1279
nmola, rising to 068 postoperative day. i 0.13
± 0.125
nmol/l on the 2nd
CLOFIBRATE-INDUCED MUSCLE DAMAGE IN PATIENTS WITH CHRONIC RENAL FAILURE
Patient 7 was excluded from the statistical analysis. After parathyroidectomy for parathyroid hyperplasia, serum T3 and T4 rose progressively (fig. 2). Both hormones reached levels well within the hyperthyroid range, with a maximum T3 of 4.6 nmol/1 on day 7, and a maximum T4 of 304 nmol/1 on days 4 and 6 after operation. Serum-rT3 showed a similar postoperative rise, with a fourfold increase in concentration on the 2nd
F. ALVAREZ-UDE A. M. PIERIDES D. N. S. KERR
Department of Medicine, University of Newcastle upon Tyne A. W. SKILLEN
Department of Clinical Biochemistry, University of Newcastle upon Tyne
postoperative day. Discussion
There
was a
highly significant postoperative
reduc-
tion in serum-T3 concentration in six subjects. The effect was apparent within 24 hours, and levels were still lower than normal after 6 days. The results confirm recent reports of the effect on serum-T3 concentration of acute
illness21and surgical operation.
17 is
In this study serum-T4 concentration was slightly reduced after operation. This result does not accord with some previous reports,22 23 and may be due to an increase in plasma volume, perhaps resulting from intravenous infusions which were given to most patients for
several days postoperatively. Serum-rT3 concentrations were significantly elevated for the first 3 days after operation. If plasma volume did increase, as we have suggested to explain the fall in serum-T4 concentration, then the rise in rT3 would be even greater than observed, while the fall in T3 would be less pronounced. In patient 7 who underwent a parathyroidectomy for glandular hyperplasia, serum concentrations of T4 and T3 rose postoperatively. It is suggested that this resulted from increased thyroidal secretion due to manipulation of the gland at surgery. When the values of T3 and rT3 are expressed relative to serum-T4 concentration (fig. 2), the changes conform to the pattern seen after other types of surgery. Evidence suggests serum-T3 concentrations may be low in various acute and chronic illnesses 18 21 24-27 as well as in certain physiological conditions, such as fasting14 and in newborn infants.13 The cause is not known, although in cirrhosis of the liver and in obese individuals after fasting there is evidence of reduced peripheral monodeiodination of T4.28 29 Low serum-T3 concentration could also be caused by diversion of T4 monodeiodination along an alternative pathway, resulting in formation of rT3 instead of T3. There is evidence to suggest that T4 monodeiodination in the liver may produce T3, while deiodination in extrahepatic tissues may result in rT3 formation.3O The results of the present study support the existence of an alternative pathway of T4 monodeiodination, leading to increased rT3 production in the postoperative period. The alternative pathway may also be active in newborn infants13 and in fasting individuals. 14 Elucidation of the metabolic pathways of vitamin D has emphasised the importance of hepatic and renal hydroxylating enzymes in the production of active metabolites. Monodeiodination of T4 to either T3 or rT3 seems to offer another example of peripheral modulation of hormonal effects. Requests for reprints should be addressed
Muscle
weakness and tenderness with a rise in serum creatine kinase (C.K.) were noted in five uræmic patients treated with 1-2 g of clofibrate (’Atromid-S’) daily. Excessive accumulation of both total and free serum chlorophenoxyisobutyric acid (C.P.I.B.), the active circulating metabolite after clofibrate therapy, was found in three patients in whom it was sought. It is suggested that chronic renal failure should be regarded as a contraindication to the use of clofibrate for the treatment of any coexisting hyperlipidæmia. If such therapy is contemplated it must be cautiously instituted at low dosage and the patient monitored by regular assessment of serum C.K. and levels of both total and free C.P.I.B.
Summary
to
R.H.
together
DR BURR AND OTHERS: REFERENCES
Braverman, L. E., Ingbar, S. H., Sterling, K. J. clin. Invest. 1970, 49, 855. Sterling, K., Brenner, M. A., Newman, E. S. Science, 1970, 169, 1099. 3. Pittman, C. S., Chambers, J. B., Read, V. H. J. clin. Invest. 1971, 50, 1187. 4. Surks, M. I., Schadlow, A. R., Stock, J. M., Oppenheimer, J. H. ibid. 1973, 1. 2.
52, 805. Inada, M., Kurata, S., Kasama, Y., Takayama, H., Torizuka, K., Fukase, M., Soma, T. ibid. 1975, 55, 1337. 6. Berson, S. A., Yalow, R. S. ibid. 1954, 33, 1533. 7. Ingbar, S. H., Freinkel, N. ibid. 1955, 34, 808. 8. Oddie, T. H., Fisher, D. A., Rogers, C. J. clin. Endocr. Metab. 1964, 24, 5.
