel) 2022 May 31;12(11).
    doi: 10.3390/ani12111428pubmed: 35681892google scholar: lookup
  12. Jager MC, Tomlinson JE, Lopez-Astacio RA, Parrish CR, Van de Walle GR. Small but mighty: old and new parvoviruses of veterinary significance. Virol J 2021 Oct 24;18(1):210.
    doi: 10.1186/s12985-021-01677-ypubmed: 34689822google scholar: lookup
Subscribe to our newsletter
Join 99,357 horse owners like you who receive our email updates on horse health and nutrition.