Cause of GGT Syndrome in Racehorses Points to Glutathione Recycling

Some Thoroughbred and Standardbred racehorses have elevated levels of the enzyme gamma-glutamyl transferase (GGT) in the face of otherwise normal blood work. They are said to have “high GGT syndrome,” which is believed to be a result of maladaptation to training. As such, elevated GGT levels are associated with poor performance.

“Research efforts have yet to identify the underlying cause for high GGT syndrome. A virus-causing hepatitis in the liver, the organ where GGT is produced, was ruled out previously. Oxidative stress was identified as one possible culprit,” said Kathleen Crandell, Ph.D., a Kentucky Equine Research nutritionist.

Pro-oxidants are produced during strenuous exercise, including reactive oxygen and nitrogen species. Antioxidants that counter the effects of pro-oxidants are glutathione, vitamin E, selenium, and coenzyme Q10 (CoQ10), and the levels of those antioxidants decrease with oxidative stress.

To further evaluate the role of pro- and antioxidants in high GGT syndrome, racehorses actively participating in training with elevated levels of GGT (50 IU/L or more) were identified. Further, a control horse from the same stable with normal GGT activity (36 IU/L or less) was included. In total, three Thoroughbred and four Standardbred case and control pairs were included in the study.^*

“Blood samples were collected from all horses prior to exercise, then again 15 and 120 minutes following exercise. In addition to GGT, pre-exercise samples were analyzed for several liver markers. Glutathione peroxidase, total glutathione, reactive oxygen and nitrogen species, vitamin E, and selenium were measured before and after exercise,” explained Crandell.

Key findings of this study included:

• Case and control horses differed only in their GGT levels (50 IU/L or more and 36 IU/L or less for cases and controls, respectively). All other liver enzyme levels were similar between the two groups and within normal limits;
• Depletion of the antioxidants vitamin E and selenium does not appear to be involved in the development of high GGT syndrome because the baseline values of these analytes did not differ between the two groups of horses; and
• Total glutathione, which is a ubiquitous antioxidant produced by the liver, was higher at both baseline and after exercise in the high GGT group.

“When glutathione is oxidized by pro-oxidants generated during exercise, it can be replaced by either newly synthesized glutathione or by recycling the oxidized glutathione. GGT is an enzyme that is involved in recycling of glutathione,” Crandell said. “GGT helps maintain intracellular glutathione by breaking down extracellular glutathione and bringing the cysteine, an amino acid piece of glutathione, into the cell for rebuilding intracellular glutathione. Thus, higher levels of GGT may be indicative of upregulation of glutathione production and increased glutathione recycling.”

In other words, enhanced glutathione recycling/altered glutathione metabolism could explain the increased GGT activity observed in some racehorses.

“Preliminary research conducted in racehorses by Kentucky Equine Research suggested that horses with higher serum coenzyme Q10 have lower GGT. CoQ10 is a powerful antioxidant, protecting cells from free radicals that can damage cells and their DNA,” Crandell said.

She added, “Nano-Q10, a highly available source of CoQ10, appears to be effective in reducing some of the problems with elevated GGT, possibly because of its powerful antioxidant effect on oxidative stress.”

^*Mann, S., A. Abuelo, T. Stokol, J.J. Wakshlag, W. Bayly, S. Reed, J. Gandy, J.D. Ramsay, and T.J. Divers. 2023. Case-control exercise challenge study on the pathogenesis of high serum gamma-glutamyl transferase activity in racehorses. Equine Veterinary Journal 55(2):182-193.