| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Institute for Endocrinology and Diabetes (L.L., A.P., N.W., Z.J., M.P.), Schnieder Children’s Medical Center of Israel, Petah Tiqva 49202; and Gertner Institute for Epidemiology and Health Policy Research (O.K.-L.), Sheba Medical Center, Tel Hashomer 59422, Israel
Address correspondence and requests for reprints to: M. Phillip, M.D., Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petah Tiqva 49202, Israel.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResults (Fig. 1)DiscussionReferences |
|---|
All patients were initially prescribed antithyroid drugs (ATDs). Overall, adverse reactions to ATDs occurred in 35%, with a higher rate among the prepubertal children (71%) than the pubertal (28%) and postpubertal (25%) patients (P = 0.08). Major adverse reactions were noted in two children, both prepubertal. Remission was achieved in 10 patients (28%). Although the rate of remission did not differ among the three groups, time to remission tended to be longer in the prepubertal children (P = 0.09).
In conclusion, thyrotoxicosis has an atypical presentation and more severe course in prepubertal children. Considering their adverse reactions to ATD, overall low remission rate, and long period to remission, definitive treatment should be considered earlier in this age group.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResults (Fig. 1)DiscussionReferences |
|---|
The diagnosis and management of Graves’ thyrotoxicosis in children is more complicated than in adults. Medical therapy with antithyroid drugs (ATDs) in this population is associated with a higher prevalence of adverse effects (20–30%) than in adults (<10%) (1, 4, 8, 9). Furthermore, the relapse rate either during treatment or shortly after discontinuation of ATD is high, and the remission rate (achievement of euthyroid state for 1 yr after discontinuation of ATD) is low (<30%) (1, 2, 3, 4, 5).
Based on our clinical experience, within the pediatric age group with Graves’ disease, the prepubertal children seem to have a more severe disease than the pubertal or postpubertal children, with regard to both the presenting symptomatology and drug response. In the past 18 yr, 40 children with Graves’ disease have been treated in our institute. Seven were prepubertal at diagnosis, and we evaluated them separately from the adolescents. The aim of the study was to determine whether differences exist in the presentation, clinical course, and outcome of Graves’ disease between these two age groups.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResults (Fig. 1)DiscussionReferences |
|---|
Patients were asked about clinical complaints typical of hyperthyroidism: irritability, lack of concentration, palpitations, increased appetite, weight loss, frequent bowel movements, increased perspiration, neck lump, and protruding eyes. On physical examination, signs of hyperthyroidism, including diffused goiter, exophthalmos, tremor, hyperreflexia, and tachycardia, were sought. Because there is no standardization of goiter size in children, it was estimated subjectively by the examiner (pediatric endocrinologist of our institute) and classified as small (less than twice the normal size) or moderate/large (more than twice the normal size). The degree of exophthalmos was graded by the pediatric ophthalmologist according to Werner’s classification adopted by the American Thyroid Association (15, 16). Laboratory measurements included basal levels of TSH (normal reference, 0.4–4 mIU/L), free T4 (FT4) (normal, 11.8–24.6 pmol/L), and total T3 (TT3) (normal, 1.3 - 2.7 nmol/L). TSH, FT4, and TT3 were initially measured with commercial RIA kits and in recent years by chemiluminescent enzyme immunoassay (Diagnostic Products Corp., Los Angeles, CA). Antithyroid antibodies, antimicrosomal and antithyroglobulin (normal reference, <75 IU/ml and <150 IU/ml, respectively), were initially measured with the hemagglutination method and in recent years with enzyme-linked immunosorbent assay (Orgentec Diagnostika GMBH, Mainz, Germany). Technetium thyroid scintigraphy was performed to rule out subacute thyroiditis, factitious hyperthyroxinemia, and toxic nodules/adenoma. ATDs, propylthiouracil (PTU) or methimazole (MTZ), were the initial therapy for all patients; ß-adrenergic blocker (propranolol) was added in patients with severe toxic signs and tachycardia.
The patients were examined at 1- to 2-week intervals until they became biochemically euthyroid. Thereafter, the ATD dose was adjusted to maintain the clinically and biochemically euthyroid state: PTU, 25–50 mg daily; or MTZ, 2.5–5 mg daily. The adjusted dose was administered for an additional 1.5–2 yr and discontinued thereafter. If the hyperthyroidism recurred, the ATD dose was increased until euthyroidism was re-achieved (1, 2, 3, 4, 7, 8, 9, 17, 18, 19).
