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Serum uric acid as a prognostic indicator in Reye's Syndrome?
BIOCHEMICAL
MEDICINE
24, 361-363
LETTER Serum
(1980)
TO THE
Uric Acid as a Prognostic Syndrome?
EDITOR Indicator
in Reye’s
Serum from patients with Reye’s Syndrome stimulate oxygen utilization in preparations of isolated rat liver mitochondria and also cause mitochondrial swelling (l-3). This serum factor has recently been identified to be uric acid by Aprille et al. (4). On the basis of this finding as well as the observations by others that uric acid is elevated in plasma of Reye’s Syndrome patients (5), Aprille et al. (4) suggest that uric acid levels in plasma (serum) may deserve attention as a possible prognostic marker in Reye’s Syndrome. Several arguments can be made against using uric acid as a prognostic marker in this disease. For example: (a) There is some disagreement in literature on the nature of the factor in the serum of patients with Reye’s Syndrome that causes alteration of mitochondrial function. Data published by Ansevin (6) indicate that the serum factor most likely is short-chain fatty acids. This seems to be supported by the observations of (i) Trauner and associates (7,8), who found that clinical improvements of patients with Reye’s Syndrome correlated most closely with the clearance of short-chain fatty acids from the plasma of the patients; and (ii) Young et al. (9), who reported that an 8-year-old boy on valproate (a short-chain fatty acid) treatment exhibited clinical symptoms akin to Reye’s Syndrome. (b) The cause-and-effect relationship between increases in serum uric acid levels and Reye’s Syndrome has not yet been established. (c) Unlike the serum factor from Reye’s Syndrome patients, uric acid does not cause mitochondrial swelling (4). (d) Hyperuricemia could arise due to a multitude of causes and may not have a direct bearing on the disease process itself. These are: (i) Increased purine synthesis and breakdown as a consequence of hemolytic hemoglobinopathies (10) and other hematologic disorders (11); (ii) Renal retention of uric acid caused by drugs, especially low doses of salicylates (11,12); (iii) Decreased uric acid excretion caused by ketoacidosis (1 l-13), 361 0006-2944/80/060361-03$02.00/O Copyright 0 1980 by Academic Press. Inc. All rights of reproduction in any form reserved.
362
LETTER
TO THE
EDITOR
lactic acidosis (11,14), renal damage due to disease. nutritional deficiency or toxic materials (1 I), and dehydration (15); (iv) Increased purine synthesis and breakdown as a consequence of defective glutamine and glutamic acid metabolism ( 11.16); and (v) An enhanced catabolic state due to caloric imbalance ( I I ). Patients suffering from Reye’s Syndrome exhibit a combination of the above symptoms. Severe vomiting, disorientation, and lethargy are typical symptoms of this disease and could contribute to dehydration. malnutrition, and debilitation. The patients have impaired liver function and associated with this. hypoglycemia (17,18), ketoacidosis (5,19,20), and severe lactic acidosis (21). In view of the known liver mitochondrial damage (22.23) and the attendant inability to detoxify ammonia (22), glutamine levels of cells can increase (21). Acute renal failure in Reye’s Syndrome patients has also been reported recently (24-26). The efficacy of hypertonic glucose administration with (20) or without insulin (27,28) in the treatment of Reye’s syndrome patients may be linked to correction