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0021-972X/01/$03.00/0 The Journal of Clinical Endocrinology & Metabolism Copyright © 2001 by The Endocrine Society Vol. 86, No. 3 Printed in U.S.A. Selenium Decreases Thyroglobulin Concentrations But Does Not Affect the Increased Thyroxine-toTriiodothyronine Ratio in Children with Congenital Hypothyroidism* JEAN-PIERRE CHANOINE, JEAN NÈVE, SY WU, JEAN VANDERPAS, PIERRE BOURDOUX AND Children’s Hospital Reine Fabiola (J.-P.C.), Laboratory of Pediatrics (P.B.), B 1020 Brussels, Belgium; Institute of Pharmacy (J.N.), B 1090 Brussels, Belgium; Centre Inter Universitaire Hôpital Ambroise Paré, Mons (J.V.), Free University of Brussels, B 7000 Brussels, Belgium; and Nuclear Medicine Medical Service (S.Y.W.), Veterans Affairs Medical Center, Long Beach, California 90822 ABSTRACT Compared with euthyroid controls, patients with congenital hypothyroidism (CH) who are receiving L-T4 treatment show elevated serum TSH relative to serum T4 concentrations and increased T4/T3 ratio. These abnormalities could be the consequence of impaired activity of the selenoenzymes deiodinases on which patients with CH rely to convert the ingested L-T4 into active T3. Eighteen patients (0.5–15.4 yr), diagnosed with CH in infancy, received selenomethionine (SeM, 20 – 60 g selenium/day) for 3 months. The study took place in Belgium, a country where selenium intake is borderline. Compared with the values observed in age- and sex-matched euthyroid controls, patients with CH had decreased selenium, thyroglobulin and T3 concentrations and increased TSH, reverse T3, and T4 T REATMENT of permanent congenital hypothyroidism (CH) consists of lifelong l-T4 oral replacement therapy. Because there is no (agenesis) or limited (ectopia, dyshormonogenesis) residual thyroid function, production of the active T3 in patients with CH is mostly dependent on enzymatic 5⬘ deiodination of the ingested l-T4 by type 1 (D1) and type 2 (D2) deiodinases (1). D1 is a selenoenzyme (2) and is present mainly in liver, kidney, and thyroid gland in humans. It catalyzes the conversion of T4 into T3 and reverse (r) T3, and its activity is increased in hyperthyroidism. In animal models, selenium deficiency readily causes an almost complete loss in the activity of liver D1 (3). Mammalian D2 has been reported to also be a selenoenzyme (4). The issue, however, is hotly debated. Cerebrocortical D2 activity is unaffected by selenium deficiency in the rat (3); and although a nonselenocysteine-containing subunit of D2 has been identified from the rat brain, no native type 2 selenodeiodinase has been identified yet (5). In contrast to D1, D2 only catalyzes deiodination of T4 into T3, and its activity is decreased Received January 19, 2000. Revised August 2, 2000. Rerevised November 8, 2000. Accepted November 8, 2000. Address all correspondence and requests for reprints to: Jean-Pierre Chanoine, M.D., Endocrinology and Diabetes Unit, British Columbia’s Children’s Hospital, 4480 Oak Street, Room 1A46, Vancouver V6H 3V4, Canada. E-mail: [email protected]. * Supported by a grant from the Belgian Study Group for Pediatric Endocrinology. concentrations and T4/T3 ratio at baseline. Selenium supplementation caused a 74% increase in plasma selenium values but did not affect the activity of the selenoenzyme glutathione peroxidase used as a marker of selenium status. SeM abolished the TSH difference observed between CH patients and euthyroid controls at baseline and caused a significant decrease in thyroglobulin values. Thyroid hormone concentrations were not affected by SeM. In conclusion, our data suggest that selenium is not a limiting factor for peripheral T4-to-T3 conversion in CH patients. In contrast, we find indirect evidence that SeM improves thyroid hormones feedback at the hypothalamo-pituitary level and decreases stimulation of the residual thyroid tissue, possibly suggesting greater intracellular T4-to-T3 conversion. (J Clin Endocrinol Metab 86: 1160 –1163, 2001) in