Adverse reactions to ATDs were recorded as minor (namely, fever, rash, arthralgia, transient leukopenia, and moderate (two to three times) increase in liver enzymes) or major (agranulocytosis and severe toxic hepatitis). Patients with minor side effects were given the alternative ATD, and patients with major side effects or uncontrolled thyrotoxicosis despite ATD therapy were given definitive therapy [i.e. radioiodine (RAI)] or surgery (9, 17, 18, 19). Remission was defined as clinical and biochemical euthyroidism for at least 1 yr after ATD withdrawal (1–3, 6).
Statistical analysis
For statistical analysis, the differences among the three groups
for normally distributed variables (e.g.
SD score height, pulse rate,
TT3 level, PTU dose corrected for body weight)
were calculated with one-way ANOVA with Tukey’s post-hoc test for
pairwise comparisons. The Kruskal Wallis test was used for comparisons
of variables with other distributions (e.g.
FT4 levels, time to remission). The statistical
significance of contingency tables was analyzed by
2 test, and matched variables were compared by
paired t test. To compare the mean BA to chronological age
(CA) ratio between the prepubertal and pubertal groups, we used the
unpaired t test.
|
Results (Fig. 1 )
|
|---|
|
TopAbstractIntroductionPatients and MethodsResults (Fig. 1)DiscussionReferences |
|---|
The 40 children (30 girls and 10 boys) included in the study were followed for a median of 4 yr (range, 2.2–11.8 yr). The group distribution was: prepubertal (group I), 7 patients (three boys, 43%) of mean age 6.4 ± 2.4 yr; pubertal (group II), 21 patients (four boys, 19%) of mean age 12.5 ± 1.1 yr; and postpubertal (group III), 12 patients (three boys, 25%) of mean age 16.2 ± 0.8 yr. Seventy percent of the patients had a positive family history of autoimmune thyroid disease, with a similar prevalence among the three groups.
|
)
The clinical presentation of group I differed from that of groups
II and III. In group I, the most common complaints were weight loss and
frequent bowel movements, whereas the typical complaints of
thyrotoxicosis (irritability, palpitations, heat intolerance, neck
lump, and fine tremor) occurred significantly less often (Table 1). All
40 patients had palpable goiters: 37% small and 63% medium to large.
It is noteworthy that although the goiters in the patients in group I
were obvious, they were not noticed by the parents. Twenty patients had
exophthalmos of class I (upper lid retraction, stare with or without
lid lag, and proptosis) or class II (excessive lacrimation, sandy
sensation, and photophobia) (15, 16). There was no significant
difference in the incidence of goiter or exophthalmos among the three
groups. However, tachycardia (pulse, >120 pulse/min) was significantly
more frequent in group I (86%) than in groups II and III (38% and
25%, respectively, P = 0.03).
|
Bone maturation was accelerated in all the prepubertal patients. Their mean BA/CA ratio was significantly higher than that of the pubertal children (1.39 ± 0.35 vs. 0.98 ± 0.06, respectively; P = 0.02).
Laboratory studies yielded undetectable TSH levels (<0.01 mIU/L) and
increased FT4 (>38 pmol/L) and
TT3 (>3.8 nmol/L) levels in all patients, and a
positive titer of antithyroid antibodies in 45%. Although there was no
significant difference in TSH or FT4 level or
prevalence of antithyroid antibodies among the three groups,
TT3 levels were significantly higher in group I
than in groups II and III (9.9 ± 2.9 nmol/L vs.
6.32 ± 1.9 nmol/L and 6.0 ± 2.0 nmol/L, respectively;
P = 0.01) (Table 1
).
Thyroid scan, performed in 38 patients, revealed an enlarged and homogeneous gland, with an increased concentration of technetium in all cases.
Treatment and side effects
The initial ATDs used were PTU (28 patients, 70%), at a mean dose of 6.4 ± 1.9 mg/kg·day, and MTZ (12 patients, 30%), at a mean dose of 0.74 ± 0.2 mg/kg·day). The distribution of the two medications and the mean initial doses were comparable in the three groups. ß-Adrenergic blockers (propranolol, 1.4 ± 0.5 mg/kg·day) were administered to 65% of the patients for 6–8 weeks. All patients became biochemically euthyroid (TT3, <2.7 nmol/L) within 6–12 weeks from initiation of ATD therapy.
