Clinic0 Chimico Acto, 211 (1992) 189-190 0 1992 Elsevier Science Publishers B.V. All rights reserved. 0009-8981/92/$05.00
189
CCA 05405
Letter to the Editor
Selenium in Graves’ disease (Received 30 May 1992; revision received 31 August 1992; accepted 9 September 1992)
Dear Editor, The clinical diagnosis of Graves’ disease is made on the basis of a number of factors including raised concentrations of the thyroid hormones thyroxine (T4) and triiodothyronine (Ts). Carbimazole is a common method of treating hyperthyroidism: it is believed to act by blocking thyroid hormone synthesis. A recent clinical study on the action of carbimazole indicated that lowering of the plasma thyroid hormone (T4, T3) concentrations is coupled to the oxidation of intracellular glutathione [l]. It is believed that the metabolism of thyroxine (T4 - T3 - Tz) is effected by the deiodinase enzymes, generating the iodium cation which hydrates to form hypo-iodite (IO-). This will act as an oxidant and requires to be efficiently removed from the proximity of the plasma and tissues. This is achieved at the expense of glutathione which, it has been postulated, may be a cofactor for the deiodinase enzymes [ 1,2]. Although, the deiodinase enzymes are poorly defined, some are known to contain selenium at their active site [3,4]. Subsequently, their activity has been shown to be sensitive to selenium deficiency [3,4]. Evidence is beginning to emerge which suggests that selenium may be important in the pathogenesis of Graves’ disease [5]. These studies led us to question the role of selenium in Graves’ disease and whether its plasma concentration was affected by therapy. Plasma selenium was measured* for a group of ten patients (2 males, 8 females, mean age 51.3 f 12.4 years) with newly diagnosed Graves’ disease prior to and 2 months after carbimazole therapy. A group of ten, normal healthy volunteers (2 males, 8 females of mean age 45.3 f 9.0) were used as a control group. Data were analysed using a Rank Wilcoxon test. Correspondence to: Dr. J. Reglinski, Department of Pure and Applied Chemistry Thomas Graham Building, 295 Cathedral St., Glasgow, Gl IXL, Scotland, UK. *Plasma selenium was determined by graphite furnace atomic absorption spectrometry with palladium as a matrix modifier. Calibration was by standard additions. For internal quality control, Seronorm Trace Elements Serum Batch 116 (Nycomed As, Oslo Norway) was run with each batch. The mean value ( * S.D.) obtained was 1.26 f 0.06 PmoUl (recommended value 1.27 pmol/l. The between batch imprecision was 5.1%.
Consistent with the earlier report [S] the untreated Graves patients are observed to be deficient in plasma selenium (630 f 160 nmol/l) by almost 50% as compared to the normal healthy volunteer group (1190 f 180 nmol/l; P < 0.001). After treatment with carbimazole the selenium levels in plasma rise (880 f 160 nmolil; P < 0.004) but remain significantly different from the levels found in the volunteer group (P < 0.001). Speciation of selenium in plasma has identified two main species, glutathione peroxidase and the deiodinase enzyme ID-I. It has been suggested that in Graves’ disease selenium deficiency cannot be ascribed to one of these species but that both species may be affected independently and to differing degrees [5]. After a 2-month course of carbimazole there is a fall in serum T, and TA but these changes do not correlate with the rise in total plasma selenium. Estimation of the oxidation-reduction balance of intracellular glutathione in intact erythrocytes measured previously in the same sample group [l] indicates that the untreated Graves’ group are similar to the normal volunteers but that after 2 months carbimazole therapy they are significantly more oxidised (P < 0.001) than the untreated group. The oxidation reduction balance of the erythrocyte measured through intracellular glutathione status (GSSG:GSH ratio) correlates weakly with plasma selenium (P < 0.05). The species involved in these correlations are both compartmentalised and present in widely different concentrations. Carbimazole is believed to act on the thyroid, the T3 (nM) and selenium (PM) are resident in the plasma, whereas the glutathione (mM) is intracellular. It is postulated that the deiodinase enzyme converts TJ to Tz in the thyroid releasing HOI into the plasma, which in turn is detoxified by erythrocyte glutathione via a membrane interaction [I]. The lack of a correlation between T3 and selenium and the less significant correlation between plasma selenium and intracellular oxidation reduction balance (P < 0.05) is as would be expected. If the important selenium enzyme is resident in the thyroid then the relationships between its activity and plasma selenium would be expected to be tenuous. However, the observed alteration in the plasma selenium concentrations with carbimazole therapy may mirror its incorporation and efficacy elsewhere in the body, i.e. in the thyroid. J. Reglinskia, W.E. Smith”, R. Wilson’. D.J. HaIF. J.H. McKillopb and J.A. Thomsonb “Department
of Pure and Applied
hDeparlment
Chemistry
of Medicine
Strolhclyde
and ‘Trace
Element
liniversiry.