hyperthyroidism. In humans, D2 is expressed in many tissues, including muscle, brain, thyroid gland, and pituitary tumor (6 – 8). Compared with euthyroid controls, thyroid function tests from children with CH who receive l-T4 treatment show abnormalities in which the deiodinases might conceivably play a role. First, Grant et al. (8) observed elevated serum TSH levels, relative to serum T4 concentrations, suggesting resetting of the feedback threshold for TSH suppression at the pituitary level by a yet-unknown mechanism. Pituitary T3, either originating from the circulation or locally generated through deiodination of T4, plays a key role in the feedback of thyroid hormones on TSH secretion (9). This process has been shown to undergo maturation with a progressive decrease of the TSH/free T4 ratio from fetal and postnatal period to adulthood (10). Second, Volta et al. observed increased T4/T3 ratio and serum rT3 concentrations (11) similar to the pattern observed with decreased D1 activity in selenium-deficient humans (12) and young rats (13). The pathophysiology of these abnormalities is relevant to the treatment of CH, the goal of which is to achieve normal T4 and T3 concentrations in all tissues. This has been shown impossible to obtain with a single dose of T4 in animal studies (14). The goal of the present study, therefore, is to investigate whether nutritional supplementation in selenium, which controls the expression and the translation of the selenoproteins, does affect thyroid function parameters in patients 1160 SELENIUM AND CONGENITAL HYPOTHYROIDISM with CH relying on deiodination of exogenous l-T4 by the deiodinases for thyroid hormone metabolism. Materials and Methods Eighteen patients, 0.5–15.4 yr old, with CH and who were followed in the Endocrine Clinic at the University Children’s Hospital Reine Fabiola (Brussels, Belgium) were enrolled in the study after informed consent was received from the parents. The study was approved by the Ethics Committee of the Faculty of Medicine at the Free University of Brussels. The patients had been diagnosed with permanent CH in infancy through systematic screening performed on the 5– 6th day of life. The etiology of the hypothyroidism was confirmed by scintigraphy in all patients. Median (range) free (F) T4 concentrations at the time of diagnosis were 2.4 (1.0 – 6.8) pmol/L (normal range, 5–10 days of life: 12.9 – 32.2). All patients were treated with daily l-T4 (Christiaens, Brussels, Belgium) with the aim of keeping serum TSH concentrations as close as possible to the normal range for age. Only patients who had been on a stable l-T4 dose for at least 3 months and who did not require adjustment of their treatment at the beginning of the study were included. Selenium supplementation was provided as a daily tablet of selenomethionine (SeM) for 3 months. The dose of SeM was adjusted according to the age of the patient (20 g Se for those between 0 –3 yr; 30 g Se, between 3– 6 yr; and 60 g Se, ⬎6 yr). Blood was drawn for determination of plasma selenium concentration, red cell and plasma glutathione peroxidase (GPx) activities, and thyroid function tests before and after supplementation with selenium. Baseline parameters of the patients with CH were compared with those of healthy euthyroid subjects matched for age and sex and referred to the endocrine clinic for benign conditions not caused by a known endocrine condition. Plasma selenium was measured by atomic absorption (15). Red cell and plasma GPx activities were measured using a commercial kit (Ransel from Randox Laboratories, Antrim, UK) according to the method described by Paglia and Valentine (16). Samples were quickly frozen to ⫺20 C until the time of assay, because we have established that serum activity decreases by 2, 6, and 23% after 24 h at 4 C, 20 C, and 37 C, respectively, but remains stable for 6 months at ⫺20 C. One unit was defined as 1 mol NADPH oxidized per minute. Thyroid function parameters were determined using commercial kits: TSH by immunoluminescent assay (BRAHMS, Berlin, Germany), rT3 by RIA (Biodata, Roma, Italy), and thyroglobulin (Tg) by immunoradiometric assay (BRAHMS). Total T4 and T3 (17), T3 sulfate (T3S), and T2 sulfate (T2S) (18, 19) were measured by RIA as described previously. All samples were run in duplicate in a single batch. Except as otherwise noted, laboratory values are presented as median (range). Comparison between thyroid function parameters, selenium concentration, and GPx activities were performed using nonparametric tests: Wilcoxon test (between euthyroid controls and patients with CH) and Mann-Whitney test (patients with CH before and after SeM supplementation). The Spearman correlation coefficient and the linear regression were used to express the relation between selenium concentration and GPx activities. A P value ⬍0.05 was considered significant. Results The characteristics of the euthyroid controls and of the patients with CH are reported in Table 1. The median dose of l-T4 in patients with CH at the start of the study was 3.4 (1.5–7.1) g/kg䡠day. TABLE 1. Characteristics of euthyroid controls and of patients with CH at baseline Age (years) Height (Z-score) Weight for height (%) Thyroid agenesis/ectopia/goitre Euthyroid controls Congenital hypothyroidism 8.1 (4.4) ⫺0.5 (1.7) 105 (20) Not applicable 8.1 (4.5) 0.1 (1.1) 100 (14) 6/10/2 Results are expressed as mean (SD). 1161 Baseline plasma selenium values were significantly lower in CH patients, compared with euthyroid controls (P ⬍ 0.05), but red cell and serum GPx activities were not significantly different (Table 2). In CH patients, SeM supplementation for 3 months caused a 74% increase in median plasma selenium concentrations (range, ⫹ 0.18 to ⫹ 1.10 mol/L) but did not affect significantly red cell and serum GPx activities, used as a marker of selenium status. There was a negative correlation between baseline plasma selenium concentrations and changes in red cell GPx activities (Spearman correlation coefficient ⫽ ⫺0.53, P ⬍ 0.05) over the 3 months of SeM supplementation (the lower the selenium concentration before supplementation, the higher the increase in GPx activity). Baseline Tg concentrations were 6 times lower in patients with CH, compared with euthyroid controls. In the 16 patients with thyroid dysgenesis (agenesis and ectopia), basal Tg concentrations were low, reflecting l-T4 treatment and the small amount or absence of functional thyroid tissue. Selenium supplementation was associated with a further significant decrease in Tg concentrations from 2.24 (0 –16.4) to 1.49 (0 –10.4) pmol/L (P ⫽ 0.036). In the 2 patients with CH caused by dyshormonogenesis, baseline Tg values were 10.4 and 32.8 pmol/L. Baseline TSH values were in the near-normal range in CH patients but significantly higher than in euthyroid controls. Although selenium supplementation did not cause a significant decrease in TSH in the CH group, it abolished the significance of the difference observed between the euthyroid and the CH group before supplementation (Table 2). Serum T4, rT3, T2S, and T3S concentrations and T4/T3 ratio were higher and serum T3 concentrations lower in CH patients, compared with euthyroid controls, and were not affected by selenium supplementation (Table 2). Except for the Tg results discussed above, the results were not influenced by the etiology of hypothyroidism. Discussion The present study investigates whether selenium availability is a limiting factor for the activity of the deiodinases in patients with CH. Selenium supplementation with SeM for 3 months causes a decrease in serum Tg concentrations in CH patients with thyroid dysgenesis under stable l-T4 replacement therapy. In addition, it abolishes the significant difference observed in TSH concentrations between CH patients and euthyroid controls before selenium supplementation. However, selenium supplementation does not correct the thyroid hormone abnormalities routinely observed in CH patients (namely, increased serum rT3 