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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 2 617-621
Copyright © 2003 by The Endocrine Society

Hyperthyrotropinemia during Iodide Administration in Normal Children and in Children Born with Neonatal Transient Hypothyroidism

Kostas B. Markou, Panagiota Paraskevopoulou, Konstantinos S. Karaiskos, Maria Makri, Neoklis A. Georgopoulos, Gregoris Iconomou, Chryssanthi Mengreli and Apostolos G. Vagenakis

Department of Medicine (K.B.M., P.P., K.S.K., M.M., N.A.G., G.I., A.G.V.), Division of Endocrinology, University of Patras Medical School, University Hospital, Patras GR-26500, Greece; and Institute of Child Health (C.M.), Athens 11527, Greece

Address all correspondence and requests for reprints to: Apostolos G. Vagenakis, Department of Internal Medicine, Division of Endocrinology, University of Patras Medical School, University Hospital, Patras GR-26500, Greece. E-mail: vag.inmd{at}med.upatras.gr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The aim of the present study was to examine the effects of chronic iodide administration in pharmacological doses on thyroid function in children with a history of transient congenital hypothyroidism (TCH). We hypothesized that such children may carry a previously undisclosed intrinsic intrathyroidal defect, rendering them susceptible to TCH. We administered for this 60–65 mg iodide daily for 60 d in 13 individuals with TCH (group A), 8 of their siblings (group B), 8 healthy controls (group C), and 11 normal adults (group D). Thyroid function was evaluated by measuring serum T3, T4, free T3, free T4, TSH, and thyroglobulin concentrations and autoantibodies against thyroid peroxidase and thyroglobulin at baseline at 15, 30, and 60 d during iodide administration, and 2 months after iodide withdrawal. Hyperthyrotropinemia greater than 4.2 mU/liter but not higher than 10 mU/liter with normal thyroid hormone concentrations was observed in one of the TCH group and in two of the group B siblings. During iodide administration, hyperthyrotropinemia was observed in 8 of 13 (62%) adolescents in group A, 4 of 7 (57%) in group B, and 6 of 8 (75%) in group C. None of the 11 adults (group D) developed hyperthyrotropinemia during iodide administration. Serum T4 and free T4 concentrations were decreased in all groups when compared with baseline values. The magnitude of the decrease of serum T4 was identical in all groups (0.7–0.8 µg/dl). Thyroid enlargement was observed in all subjects and was more pronounced in children. There were no cases of subclinical and/or overt hyperthyroidism. After iodine withdrawal, serum TSH decreased in all groups and returned to baseline levels, as well as the thyroid volume. In conclusion, the hypothalamic-pituitary-thyroid axis of adolescents with TCH responds to pharmacological doses of iodide similarly to that observed in normal children. The hyperthyrotropinemia observed in the adolescents exposed to iodides may reflect incipient transient hypothyroidism or simply a brisk TSH response to a small serum T4 decrease. Whatever the mechanism, chronic use of excessive quantities of iodide should be avoided until the end of puberty.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN NORMAL INDIVIDUALS, the acute and chronic excess of iodine rarely leads to profound clinical thyroid dysfunction, due to several autoregulatory mechanisms including the so-called Wolff-Chaikoff effect (1, 2). However, in a few apparently normal individuals, in newborns and fetuses, in patients with an underlying thyroid disease (such as euthyroid patients with autoimmune thyroiditis, or Graves’ disease; patients previously treated with radioactive iodine, surgery, or antithyroid drugs; or after a previous episode of subacute thyroiditis), the escape from the inhibitory effect of large doses of iodides is not achieved and clinical, or subclinical hypothyroidism ensues. The hypothyroidism is transient in nature, and thyroid function returns to normal in 2–3 wk after iodide withdrawal, but transient T4 replacement therapy may be required in some patients (3, 4).

During the neonatal period in some newborns, transient congenital hypothyroidism (TCH) is observed. In Europe, TCH is mainly attributed to iodine deficiency. The World Health Organization, UNICEF, and the International Council for the Control of Iodine Deficiency Disorders included neonatal TSH as one of the indicators for assessing iodine deficiency disorders (5). In Greece, a national screening program for congenital hypothyroidism was established in 1979. The data from this program revealed that the incidence of congenital hypothyroidism in Greece is about the same as that reported in other European countries, but the TCH prevalence is relatively high, reflecting geographic iodine deficiency (6). In North America, most cases of TCH are thought to be due to the transplacental passage of maternal antibodies with an incidence estimated to be 1 in 180,000 infants (7). Some cases of TCH are probably related to immaturity of thyroidal iodine organification (8).