of many of the above factors contributing to the malady of Reye’s Syndrome. In view of the above, it is not surprising that plasma (serum) uric acid levels are increased in Reye’s Syndrome patients. However, one has to be extremely cautious of using the uric acid levels as a prognostic indicator in view of multiple factors affecting its levels in plasma (serum), some of which may not have any direct bearing on the course of the disease but rather may be secondary to the numerous biochemical abnormalities found in patients with the disease. REFERENCES I. Aprille. J. R., Science 197, 908 (1977). 2. Asimakis, G. K., and Aprille. J. R., Biochem. Bid&s. Res. Commun. 79, I122 ( 1977). 3. Aprille, J. R., and Asimakis, G. K., in “Reye’s Syndrome II” (J. F. S. Cracker, Ed.) p. 361. Grune and Stratton, New York, 1979. 4. Aprille, J. R., Austin, J., Costello, C. E.. and Royal, N.. Biochem. Biophys. Res. Commun. 94, 381 (1980). 5. Alvira. M. M.. and Forman, D. T., Ann. Clin. Lub. Sci. 4, 477 (1974). 6. Ansevin, C. F., Neurology 30, I60 (1980). 7. Trauner, D., Sweetman, L., Holm. J., Kulovich, S., and Nyhan. W. L., Ann. New-of. 2, 238 (1977). 8. Sweetman. L., and Trauner, D., Ann. Nuerol. 4, 484 (1978). 9. Young, R. S. K., Bergman, I., Gang, D. L.. and Richardson, Jr., E. P., Ann. Neural. 7, 389 (1980). IO. Ballou. S. P., Khan, M. A.. Kushner, I., and Harris, J. W.. Amer. J. Hemurol. 2, 397 (1977). 1 I. Wyngaarden, J. B., and Kelley, W. N., in “The Metabolic Basis of Inherited Disease” (J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson, Eds.), p. 916. McGrawHill, New York, 1978. I?. Klinenberg, J. R., Postgrnd. Med. 63, 145 (197X).
LETTER
363
TO THE EDITOR
13. Goldfinger, S., Klinenberg, J. R., and Seegmiller, J. E., N. Engl. J. Med. 272, 351 (1965). 14. Knochel, J. P., Dotin, L. N., and Hamburger, R. J., Ann. Intern. Med. 81,321 (1974). 15. Yu, T. F., Posrgrad. Med. 63, I64 (1978). 16. Wyngaarden, J. B., and Holmes, E. W., CIBA Foundation Symp. 48, 43 (1977). 17. Yamashita, F., Yamamoto, M., Okada, S., Yoshida, I., and Yoshino, M., in “Reye’s Syndrome II“ (J. F. S. Cracker, Ed.), p. 51. Grune and Stratton, New York, 1979. 18. Dhiensiri, K., Sinavatana, P., and Lertsookprasert, S., in “Reye’s Syndrome II” (J. F. S. Cracker, Ed.), p. 77. Grune and Stratton, New York, 1979. 19. Brown, R. E., in “Reye’s Syndrome” (J. D. Pollack, Ed.), p. 387. Grune and Stratton, New York, 1975. 20. Trauner, D., Ann. Neural. 7, 2 (1979). 21. Juggi, J. S., lyngkaran, N., and Prathap, K., in “Reye’s Syndrome II” (J. F. S. Cracker, Ed.), p. 411. Grune and Stratton, New York, 1979. 22. Thaler, M. M., in “Reye’s Syndrome II” (J. F. S. Cracker, Ed.), p. 115. Grune and Stratton, New York, 1979. 23. Partin, J. C., Bove, K., Partin, J. S., and Schubert, W. K., in “Reye’s Syndrome II” (J. F. S. Cracker, Ed.), p. 217. Grune and Stratton, New York, 1979. 24. Baliga, R., Fleischmann, L. E., Chang, C. H., Sarnaik, A. P., Bidani, A. K., and Arcinue, E. L., Amer. J. Dis. Child. 133, 1009 (1979). 25. Gilboa, N., J. Ped. 95, 664 (1979). 26. Ahronheim. G. A., J. Ped. 95, 665 (1979). 27. DeVivo, D. C., Keating, J. P., and Haymond, M. W., in “Reye’s Syndrome” (J. D. Pollack, Ed.), p. 315. Grune and Stratton, New York, 1975. 28. DeVivo. D. C., and Keating, J. P., Advan. Ped. 22, 175 (1976).
C.
BHIJVANESWARAN M.
Departments of Biochemistry and Pathology University of Arkansas for Medical Sciences and Arkansas Childrens Hospital Little Rock, Arkansas 72205 Received August 14, 1980
A.