Glasgow.
Unir, Insritute
Glas~o~~~ Royal
Infirmary.
Glasgow.
LM,
JH, Thomson
GI
IXL.
of’ Bi0chemisrr.v. G3/ 2ER
I c(K)
References 1
Reglinski
J, Smith WE,
Wilson
studies on intact erythrocytes: therapy. 2
Clin Endocrinol
3
Arthur
3. (Glutathione:
JR. The
McKillop metabolism
JA. Spin echo NMR
as a’consequence
of carbimazole
1992;in press.
Visser TJ. Role of glutathione co-factors
R, Buchanan
changes in cellular
and other thiols in thyroid
Chem.
Bicchem.
role of selenium
hormone
metabolism.
Co-enzymes
and
Med Aspects Pt. B) 1989;571-612.
in thyroid
hormone
metabolism.
Can
J Physiol Pharmacol
1991;69:1648-1652. 4
Berry MJ, Banu L, Larsen PR. Type enzyme. Nature
5
Beckett GJ, Peterson FE, Choudhury mone metabolism
I
lodothyronine
de-iodinase
is a selenocysteine containing
1991;349:438-440. K et al. Inter-relationship
in the rat and man. J. Trace
Elem Electrolyt
between selenium and thyroid horHealth
Dis 199\:5:265-267.
189
CCA 05405
Letter to the Editor
Selenium in Graves’ disease (Received 30 May 1992; revision received 31 August 1992; accepted 9 September 1992)
Dear Editor, The clinical diagnosis of Graves’ disease is made on the basis of a number of factors including raised concentrations of the thyroid hormones thyroxine (T4) and triiodothyronine (Ts). Carbimazole is a common method of treating hyperthyroidism: it is believed to act by blocking thyroid hormone synthesis. A recent clinical study on the action of carbimazole indicated that lowering of the plasma thyroid hormone (T4, T3) concentrations is coupled to the oxidation of intracellular glutathione [l]. It is believed that the metabolism of thyroxine (T4 - T3 - Tz) is effected by the deiodinase enzymes, generating the iodium cation which hydrates to form hypo-iodite (IO-). This will act as an oxidant and requires to be efficiently removed from the proximity of the plasma and tissues. This is achieved at the expense of glutathione which, it has been postulated, may be a cofactor for the deiodinase enzymes [ 1,2]. Although, the deiodinase enzymes are poorly defined, some are known to contain selenium at their active site [3,4]. Subsequently, their activity has been shown to be sensitive to selenium deficiency [3,4]. Evidence is beginning to emerge which suggests that selenium may be important in the pathogenesis of Graves’ disease [5]. These studies led us to question the role of selenium in Graves’ disease and whether its plasma concentration was affected by therapy. Plasma selenium was measured* for a group of ten patients (2 males, 8 females, mean age 51.3 f 12.4 years) with newly diagnosed Graves’ disease prior to and 2 months after carbimazole therapy. A group of ten, normal healthy volunteers (2 males, 8 females of mean age 45.3 f 9.0) were used as a control group. Data were analysed using a Rank Wilcoxon test. Correspondence to: Dr. J. Reglinski, Department of Pure and Applied Chemistry Thomas Graham Building, 295 Cathedral St., Glasgow, Gl IXL, Scotland, UK. *Plasma selenium was determined by graphite furnace atomic absorption spectrometry with palladium as a matrix modifier. Calibration was by standard additions. For internal quality control, Seronorm Trace Elements Serum Batch 116 (Nycomed As, Oslo Norway) was run with each batch. The mean value ( * S.D.) obtained was 1.26 f 0.06 PmoUl (recommended value 1.27 pmol/l. The between batch imprecision was 5.1%.