In humans, maturation of the hypothalamic-pituitary-thyroid axis is a complex process starting from midgestation and ending in adult life (9). Children who experienced TCH seem to have normal thyroid function at least prepubertally as well as normal growth and school achievement (10), but the latter issue is controversial (11, 12). It is not known whether these individuals developed transient neonatal hypothyroidism due to detrimental effects of extrathyroidal causes or whether their thyroid may harbor an intrinsic organification defect that was unmasked during neonatal life under the stressful conditions of pregnancy. In the present study, we report the effects of chronic iodide administration in pharmacological doses on thyroid function in euthyroid children with previous TCH. We hypothesized that if there was an underlying thyroid defect predisposing to the transient hypothyroidism in neonatal life, and if this defect persisted later in life, these individuals may show an abnormal response to the inhibitory effects of iodide during their childhood.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Studies were conducted in 13 individuals (group A) aged 12–18 yr (7 boys and 6 girls) who had experienced TCH and were detected through the screening program for congenital hypothyroidism in Greece (Institute of Child Health, Athens). The transient neonatal increase of TSH (>30 mU/liter on whole blood) returned to normal levels within 1 month after birth. All subjects were full term, and on the follow-up their serum levels of T4 were greater than 8.5 µg/dl. Group B included 8 subjects aged 12–18 yr (5 boys and 3 girls) who are brothers or sisters of the participants in group A. The control group (group C) consisted of 8 normal subjects aged 12–18 yr (5 boys and 3 girls). None of the subjects in groups B and C had experienced thyroid dysfunction perinatally. Group D included 11 normal adults aged 26–47 yr (5 males and 6 females). None had experienced thyroid dysfunction, all laboratory parameters were normal, and thyroid autoantibodies were negative. Before the initiation of the study, informed consent was obtained from all participants or from their parents. The study protocol and informed consent forms were approved by the Ethics Committees of the University Hospital of Patras and the Athens Institute of Child Health.

Serum was obtained for measurements of T3, T4, free T3 (FT3), free T4 (FT4), TSH, and thyroglobulin (Tg) concentrations, autoantibodies against thyroid peroxidase (anti-TPO), and autoantibodies against Tg (anti-Tg). Urinary iodine in spot urine and the thyroid volume by Ultrasound (Siemens SI-250 Sonoline, prompt 7.5 MHz; Siemens, New York, NY) were determined in all subjects. Basal serum TSH concentrations were considered elevated (hyperthyrotropinemia) when they exceeded 4.2 mU/liter (13). All subjects received 10 drops of Lugol solution (60–65 mg iodine) daily for 60 d. Clinical examination, serum T3, T4, FT3, FT4, TSH, and Tg concentrations, anti-TPO and anti-Tg, urinary iodine, and thyroid volume were measured at 15, 30, and 60 d during iodide administration and 2 months after iodide withdrawal. During iodide administration, urine samples were taken for iodine determination to verify compliance.

Serum samples were kept frozen at -20 C until assayed at the end of the study. All samples were assayed in duplicate in the same assay and in random order. The serum T3, T4, and TSH determinations were analyzed by a semiautomatic analyzer IMX (Abbott Laboratories, Abbott Park, IL); FT3 and FT4 were measured by a direct One-Step RIA Kit (GammaCoat, INCSTAR Corp., Stillwater, MN), anti-TPO was measured by a RIA kit (B.R.A.H.M.S. Dynotest, Diagnostica GmbH, Berlin, Germany), anti-Tg was measured by an immunoradiometric method (s.r.l. 13040, DiaSorin, Inc., Saluggia, Italy), and Tg was measured by an immunoradiometric assay kit (s.r.l. 13040, DiaSorin, Inc.). Urinary iodine was determined by the photometric method (Sandell-Kolthoff reaction, after digestion with chloric acid at 110 C for 1 h) (14).

The volume of each thyroid lobe was calculated according to the formula for a volume of a rotation ellipsoid by multiplication of maximal thickness, width, and height of the lobe using the correction factor 0.479 (15). The upper limits of normal were estimated according to body surface area as proposed by Delange et al. (16).