BREWSTER
MEDICINE
24, 361-363
LETTER Serum
(1980)
TO THE
Uric Acid as a Prognostic Syndrome?
EDITOR Indicator
in Reye’s
Serum from patients with Reye’s Syndrome stimulate oxygen utilization in preparations of isolated rat liver mitochondria and also cause mitochondrial swelling (l-3). This serum factor has recently been identified to be uric acid by Aprille et al. (4). On the basis of this finding as well as the observations by others that uric acid is elevated in plasma of Reye’s Syndrome patients (5), Aprille et al. (4) suggest that uric acid levels in plasma (serum) may deserve attention as a possible prognostic marker in Reye’s Syndrome. Several arguments can be made against using uric acid as a prognostic marker in this disease. For example: (a) There is some disagreement in literature on the nature of the factor in the serum of patients with Reye’s Syndrome that causes alteration of mitochondrial function. Data published by Ansevin (6) indicate that the serum factor most likely is short-chain fatty acids. This seems to be supported by the observations of (i) Trauner and associates (7,8), who found that clinical improvements of patients with Reye’s Syndrome correlated most closely with the clearance of short-chain fatty acids from the plasma of the patients; and (ii) Young et al. (9), who reported that an 8-year-old boy on valproate (a short-chain fatty acid) treatment exhibited clinical symptoms akin to Reye’s Syndrome. (b) The cause-and-effect relationship between increases in serum uric acid levels and Reye’s Syndrome has not yet been established. (c) Unlike the serum factor from Reye’s Syndrome patients, uric acid does not cause mitochondrial swelling (4). (d) Hyperuricemia could arise due to a multitude of causes and may not have a direct bearing on the disease process itself. These are: (i) Increased purine synthesis and breakdown as a consequence of hemolytic hemoglobinopathies (10) and other hematologic disorders (11); (ii) Renal retention of uric acid caused by drugs, especially low doses of salicylates (11,12); (iii) Decreased uric acid excretion caused by ketoacidosis (1 l-13), 361 0006-2944/80/060361-03$02.00/O Copyright 0 1980 by Academic Press. Inc. All rights of reproduction in any form reserved.
362
LETTER
TO THE
EDITOR
lactic acidosis (11,14), renal damage due to disease. nutritional deficiency or toxic materials (1 I), and dehydration (15); (iv) Increased purine synthesis and breakdown as a consequence of defective glutamine and glutamic acid metabolism ( 11.16); and (v) An enhanced catabolic state due to caloric imbalance ( I I ). Patients suffering from Reye’s Syndrome exhibit a combination of the above symptoms. Severe vomiting, disorientation, and lethargy are typical symptoms of this disease and could contribute to dehydration. malnutrition, and debilitation. The patients have impaired liver function and associated with this. hypoglycemia (17,18), ketoacidosis (5,19,20), and severe lactic acidosis (21). In view of the known liver mitochondrial damage (22.23) and the attendant inability to detoxify ammonia (22), glutamine levels of cells can increase (21). Acute renal failure in Reye’s Syndrome patients has also been reported recently (24-26). The efficacy of hypertonic glucose administration with (20) or without insulin (27,28) in the treatment of Reye’s syndrome patients may be linked to correction of many of the above factors contributing to the malady of