628. 9. Surks, M. I., Oppenheimer, J. H. ibid. 1971, 33, 612. 10. Pittman, J. A., Brown, R. W., Register, H. B. Endocrinology, 1962, 70, 79. 11. Chopra, I. J. J. clin. Invest. 1974, 54, 583. 12. Meinhold, H., Wenzel, K. W., Schurnbrand, P. Z. klin. Chem. klin. Biochem. 1975, 13, 571. 13. Chopra, I. J., Sack, J., Fisher, D. A. J. clin. Invest. 1975, 55, 1137. 14. Vagenakis, A. G., Burger, A., Portnay, G. I., Rudolph, M., O’Brian, J. T., Azizi, F., Arkv, R. A., Nicod, P., Ingbar, S. H., Braverman, L. E. J. clin. Endocr. Metab. 1975, 41, 191. 15. Abuid, J., Klein, A. H., Foley, T. P., Larsen, P. R. ibid. 1974, 39, 263. 16. Portnay, G. I., O’Brian, J. T., Bush, J., Vagenakis, A. G., Azizi, F., Arky, R. A., Ingbar, S. H., Braverman, L. E. ibid. p. 199. 17. Burr, W. A., Black, E. G., Griffiths, R. S., Princé, P., Ramsden, D. B. Clin. Sci. molec. Med. 1975, 49, 22P (abstr.). 18. Bermudez, F., Surks, M. I., Oppenheimer, J. H. J. clin. Endocr. Metab. 1975, 41, 27. 19. Burr, W. A., Black, E. G., Griffiths, R. S., Ramsden, D. B., Hoffenberg, R. 20.
Unpublished. Black, E. G., Griffiths, R. S., Finucane, J., Hoffenberg, R. in Thyroid Hormone Metabolism (edited by W. A. Harland and J. S. Orr); p. 347. Lon-
21.
McLarty, D. G., Ratcliffe, W. A., McColl, K., Stone, D., Ratcliffe, J. G. Lan-
don, 1975. cet,
1975, ii. 275.
22. Harland, W. A., Orr, J. S., Richards, J. R. Scott. med. J. 1972, 17, 92. 23. Kirby, R., Clark, F., Johnston, I. D. A. Clin. Endocr. 1973, 2, 89. 24. Carter, J. N., Eastman, C. J., Corcoran, J. M., Lazarus, L. Lancet,
1974,
ii, 971. 25.
Chopra, I. J., Solomon, D. H., Chopra, U., Young, N. J. clin. Endocr. Metab. 1974, 39, 501.
R. T., Chua
Teco, G.
Burke, C. W., Eastman, C. J. Br. med. Bull. 1974, 30, 93. Moshang, T., Parks, J. S., Baker, L., Vaidya, V., Utiger, R. D., Bongiovanni, A. M., Snyder, P. J. J. clin. endocr. Metab. 1975, 40, 470. 28. Nomura, S., Pittman, C. S., Chambers, J. B., Buck, M. W., Shimizu, T. J. clin. Invest. 1975, 56, 643. 29. Portnay, G. I., O’Brian, J. T., Rudolph, M., Vagenakis, A. G., Azizi, F., Arky, A., Ingbar, S. H., Braverman, L. E. Endocrinology, 1974, 93, T-15 (abstr). 30. Flock, E. V., Bollman, J. L., Grindlay, J. H., Stobie, G. H. ibid. 1961, 69, 26. 27.
696
1280 Introduction
CLOFIBRATE has been widely used in hyperlipidaemic patients for over a decade and few side-effects or complications have been reported. 1A syndrome characterised by muscle weakness and tenderness and raised serum creatine kinase (C.K.) and lactate dehydrogenase (L.D.) a few non-uraemic hyperlipidsemic similar 4 and a syndrome has also been noted patients3 in hypoalbuminæmic, hyperlipidaemic nephrotic patients given standard doses of clofibrate.5 6 Katsilambros et al.7 described a 36-year-old diabetic ursemic patient who presented with progressive muscle weakness and tenderness and inability to walk a few months after she started therapy with clofibrate 500 mg four times daily. We describe here our experience with five uraemic patients who developed a similar muscle syndrome and other complications when overtreated with clofibrate. It is hoped that awareness of these complications will ensure a more cautious use of the drug in uraemia and therefore restrict the temptation to treat mild biochemical abnormalities without regard to the underlying lesion.