Statistical analysis

Data were analyzed using SPSS 9.0 for Windows (SPSS, Inc., Chicago, IL). Differences within groups were analyzed using paired t tests. For between-group comparisons, one-way ANOVA for continuous measures was used with the Bonferroni procedure for post hoc comparisons and {chi}2 tests for categorical variables.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Thyroid parameters before iodide administration

Baseline serum T3, FT4, FT3, FT4, TSH, and Tg concentrations in all groups are shown in Table 1Go. Mean TSH, FT4, T4, FT3, and T3 values were in the normal range in all groups.


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  		Table 1. Serum TSH, FT4, T4, FT3, T3, and Tg concentrations and thyroid volume in adolescents with TCH (group A), in their siblings (group B), in normal adolescents (group C), and in normal adults (group D) before and during iodide administration and after withdrawal

 
Hyperthyrotropinemia (TSH > 4.2 mU/liter but not higher than 10 mU/liter in association with normal thyroid hormone concentrations) was observed in 1 of 13 (8%) of the subjects in group A, 2 of 8 (25%) in group B, and in none of the group C or D individuals. Inadequate iodine intake was found in one child from group A (urinary iodine 35 µg/liter and TSH 3.4 mU/liter) and in two children from group B (urinary iodine values 76 and 50 µg/liter and TSH 3.4 and 6.0 mU/liter, respectively). Urine iodine in the remaining subjects ranged from 100–200 µg/liter. In all subjects, the anti-TPO and anti-Tg were negative, and thyroid volumes were below the upper limits of normal for body surface area.

Thyroid parameters during iodide administration

There were no cases of subclinical and/or overt hyperthyroidism during iodine administration. Mean TSH, FT4, T4, FT3, T3, and Tg concentrations (calculated as the mean of assessments at d 15, 30, and 60 in each individual) were in the normal range in all groups (Table 1Go). TSH increased significantly in all groups during iodide administration when compared with baseline values (P < 0.05–0.001; Fig. 1Go). Serum FT4 concentrations decreased significantly in groups A, C, and D (P < 0.05–0.001), and serum T4 decreased significantly in groups A, B, and D (but not C) when compared with the corresponding baseline values (P < 0.05–0.001). The magnitude of the serum T4 decrease was similar in all four groups (range, 0.7–0.8 µg/dl). The decrease in FT4 varied from 0.1–0.4 ng/dl in the four groups. Serum FT3 and T3 were decreased in groups A (P < 0.01) and B (P < 0.05) but not in groups C and D (Table 1Go). Serum Tg was increased in all groups (P < 0.05). Thyroid autoantibodies remained negative.



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  		Figure 1. Serum TSH concentrations before, during, and after iodide administration. A, Children with transient congenital hypothyroidism; B, their siblings; C, normal children; D, adults. a, P values ranging from 0.05–0.001.

 
Hyperthyrotropinemia (defined as TSH exceeding at least once the cut-off point of 4.2 mU/liter during the observation time of 15, 30, and 60 d) was observed in 8 of 13 (62%) individuals in group A, 4 of 7 (57%) in group B, and 6 of 8 (75%) in group C. No hyperthyrotropinemia was observed in the adult group (D). When the number of the children who developed transient hyperthyrotropinemia in groups A, B, and C were pooled (group E), the overall incidence was 64% (18 of 28). The mean TSH (4.10 ± 2.0) during iodide administration in children was higher than in the adults (2.30 ± 1.60 mU/liter; P < 0.05). Sustained hyperthyrotropinemia during iodide administration was observed in 6 of 28 (21%) children.

Thyroid volume (calculated as the mean of assessments at d 15, 30, and 60 in each individual) was increased in all children from a baseline of 5.5 ± 2.6 to 6.8 ± 1.9 ml during iodide administration (P < 0.01). In the adults, the thyroid volume was increased from baseline 13.1 ± 4.1 to 16.5 ± 4.4 ml (P = 0.05).

Thyroid parameters 2 months after iodide withdrawal

After iodine withdrawal, there were no cases of subclinical and/or overt hyperthyroidism. Mean serum TSH decreased in all four groups and returned to baseline levels, as did serum Tg (Table 1Go). Thyroid autoantibodies remained negative throughout the study period. Thyroid volume decreased in all groups and returned to baseline values.