concentrations and T4/T3 ratio). Belgium is a country where selenium intake is close to 50 g/day in adults (20). Baseline plasma selenium concentrations reported here are lower than those reported in 1980 – 81 for children 5–19 yr old. This is consistent with the decrease in plasma selenium values reported in Belgium (20) and in Europe (21) over the past 20 yr. The reason for significantly lower baseline selenium values in patients with CH, compared with euthyroid subjects, in the present study is unclear. Interestingly, the mean basal selenium values listed by Kauf et al. (22) for their CH patients are also lower (23%) than 1162 JCE & M • 2001 Vol. 86 • No. 3 CHANOINE ET AL. TABLE 2. Plasma selenium concentrations, GPx activities, and thyroid function parameters in euthyroid controls and in patients with CH before and after SeM supplementation Euthyroid controls Patients with congenital hypothyroidism Before After Se supplementation Selenium (mol/L) RBC GPx (U/g Hb) Plasma GPx (U/L) Tg (pmol/L) TSH (mU/L) T4 (nmol/L) T3 (nmol/L) T4/T3 rT3 (nmol/L) T3S (pmol/L) T2S (pmol/L) 0.86 (0.38 –1.28)a 36 (22–75) 684 (413–969) 26.8 (7.5–96.9)a 2.0 (0.7–3.6) 90 (60 –143)a 2.17 (1.64 –3.20)a 41 (31– 61)a 0.27 (0.21– 0.64)a 13 (7–350)d 74 (8 –137)d 0.76 (0.18 –1.14)b 39 (23–54) 632 (242– 867) 4.5 (0 –32.8)b 4.8 (0.1–10.8)c 135 (87–230) 1.87 (1.40 –2.29) 71 (39 –100) 0.41 (0.18 – 0.87) 204 (7–987) 90 (48 –169) 1.32 (0.80 –1.71) 43 (29 – 60) 656 (340 – 828) 3.0 (0 –53.6) 2.6 (0.2–27.4) 134 (90 –167) 1.79 (1.19 –2.26) 71 (40 –103) 0.41 (0.21– 0.67) 247 (7–387) 84 (21–158) Results are expressed as median (range). RBC, Red blood cell. Conventional units: Selenium: ng/mL ⫽ mol/L ⫻78.7; T4: g/dL ⫽ nmol/L ⫻ 0.0777; T3, r T3: ng/dL ⫽ nmol/L ⫻ 65.1; T4/T3: ⫻ 1.19; Tg: ng/mL ⫽ pmol/L ⫻ 0.670; T3S: ng/dL ⫽ pmol/L ⫻ 0.075; T2S: ng/dL ⫽ pmol/L ⫻ 0.062. a P ⬍ 0.05, compared with patients with CH, before and after SeM supplementation. b P ⬍ 0.05, compared with CH patients, after SeM supplementation. c P ⬍ 0.05, compared with euthyroid controls only. d 0.05 ⬍ P ⬍ 0.1, compared with patients with CH, before and after SeM supplementation. the normal range; but because of the lack of a control group, the statistical significance of this observation is unknown. SeM was chosen for selenium supplementation, over inorganic selenium such as selenite, because SeM is absorbed efficiently from all intestinal segments (23) and because it has been shown to induce a greater modification in some markers of selenium status (20). SeM supplementation caused an increase in plasma selenium concentrations in all patients but failed to result in an increase in red cell or plasma GPx activities. This is consistent with previous data showing that GPx activities in these biological compartments are saturated for selenium intakes of approximately 40 g or greater and therefore do not respond to selenium supplementation (24). In the following discussion, we will consider TSH feedback control and peripheral deiodination separately. Léger et al. (25) have shown that in patients with CH secondary to thyroid dysgenesis, the residual thyroid tissue does not involuate with time and that an increase in TSH after a decrease in T4 replacement therapy is associated with a concomitant increase in serum Tg concentrations. In the present study, the finding of decreased Tg concentrations and of a trend toward normalization of the TSH values under a constant dose of l-T4 provide indirect evidence of an improvement of pituitary feedback at the hypothalamo-pituitary level. A potential explanation for this finding is that selenium supplementation would improve deiodinase activity in the pituitary. Studies in the rat have shown that both D1 and D2 activities are present in the pituitary (reviewed in Ref. 1) but that pituitary tissue is resistant to selenium deficiency (26). Whether this is also true in humans remains unknown. In humans, circulating T3 is traditionally regarded as originating from the thyroid gland (20%) and