Consistent with the earlier report [S] the untreated Graves patients are observed to be deficient in plasma selenium (630 f 160 nmol/l) by almost 50% as compared to the normal healthy volunteer group (1190 f 180 nmol/l; P < 0.001). After treatment with carbimazole the selenium levels in plasma rise (880 f 160 nmolil; P < 0.004) but remain significantly different from the levels found in the volunteer group (P < 0.001). Speciation of selenium in plasma has identified two main species, glutathione peroxidase and the deiodinase enzyme ID-I. It has been suggested that in Graves’ disease selenium deficiency cannot be ascribed to one of these species but that both species may be affected independently and to differing degrees [5]. After a 2-month course of carbimazole there is a fall in serum T, and TA but these changes do not correlate with the rise in total plasma selenium. Estimation of the oxidation-reduction balance of intracellular glutathione in intact erythrocytes measured previously in the same sample group [l] indicates that the untreated Graves’ group are similar to the normal volunteers but that after 2 months carbimazole therapy they are significantly more oxidised (P < 0.001) than the untreated group. The oxidation reduction balance of the erythrocyte measured through intracellular glutathione status (GSSG:GSH ratio) correlates weakly with plasma selenium (P < 0.05). The species involved in these correlations are both compartmentalised and present in widely different concentrations. Carbimazole is believed to act on the thyroid, the T3 (nM) and selenium (PM) are resident in the plasma, whereas the glutathione (mM) is intracellular. It is postulated that the deiodinase enzyme converts TJ to Tz in the thyroid releasing HOI into the plasma, which in turn is detoxified by erythrocyte glutathione via a membrane interaction [I]. The lack of a correlation between T3 and selenium and the less significant correlation between plasma selenium and intracellular oxidation reduction balance (P < 0.05) is as would be expected. If the important selenium enzyme is resident in the thyroid then the relationships between its activity and plasma selenium would be expected to be tenuous. However, the observed alteration in the plasma selenium concentrations with carbimazole therapy may mirror its incorporation and efficacy elsewhere in the body, i.e. in the thyroid. J. Reglinskia, W.E. Smith”, R. Wilson’. D.J. HaIF. J.H. McKillopb and J.A. Thomsonb “Department
of Pure and Applied
hDeparlment
Chemistry
of Medicine
Strolhclyde
and ‘Trace
Element
liniversiry.
Glasgow.
Unir, Insritute
Glas~o~~~ Royal
Infirmary.
Glasgow.
LM,
JH, Thomson
GI
IXL.
of’ Bi0chemisrr.v. G3/ 2ER
I c(K)
References 1
Reglinski
J, Smith WE,
Wilson
studies on intact erythrocytes: therapy. 2
Clin Endocrinol
3
Arthur
3. (Glutathione:
JR. The
McKillop metabolism
JA. Spin echo NMR
as a’consequence
of carbimazole
1992;in press.
Visser TJ. Role of glutathione co-factors
R, Buchanan
changes in cellular
and other thiols in thyroid
Chem.
Bicchem.
role of selenium
hormone
metabolism.
Co-enzymes
and
Med Aspects Pt. B) 1989;571-612.
in thyroid
hormone
metabolism.
Can
J Physiol Pharmacol
1991;69:1648-1652. 4
Berry MJ, Banu L, Larsen PR. Type enzyme. Nature
5
Beckett GJ, Peterson FE, Choudhury mone metabolism
I
lodothyronine
de-iodinase
is a selenocysteine containing
1991;349:438-440. K et al. Inter-relationship
in the rat and man. J. Trace
Elem Electrolyt
between selenium and thyroid horHealth
Dis 199\:5:265-267.