Adverse drug reactions occurred in 14 patients (35%) during the first 24 weeks of therapy (median, 3 weeks): major in 2 (5%) patients and minor in 12 (30%) patients. There was no difference in either the type or frequency of side effects between patients receiving PTU or MTZ within the same age group. Despite the comparable ATD dose in all three groups, group I tended to have a higher rate of side effects than groups II and III: 71% vs. 28% and 25%, respectively (P = 0.08). Their side effects were also more severe: agranulocytosis (white blood cell count, 3600/mm3 with only 2% polymorphonuclears) in one patient, severe toxic hepatitis (aspartate aminotransferase, 1138 IU/mL; alanine aminotransferase, 1150 IU/mL—a 15-fold increase from normal) in one patient, a moderate increase (3- to 6-fold) in liver enzymes in two patients, and leukopenia in one patient. The side effects in groups II and III were hypersensitive reactions in four patients (one group II and three group III), leukopenia in three patients, and moderately increased liver enzymes in two patients (all group II). Both minor and major side effects resolved in all patients after discontinuation of the ATDs. Of the 14 patients with side effects, 4 received RAI and 10 switched to the alternative ATDs. In none of these patients did similar or other side effects occur in association with the new ATDs.
Course and outcome
Thirty-six patients received ATD treatment for 2–7.5 yr. In all of them, signs of hyperthyroidism (large goiter and exophthalmos) were ameliorated and heart rate became normal. The prepubertal children showed a significantly attenuated growth rate after 2 yr of ATD treatment (mean SD score difference, 1.34 ± 0.37; P = 0.01), but tended to remain taller than their target height, although this difference was no longer statistically significant (height SD score 1.3 ± 0.57 vs. 0.26 ± 0.7, respectively; P = 0.06). By contrast, in the pubertal and postpubertal groups, there was no significant change in height SD score after ATD treatment. In addition, in group I, accelerated bone maturation was also arrested with therapy, with BA corresponding to CA after 3–4 yr. In group II, growth and puberty were normal before diagnosis and continued at a normal rate during treatment.
Remission was achieved in 10 of the patients receiving ATD (28%) after
3.7 ± 1.1 yr of treatment (Table 2). Although the remission rate was
similar in the three groups (33%, 28%, and 25%), the time to
achievement of remission tended to be longer in group I
(P = 0.09) (Table 2). Remission occurred in only 10%
of the boys compared with 35% of the girls, but this difference was
not statistically significant. Seven of the 10 remitted patients
remained euthyroid for 1.5–8 yr after cessation of treatment; in the
other 3 patients, hypothyroidism developed 2–3 yr after euthyroidism
was achieved. None of the remitted patients had a relapse of
thyrotoxicosis.
|
). The duration of treatment in the
nonremitted patients was similar in the three groups. Seven of them
required a relatively high dose of PTU (100–200 mg/day); in the other
19, hyperthyroidism recurred. Some of the nonremitted patients admitted
lack of compliance.
No significant associations were found between outcome and age or
pubertal stage at diagnosis, initial dosage of ATD, duration of therapy
until achievement of biochemical euthyroidism, or frequency of family
history of autoimmune thyroid disease. A borderline positive
association was found between remission rate and antithyroid antibodies
(2 = 3.47, P = 0.062). A
significant negative association was found between remission rate and
TT3 levels at diagnosis
(2 = 4.67, P = 0.031).
Definitive therapy
Seven patients received RAI treatment, four (age, 4.9–12.5 yr) because of severe side effects and three (age, 14.5–17.5 yr) because of an uncontrolled course. Two additional patients (age, 15 and 15.5 yr) underwent thyroidectomy because of a large goiter and failure to achieve remission after 2.5 yr of ATD therapy. All nine patients who were given definitive therapy became hypothyroid within a few weeks or months. One girl showed permanent hypoparathyroidism after surgery. During the follow-up period of up to 8 yr, none of the seven patients treated with RAI had a thyroid malignancy.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResults (Fig. 1)DiscussionReferences |
|---|
Complaints typical of thyrotoxicosis, such as palpitations, heat intolerance, irritability, neck lump, and protruding eyes, were mentioned less frequently in the prepubertal group. It is possible that these symptoms and signs were present but were overlooked or misinterpreted by the parents. This assumption is supported by our additional findings in the prepubertal group of tachycardia in 86%, palpable goiter in 100%, and exophthalmos in about 50%, none of which were noticed by the parents. It is also in agreement with the study of Shulman et al. (20).
