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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). Although baseline T3S and T2S concentrations were
elevated in patients with CH, compared with euthyroid subjects, they were unaffected by SeM supplementation.
In conclusion, the present study shows that SeM supplementation for 90 days does not affect serum thyroid hormone
concentrations in patients with CH who rely mainly on T4 to
T3 deiodination for T3 production, suggesting that selenium
is not a limiting factor for peripheral T4 to T3 conversion. In
contrast, we find indirect evidence that selenium supplementation improves the feedback of thyroid hormones at the
hypothalamo-pituitary level and decreases stimulation of the
residual thyroid tissue, possibly suggesting greater T4 to T3
conversion at the cellular level.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
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