Down's syndrome (DS) is the most frequent chromosome anomaly, and
there is a still unclear association between it and thyroid disorders.
The prevalence of thyroid dysfunction in DS is higher than in the
general population, ranging from 20 to 66%, depending on the study
design, sample size, geographical region, age group and on whether
cases of hypothyroidism and/or hyperthyroidism were analyzed ().
These studies conclude that, due to such high prevalence, it is
necessary to assess the thyroid function in the follow-up of DS
The most common finding in these patients is the isolated elevation
of thyroid-stimulating hormone (TSH) levels, but normal thyroid
hormone levels, known as subclinical hypothyroidism, with TSH levels
slightly greater than the reference values (between 5 and 10 U/ml)
and, in many cases, with no detectable etiology ().
Studies have demonstrated an increased response of TSH to thyrotropin-releasing
hormone (TRH) in DS patients (),
and this response pattern persists up to the age of three years
The transient elevation of TSH levels has been documented in children
with DS ().
Controversy exists over whether such elevation is a risk factor
for impaired intellectual outcome in these children ()
and the cause for such elevation has not been clarified yet ().
Culter et al. ()
suggest that the isolated elevation of TSH levels in children with
DS, even in the absence of thyroid peroxidase autoantibody (anti-TPO),
might be an early sign of primary autoimmune hypothyroidism. Cases
with positive anti-TPO are expected to have a frequent progression
to overt thyroid disease ().
The age and sex of patients with DS and positive anti-TPO varied
in comparison to patients with autoimmune thyroiditis without DS.
The incidence was higher among females, and there was a large number
of patients with elevated TSH levels, which increased with age.
Several studies have shown an increased incidence of positive anti-TPO
and/or T4 and TSH variation with the advance of age ().
Rubello et al. ()
found a high prevalence of circulating anti-TPO at all ages in DS
patients, including very young ones, and a similar distribution
in both sexes. Pueschel & Pezzullo ()
observed a significant increase in TSH levels among male patients
with DS. Sare et al. ()
noted that female patients with DS, younger than 20 years of age,
presented hypothyroidism more often than their male counterparts.
The aim of the present study was to assess the prevalence of elevated
TSH levels and investigate their probable etiology among children
with DS treated at the Division of Genetics of Policlínica
Antônio Cândido, which belongs to the health system
of Belo Horizonte, state of Minas Gerais, Brazil.
Patients and methods
All patients with DS, confirmed by karyotyping, treated at the Division
of Genetics of Policlínica Antônio Cândido, in
Belo Horizonte, between 1994 and 2001, were included in the study.
Patients' medical records were reviewed in order to assess the prevalence
of thyroid dysfunction. Of all patients, 169 children, median age
of four years (range of 1 to 16 years), had a documented history
of thyroid dysfunction. Of these patients, 86 were male and 83 female
Children with elevated TSH levels (above 5 U/ml) in at least one
test, as reported on the medical chart, were called for a new assessment
of their thyroid function. Forty-six children, aged between 1 and
16 years (mean of 5.04 2.88 years) presented themselves for reassessment.
In cases in which thyroid dysfunction proved persistent, attempts
were made to determine its etiology. Patients who were receiving
hormone therapy due to hypothyroidism had their thyroid function
reassessed after discontinuation of the treatment for four weeks.
The following tests were employed to assess thyroid function:
Measurement of serum TSH: use of immunometric assay methodology,
with IMMULITE analyzer (normal values range from 0.4 to 5.0 U/ml).
Measurement of thyroid hormones: an analogous competitive immunoassay
using IMMULITE analyzer was employed to measure free T4 levels.
Normal values were those ranging from 0.8 to 1.9 ng/dl. A competitive
immunoassay employing IMMULITE analyzer was used to measure total
T4 levels. Normal values were those between 4.5 and 12.5 g/dl.
Measurement of thyroid autoantibodies: a sequential immunometric
assay using EDTA in serum and plasma and IMMULITE analyzer was used
to measure anti-TPO. Levels greater than 35 U/ml were regarded as
Thyroid ultrasound: used to determine the size, shape, texture,
and echogenicity of the thyroid gland and presence of nodules (position,
size and aspect). Ultrasonography was performed using an ultrasound
unit with 256 gray-scale gradations equipped with a 10-MHz linear
transducer. Thyroid volume was calculated according to the method
proposed by Ueda (1990).24
Iodine-131 scintigraphy: the scintigraphic assessment of the thyroid
gland was made using an ADAC VERTEX PLUS camera, 24 hours after
the oral administration of iodine-131. Anterior and anterior oblique
images were obtained.
Perchlorate discharge test: the assessment of iodine organification
in the thyroid gland was made by measuring thyroid iodine uptake
two hours after the administration of iodine-131 and by performing
serial uptake measurements preceded by the oral administration of
1 g of perchlorate (normal values < 20%).