The most prominent manifestations of Graves’ disease in the prepubertal children was accelerated growth and bone maturation, as described previously by other investigators (1, 3, 4). All the prepubertal children had tall stature at diagnosis, with a height SD score significantly greater than that of their parents. Their medical history revealed growth acceleration for several months before diagnosis, and their BA was advanced by 1.5–2.5 yr compared with their CA. This may be explained by the fact that at prepuberty bone maturation is affected by GH and thyroid hormone (21), whereas at puberty it is mainly influenced by sex hormones (22). These differences may also account for our failure to observe similar growth acceleration and bone maturation in the pubertal patients; accordingly, their height remained consistent with their target height, and their bone maturation corresponded to their CA. It may also be that the bone epiphyses in the prepubertal children had been exposed to high levels of thyroid hormone for a long period of time due to a delayed diagnosis of the thyrotoxic state.
It is of note that the accelerated growth in the prepubertal children occurred despite weight loss and frequent bowel movements.
The course of the thyrotoxicosis was also different in the prepubertal children compared with the other groups. Although the remission rate was similar in all three groups, the course until achievement of remission tended to be longer in the prepubertal children. Our findings are in agreement with those of Shulman et al. (20), who noted that remission of thyrotoxicosis was less frequent and delayed in prepubertal children, but they contradict the study of Lippe et al. (7), which reported a remission rate of 25% every 2 yr in children and adolescents, regardless of age. The remission rate in our study was negatively correlated with TT3 levels, as shown by others (5, 7, 20). Indeed, the higher TT3 levels at presentation in the prepubertal children may explain the longer time to remission in this group.
Statistical analysis revealed a borderline correlation between remission rate and the presence of antithyroid antibodies, which is a sign of autoimmune thyroid destruction eventually leading to euthyroidism or hypothyroidism (23). The prevalence of thyroid autoantibodies tended to be lower in the prepubertal group than in the other groups. This may imply a different underlying pathophysiological mechanism of thyrotoxicosis and a different nature of the disease in prepubertal children.
Drug toxicity was also more prevalent among the younger children. Despite the similar weight-adjusted ATD dose in the three groups, which was consistent with the recommended dose for children (1, 2, 3, 4, 9, 17, 19), the prepubertal patients were the only ones to show major side effects, and they also had a higher rate of minor side effects. We suggest that younger patients may be more sensitive to ATD, and doses considered safe in older children are more toxic in younger ones. Furthermore, being that all the side effects in our cohort appeared during the first 24 weeks of therapy, it is essential to check the white blood cell count and liver function very frequently and meticulously throughout this period, especially in younger children.
The combination of a high rate of side effects of ATD, an overall low rate of remission, and a longer treatment period to remission in the prepubertal children may justify offering them definitive therapy with either surgery or RAI earlier in the course of the disease. This approach has been supported by Hamburger (8) and Rivkees et al. (17). Rivkees et al. (17) noted that risks of thyroid cancer after external irradiation beyond age 5 yr progressively decline with advancing age; therefore, it may be prudent to avoid RAI therapy in children less than 5 yr old.
In conclusion, Graves’ thyrotoxicosis is a severe disease in prepubertal children because of difficulties in diagnosis and management. Misinterpretation of the atypical clinical symptoms at presentation may result in delayed diagnosis with a more severe course of disease. Therefore, thyrotoxicosis should be suspected by pediatricians in any child with clinical complaints of weight loss and frequent bowel movements, especially when accompanied by accelerated growth and bone maturation. The more severe course of thyrotoxicosis may also result from a different nature of the disease in this age group. Frequent side effects of ATD associated with a low rate of remission and a need for long-term therapy until remission may point to the need for earlier definitive treatment with RAI in the prepubertal age group.
Received December 17, 1999.
Revised March 1, 2000.
Accepted June 30, 2000.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResults (Fig. 1)DiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  N. S. Glaser, D. M. Styne, and for the Organization of Pediatric Endocrinologists Predicting the Likelihood of Remission in Children With Graves' Disease: A Prospective, Multicenter Study Pediatrics, March 1, 2008; 121(3): e481 - e488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Rivkees and C. Dinauer An Optimal Treatment for Pediatric Graves' Disease Is Radioiodine J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 797 - 800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P Dharmaraj and A Grueters The management of thyrotoxicosis in a pre-pubertal child with 18p deletion syndrome Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S145 - S147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G E Krassas, M Segni, and W M Wiersinga Childhood Graves' ophthalmopathy: results of a European questionnaire study Eur. J. Endocrinol., October 1, 2005; 153(4): 515 - 521. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Birrell and T Cheetham Juvenile thyrotoxicosis; can we do better? Arch. Dis. Child., August 1, 2004; 89(8): 745 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Rivkees and E. A. Cornelius Influence of Iodine-131 Dose on the Outcome of Hyperthyroidism in Children Pediatrics, April 1, 2003; 111(4): 745 - 749. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
, alternative ATD.