has been reported in
his serum total C.P.I.B. was high at 166 g/ml and the calculated value on the last day of treatment was 315 µg/ml indicating gross retention with overdosage (therapeutic range 80-150 µg/ml). The serum free (non-protein-bound) C.P.I.B. was also high at 19.8% (therapeutic range
nmola, rising to 068 postoperative day. i 0.13
± 0.125
nmol/l on the 2nd
CLOFIBRATE-INDUCED MUSCLE DAMAGE IN PATIENTS WITH CHRONIC RENAL FAILURE
Patient 7 was excluded from the statistical analysis. After parathyroidectomy for parathyroid hyperplasia, serum T3 and T4 rose progressively (fig. 2). Both hormones reached levels well within the hyperthyroid range, with a maximum T3 of 4.6 nmol/1 on day 7, and a maximum T4 of 304 nmol/1 on days 4 and 6 after operation. Serum-rT3 showed a similar postoperative rise, with a fourfold increase in concentration on the 2nd
F. ALVAREZ-UDE A. M. PIERIDES D. N. S. KERR
Department of Medicine, University of Newcastle upon Tyne A. W. SKILLEN
Department of Clinical Biochemistry, University of Newcastle upon Tyne
postoperative day. Discussion
There
was a
highly significant postoperative
reduc-
tion in serum-T3 concentration in six subjects. The effect was apparent within 24 hours, and levels were still lower than normal after 6 days. The results confirm recent reports of the effect on serum-T3 concentration of acute
illness21and surgical operation.
17 is
In this study serum-T4 concentration was slightly reduced after operation. This result does not accord with some previous reports,22 23 and may be due to an increase in plasma volume, perhaps resulting from intravenous infusions which were given to most patients for
several days postoperatively. Serum-rT3 concentrations were significantly elevated for the first 3 days after operation. If plasma volume did increase, as we have suggested to explain the fall in serum-T4 concentration, then the rise in rT3 would be even greater than observed, while the fall in T3 would be less pronounced. In patient 7 who underwent a parathyroidectomy for glandular hyperplasia, serum concentrations of T4 and T3 rose postoperatively. It is suggested that this resulted from increased thyroidal secretion due to manipulation of the gland at surgery. When the values of T3 and rT3 are expressed relative to serum-T4 concentration (fig. 2), the changes conform to the pattern seen after other types of surgery. Evidence suggests serum-T3 concentrations may be low in various acute and chronic illnesses 18 21 24-27 as well as in certain physiological conditions, such as fasting14 and in newborn infants.13 The cause is not known, although in cirrhosis of the liver and in obese individuals after fasting there is evidence of reduced peripheral monodeiodination of T4.28 29 Low serum-T3 concentration could also be caused by diversion of T4 monodeiodination along an alternative pathway, resulting in formation of rT3 instead of T3. There is evidence to suggest that T4 monodeiodination in the liver may produce T3, while deiodination in extrahepatic tissues may result in rT3 formation.3O The results of the present study support the existence of an alternative pathway of T4 monodeiodination, leading to increased rT3 production in the postoperative period. The alternative pathway may also be active in newborn infants13 and in fasting individuals. 14 Elucidation of the metabolic pathways of vitamin D has emphasised the importance of hepatic and renal hydroxylating enzymes in the production of active metabolites. Monodeiodination of T4 to either T3 or rT3 seems to offer another example of peripheral modulation of hormonal effects. Requests for reprints should be addressed
Muscle
weakness and tenderness with a rise in serum creatine kinase (C.K.) were noted in five uræmic patients treated with 1-2 g of clofibrate (’Atromid-S’) daily. Excessive accumulation of both total and free serum chlorophenoxyisobutyric acid (C.P.I.B.), the active circulating metabolite after clofibrate therapy, was found in three patients in whom it was sought. It is suggested that chronic renal failure should be regarded as a contraindication to the use of clofibrate for the treatment of any coexisting hyperlipidæmia. If such therapy is contemplated it must be cautiously instituted at low dosage and the patient monitored by regular assessment of serum C.K. and levels of both total and free C.P.I.B.
Summary
to
R.H.
together
DR BURR AND OTHERS: REFERENCES
Braverman, L. E., Ingbar, S. H., Sterling, K. J. clin. Invest. 1970, 49, 855. Sterling, K., Brenner, M. A., Newman, E. S. Science, 1970, 169, 1099. 3. Pittman, C. S., Chambers, J. B., Read, V. H. J. clin. Invest. 1971, 50, 1187. 4. Surks, M. I., Schadlow, A. R., Stock, J. M., Oppenheimer, J. H. ibid. 1973, 1. 2.
52, 805. Inada, M., Kurata, S., Kasama, Y., Takayama, H., Torizuka, K., Fukase, M., Soma, T. ibid. 1975, 55, 1337. 6. Berson, S. A., Yalow, R. S. ibid. 1954, 33, 1533. 7. Ingbar, S. H., Freinkel, N. ibid. 1955, 34, 808. 8. Oddie, T. H., Fisher, D. A., Rogers, C. J. clin. Endocr. Metab. 1964, 24, 5.