Hyperthyrotropinemia (TSH > 4.2 mU/liter) persisted only in one subject in group A. It is interesting to note that this was the same child in whom slightly increased TSH values were observed before the iodide administration.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
TCH has been variously attributed to immaturity of the thyroid gland of the fetus, and therefore its inability to handle an iodide load, to circulating maternal autoantibodies, or to iodine deficiency (7, 8). An increased incidence of TCH after skin application of iodine-containing agents both in premature (17) and full-term newborns (18) has been reported, although it is not clear whether excessive iodine skin absorption in premature infants is associated with thyroid-independent toxic effects (19). In Greece, TCH is attributed to the mild to moderate iodine-deficient environment. The consequences of postnatal abnormalities in thyroid function, even when transient, are still a matter of controversy. Kohler et al. (10) reported that children with TCH exhibited normal growth and thyroid function throughout childhood and puberty, but it has been suggested that TCH has a detrimental effect on intellectual development (11, 12).

TCH can be regarded as a sign of possible congenital mild to moderate thyroid dysfunction that can be detected only under conditions of high functional demand by the thyroid (20). To asses this possibility, in the present study we evaluated the integrity of the pituitary-thyroidal axis later in life in children who had experienced neonatal TCH. A possible underlying thyroidal defect in these children might be disclosed when the thyroid is exposed to iodine deficiency if the defect persisted during adolescence. The study was extended to include members of their families, because several families have been reported with genetic defects involving the TSH receptor (21), Tg (22), the thyroid sodium-iodide symporter (23), and thyroid peroxidase (24).

Kohler et al. (10) studied 61 schoolchildren with a history of neonatal transient hyperthyrotropinemia or frank hypothyroidism and found normal baseline thyroid function values in the majority. Our findings are in concordance with this report. We observed that the TCH children as well as their siblings had normal baseline thyroid hormone values and normal serum TSH concentrations. In addition, they responded to an iodide load similarly to control children, suggesting the absence of an intrinsic defect of thyroid function.

Several points of the thyroidal response to iodide challenge in children deserve comment. Compared with the adults, the three groups of adolescents (A, B, and C) when exposed to iodide loading developed significantly higher TSH levels (62%, 57%, and 75%, respectively) and a greater increase in thyroid volume, which returned to baseline values after iodide withdrawal. The mechanism of the greater increase in thyroid volume in children during iodine administration in comparison to the adults is not clear. It may be due to the increased serum TSH levels found in all children during iodine administration, either alone or in synergism with IGF-I, which is expected to be increased during childhood and adolescence. Cheung et al. (25) have reported that IGF-I promotes thyroid cell proliferation by potentiating the mitogenic action of TSH.

Maturation of thyroid hormone feedback regulation is a complex process involving ontogenesis of hypothalamic TRH, pituitary TSH, thyroid hormone secretory processes, pituitary TRH receptors, hypothalamic and pituitary thyroid hormone receptors, and iodothyronine monodeiodinase enzyme activities, thyroid gland TSH receptors, and postreceptor response systems (26). This maturation process extends through the adolescent period and is characterized by a progressively slow decrease in serum TSH without significant change in FT4 levels (8). Transient elevated TSH levels have been noted after excess iodide administration to iodine-deficient children (27, 28). This hyperthyrotropinemia, therefore, probably reflects an increased sensitivity of the thyroid to the inhibitory effect of iodide in childhood or, more probably, an increased sensitivity of the hypothalamic-pituitary-thyroid axis to the small decreases in serum thyroid hormone concentration, in comparison with adults. A relative sensitivity effect is strengthened by the fact that the magnitude of the decrease in serum T4 was similar in all children and adults (mean, 0.7 µg/dl) during the iodide administration.

The observation that adolescents may develop iodine-induced hyperthyrotropinemia suggests that iodine-containing medications should be avoided in this vulnerable population group. Adolescent growth and development are very sensitive to hormonal disturbances, and normal thyroid status is a prerequisite for the normal growth and development of many tissues. For instance, it has been reported that serum IGF-I levels are low in hypothyroidism and rise on normalization of thyroid function after treatment with T4 (29).

In conclusion, the hypothalamic-pituitary-thyroid axis of adolescents with TCH responds to pharmacological doses of iodide similarly to normal children. The observed hyperthyrotropinemia and increase in thyroid volume in all children exposed to iodides may reflect incipient transient hypothyroidism, or simply a brisk TSH response to a small serum T4 decrease compared with the adult response. Whatever the mechanism, chronic use of excessive quantities of iodide should be avoided until the end of puberty.


   Acknowledgments
 


   Footnotes
 
Abbreviations: anti-Tg, Autoantibodies against Tg; anti-TPO, autoantibodies against thyroid peroxidase; FT3, free T3; FT4, free T4; TCH, transient congenital hypothyroidism; Tg, thyroglobulin.

Received May 2, 2002.

Accepted October 30, 2002.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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