from peripheral deiodination of T4 to T3 (80%) (27), at least partly by liver D1. The respective roles of D1 and D2 pathways in the generation of circulating T3 remain unknown, but D2 pathway may play a more important role than originally thought. For instance, specific inhibition of liver D1 by propylthiouracil in l-T4treated athyreotic humans (28) causes only a 30% decrease in circulating T3. In addition, according to the known regulation of D1 (namely, increased activity in the face of increased T4 concentrations), increased circulating T4, as seen in CH patients, should cause an increase in D1 activity and facilitate T4-to-T3 conversion. Recent evidence that D2 activity is negligible in liver (29) but abundant in muscle (4) in humans may lead to the confirmation of sources of circulating T3 other than D1 and explain the basis for what can be regarded as a protective mechanism against iatrogenic hyperthyroidism. In the present study, we confirm the existence of an increased T4/T3 ratio (11) in CH patients, compared with euthyroid controls. We also investigate whether limited availability of selenium could lead to suboptimal D1 activity and play a role in this increased T4/T3 ratio. In humans, whereas red cell or plasma GPx activities are easily measured and used as a marker of selenium status, evaluation of deiodinase activity can only be indirectly assessed through determination of thyroid function parameters in the circulation. T4/T3 ratio is commonly used in vivo as the marker of choice to evaluate peripheral T4 deiodination. We chose to measure T4 over FT4 for the following reasons. First, in the rat, though T4 concentrations are systematically increased in seleniumdeficient animals, normal (30) or increased (31) FT4 concentrations have been measured. Second, in two studies discussed below (12, 32), FT4 did not provide additional information over T4 determinations. Phenylketonuric (PKU) children receive a low protein diet soon after birth and, if not supplemented with selenium, are severely deficient in this trace element. In contrast to the patients reported in our study, they have a presumably normal thyroid gland. Calomme et al. (32) observed a 25% decrease in serum T4 and rT3 concentrations without changes in TSH or T3 concentrations after short-term selenium supplementation in PKU patients, suggesting that selenium supplementation caused an increase in D1 activity. In another population of unsupplemented PKU children with milder selenium deficiency, van Bakel et al. (33) reported a negative correlation between basal plasma selenium concentrations and FT4 or rT3 concentra- SELENIUM AND CONGENITAL HYPOTHYROIDISM tions. In their study, as in the study described below (12), FT4 concentrations were higher in the selenium-deficient group than in the control group. In Zaire, Contempre et al. (12) observed an increase in T3/T4 ratio and a decrease in rT3 after selenium supplementation in school children from a selenium-deficient area [serum selenium, 0.34 mol/L (27 ng/dL)], suggesting improved peripheral deiodination of T4 by D1. In contrast to the above examples, the patients in the present study have a marginally low selenium intake but no or little functional thyroid tissue. No association was found between SeM supplementation and T4/T3 ratio or rT3, suggesting that peripheral deiodination was not affected. In the only other report of selenium supplementation in patients with CH, Kauf et al. (22), using selenium selenite at a dose of 115 g/M2䡠day, found no changes in T4 or T3 concentrations after a modest 29% increase in plasma selenium values, in contrast to the 74% reported in the present study. T3S and T2S concentrations (two sulfoconjugates of thyroid hormones) were also measured, because they are preferred substrates for D1 and because animal studies have shown that decreased D1 activity secondary to selenium deficiency was associated with a marked increase in T3S serum values (18). 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