628. 9. Surks, M. I., Oppenheimer, J. H. ibid. 1971, 33, 612. 10. Pittman, J. A., Brown, R. W., Register, H. B. Endocrinology, 1962, 70, 79. 11. Chopra, I. J. J. clin. Invest. 1974, 54, 583. 12. Meinhold, H., Wenzel, K. W., Schurnbrand, P. Z. klin. Chem. klin. Biochem. 1975, 13, 571. 13. Chopra, I. J., Sack, J., Fisher, D. A. J. clin. Invest. 1975, 55, 1137. 14. Vagenakis, A. G., Burger, A., Portnay, G. I., Rudolph, M., O’Brian, J. T., Azizi, F., Arkv, R. A., Nicod, P., Ingbar, S. H., Braverman, L. E. J. clin. Endocr. Metab. 1975, 41, 191. 15. Abuid, J., Klein, A. H., Foley, T. P., Larsen, P. R. ibid. 1974, 39, 263. 16. Portnay, G. I., O’Brian, J. T., Bush, J., Vagenakis, A. G., Azizi, F., Arky, R. A., Ingbar, S. H., Braverman, L. E. ibid. p. 199. 17. Burr, W. A., Black, E. G., Griffiths, R. S., Princé, P., Ramsden, D. B. Clin. Sci. molec. Med. 1975, 49, 22P (abstr.). 18. Bermudez, F., Surks, M. I., Oppenheimer, J. H. J. clin. Endocr. Metab. 1975, 41, 27. 19. Burr, W. A., Black, E. G., Griffiths, R. S., Ramsden, D. B., Hoffenberg, R. 20.
Unpublished. Black, E. G., Griffiths, R. S., Finucane, J., Hoffenberg, R. in Thyroid Hormone Metabolism (edited by W. A. Harland and J. S. Orr); p. 347. Lon-
21.
McLarty, D. G., Ratcliffe, W. A., McColl, K., Stone, D., Ratcliffe, J. G. Lan-
don, 1975. cet,
1975, ii. 275.
22. Harland, W. A., Orr, J. S., Richards, J. R. Scott. med. J. 1972, 17, 92. 23. Kirby, R., Clark, F., Johnston, I. D. A. Clin. Endocr. 1973, 2, 89. 24. Carter, J. N., Eastman, C. J., Corcoran, J. M., Lazarus, L. Lancet,
1974,
ii, 971. 25.
Chopra, I. J., Solomon, D. H., Chopra, U., Young, N. J. clin. Endocr. Metab. 1974, 39, 501.
R. T., Chua
Teco, G.
Burke, C. W., Eastman, C. J. Br. med. Bull. 1974, 30, 93. Moshang, T., Parks, J. S., Baker, L., Vaidya, V., Utiger, R. D., Bongiovanni, A. M., Snyder, P. J. J. clin. endocr. Metab. 1975, 40, 470. 28. Nomura, S., Pittman, C. S., Chambers, J. B., Buck, M. W., Shimizu, T. J. clin. Invest. 1975, 56, 643. 29. Portnay, G. I., O’Brian, J. T., Rudolph, M., Vagenakis, A. G., Azizi, F., Arky, A., Ingbar, S. H., Braverman, L. E. Endocrinology, 1974, 93, T-15 (abstr). 30. Flock, E. V., Bollman, J. L., Grindlay, J. H., Stobie, G. H. ibid. 1961, 69, 26. 27.
696
1280 Introduction
CLOFIBRATE has been widely used in hyperlipidaemic patients for over a decade and few side-effects or complications have been reported. 1A syndrome characterised by muscle weakness and tenderness and raised serum creatine kinase (C.K.) and lactate dehydrogenase (L.D.) a few non-uraemic hyperlipidsemic similar 4 and a syndrome has also been noted patients3 in hypoalbuminæmic, hyperlipidaemic nephrotic patients given standard doses of clofibrate.5 6 Katsilambros et al.7 described a 36-year-old diabetic ursemic patient who presented with progressive muscle weakness and tenderness and inability to walk a few months after she started therapy with clofibrate 500 mg four times daily. We describe here our experience with five uraemic patients who developed a similar muscle syndrome and other complications when overtreated with clofibrate. It is hoped that awareness of these complications will ensure a more cautious use of the drug in uraemia and therefore restrict the temptation to treat mild biochemical abnormalities without regard to the underlying lesion.
has been reported in
his serum total C.P.I.B. was high at 166 g/ml and the calculated value on the last day of treatment was 315 µg/ml indicating gross retention with overdosage (therapeutic range 80-150 µg/ml). The serum free (non-protein-bound) C.P.I.B. was also high at 19.8% (therapeutic range