Reye’s Syndrome. In view of the above, it is not surprising that plasma (serum) uric acid levels are increased in Reye’s Syndrome patients. However, one has to be extremely cautious of using the uric acid levels as a prognostic indicator in view of multiple factors affecting its levels in plasma (serum), some of which may not have any direct bearing on the course of the disease but rather may be secondary to the numerous biochemical abnormalities found in patients with the disease. REFERENCES I. Aprille. J. R., Science 197, 908 (1977). 2. Asimakis, G. K., and Aprille. J. R., Biochem. Bid&s. Res. Commun. 79, I122 ( 1977). 3. Aprille, J. R., and Asimakis, G. K., in “Reye’s Syndrome II” (J. F. S. Cracker, Ed.) p. 361. Grune and Stratton, New York, 1979. 4. Aprille, J. R., Austin, J., Costello, C. E.. and Royal, N.. Biochem. Biophys. Res. Commun. 94, 381 (1980). 5. Alvira. M. M.. and Forman, D. T., Ann. Clin. Lub. Sci. 4, 477 (1974). 6. Ansevin, C. F., Neurology 30, I60 (1980). 7. Trauner, D., Sweetman, L., Holm. J., Kulovich, S., and Nyhan. W. L., Ann. New-of. 2, 238 (1977). 8. Sweetman. L., and Trauner, D., Ann. Nuerol. 4, 484 (1978). 9. Young, R. S. K., Bergman, I., Gang, D. L.. and Richardson, Jr., E. P., Ann. Neural. 7, 389 (1980). IO. Ballou. S. P., Khan, M. A.. Kushner, I., and Harris, J. W.. Amer. J. Hemurol. 2, 397 (1977). 1 I. Wyngaarden, J. B., and Kelley, W. N., in “The Metabolic Basis of Inherited Disease” (J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson, Eds.), p. 916. McGrawHill, New York, 1978. I?. Klinenberg, J. R., Postgrnd. Med. 63, 145 (197X).
LETTER
363
TO THE EDITOR
13. Goldfinger, S., Klinenberg, J. R., and Seegmiller, J. E., N. Engl. J. Med. 272, 351 (1965). 14. Knochel, J. P., Dotin, L. N., and Hamburger, R. J., Ann. Intern. Med. 81,321 (1974). 15. Yu, T. F., Posrgrad. Med. 63, I64 (1978). 16. Wyngaarden, J. B., and Holmes, E. W., CIBA Foundation Symp. 48, 43 (1977). 17. Yamashita, F., Yamamoto, M., Okada, S., Yoshida, I., and Yoshino, M., in “Reye’s Syndrome II“ (J. F. S. Cracker, Ed.), p. 51. Grune and Stratton, New York, 1979. 18. Dhiensiri, K., Sinavatana, P., and Lertsookprasert, S., in “Reye’s Syndrome II” (J. F. S. Cracker, Ed.), p. 77. Grune and Stratton, New York, 1979. 19. Brown, R. E., in “Reye’s Syndrome” (J. D. Pollack, Ed.), p. 387. Grune and Stratton, New York, 1975. 20. Trauner, D., Ann. Neural. 7, 2 (1979). 21. Juggi, J. S., lyngkaran, N., and Prathap, K., in “Reye’s Syndrome II” (J. F. S. Cracker, Ed.), p. 411. Grune and Stratton, New York, 1979. 22. Thaler, M. M., in “Reye’s Syndrome II” (J. F. S. Cracker, Ed.), p. 115. Grune and Stratton, New York, 1979. 23. Partin, J. C., Bove, K., Partin, J. S., and Schubert, W. K., in “Reye’s Syndrome II” (J. F. S. Cracker, Ed.), p. 217. Grune and Stratton, New York, 1979. 24. Baliga, R., Fleischmann, L. E., Chang, C. H., Sarnaik, A. P., Bidani, A. K., and Arcinue, E. L., Amer. J. Dis. Child. 133, 1009 (1979). 25. Gilboa, N., J. Ped. 95, 664 (1979). 26. Ahronheim. G. A., J. Ped. 95, 665 (1979). 27. DeVivo, D. C., Keating, J. P., and Haymond, M. W., in “Reye’s Syndrome” (J. D. Pollack, Ed.), p. 315. Grune and Stratton, New York, 1975. 28. DeVivo. D. C., and Keating, J. P., Advan. Ped. 22, 175 (1976).
C.
BHIJVANESWARAN M.
Departments of Biochemistry and Pathology University of Arkansas for Medical Sciences and Arkansas Childrens Hospital Little Rock, Arkansas 72205 Received August 14, 1980
A.
BREWSTER