Children with TSH levels greater than 5 U/ml were called to undergo
the tests described above. A cross-sectional study was carried out
to verify whether there was some association of the variables with
the persistence of elevated TSH levels. The patients were placed
in two groups: Group 1 - patients with normal TSH levels and Group
2 - those whose TSH levels were greater than 5 U/ml. Group 1 was
compared to Group 2 with regard to sex, ultrasound findings, scintigraphic
findings, and positive anti-TPO. A patient with hyperthyroidism
and positive anti-TPO was excluded from this analysis. The abnormal
TSH level described on the medical records was compared with the
TSH level measured when patients were reassessed, in an attempt
to establish a relationship between TSH levels and the tendency
of these levels to remain elevated. The statistical analysis was
made using Epi-Info 6.0, and Student's t test was used to compare
the means, whereas the chi-square test and Fisher's exact test were
used for the frequency distributions. Statistical significance was
established at 5% (p < 0.05). The study protocol was approved
by the Ethics and Research Committee of Universidade Federal de
Minas Gerais (UFMG). Parents or those legally representing study
participants signed an informed consent form giving their permission
for laboratory testing.
Of the 169 medical records, 67 showed elevated TSH levels (above
5 U/ml), indicating a prevalence of 39.6%. Of these 67 patients,
46 could be tracked; the remaining 21 patients could not be found
because the addresses informed on their records had not been updated.
All 46 patients were submitted to TSH, total T4, free T4, and anti-TPO
measurements. Forty of these patients underwent ultrasonographic
(US) examination and 34 were submitted to iodine-131 scintigraphy
and to the perchlorate discharge test. Two patients were lost to
follow-up because their families did not agree with their participation
in the study, one died from complications after a surgery for congenital
heart disease and other losses occurred due to problems traveling
to and from the places where the tests were performed, since many
patients lived in other towns. The main difficulty involved scintigraphy
and the perchlorate discharge test, which took three days.
Of the 46 children who participated in the study, eight (4.7%)
were being treated for hypothyroidism with hormone replacement therapy.
After discontinuation of levothyroxine for four weeks, two of them
showed TSH levels greater than 10 U/ml, whereas four had TSH levels
between 5 and 10 U/ml with normal free T4 levels (which characterizes
hyperthyrotropinemia), and two exhibited normal TSH levels.
Of the remaining 38 children, whose previous TSH levels were greater
than 5 U/ml, 29 (76.3%) spontaneously normalized their TSH levels,
seven (18.4%) still showed TSH levels between 5 and 10 U/ml, and
only one (2.6%) had a TSH level greater than 10 U/ml. On the other
hand, one of the patients developed hyperthyroidism. In this group
of 38 patients, the median TSH level was 3.60 U/ml, with minimum
values ranging from 0.01 (patient who developed hyperthyroidism)
to 0.81 U/ml and maximum values of 13.70 U/ml. The mean (4.08 U/ml)
was close to the median, with a standard deviation of 2.56 U/ml.
Therefore, considering the 46 patients who were reassessed, now
including those who were being treated with hormone replacement
but had discontinued the treatment for four weeks, we observed that
TSH levels returned to normal in 31 (67.4%) children, 11 (23.9%)
still showed values between 5 and 10 U/ml, three (6.5%) revealed
TSH values greater than 10 U/ml and one developed hyperthyroidism,
with a TSH of 0.01 U/ml .
With regard to anti-TPO, six (13%) had positive results (56.6 to
1,000 U/ml), three of whom belonged to the group of eight patients
who were being treated with levothyroxine replacement therapy. TSH
levels were elevated (5.55 to 16.6 U/ml) in four patients, normal
(4.27 U/ml) in one and suppressed (0.01 U/ml) in one.
Among 40 patients submitted to thyroid ultrasound, 13 (32.5%) showed
some dysfunction. Enlargement of the thyroid gland was the most
he thyroid gland was enlarged in seven (17.5%%) patients, and two
patients of this subgroup also showed abnormal thyroid gland texture
and one presented with suspected colloid goiter (the same patient
treated with levothyroxine and positive for anti-TPO - 365 U/ml).
Hypoplasia was observed in three patients (7.5%), and one of them
had only hypoplasia of the left lobe. One patient (2.5%) presented
with abnormal thyroid gland texture only. The US of another patient
suggested Hashimoto's thyroiditis. This patient was not receiving
any kind of therapy, TSH levels returned to normal (4.27 U/ml) and
anti-TPO was positive (142 U/ml).
Of the 34 patients submitted to thyroid scintigraphy, seven (20.6%)
showed some kind of dysfunction, a low thyroid uptake in three and
enlargement in the other cases. The six-hour iodine uptake had minimum
and maximum values of respectively 3% and 19%, with a median of
8%. The 24-hour iodine uptake was 5% and 20% (minimum and maximum
values, respectively), with a median of 11%.
As for the perchlorate discharge test, only one child had a positive
result (> 20%) without detectable anti-TPO, suggesting a congenital
defect in thyroperoxidase synthesis. This patient had normal thyroid
US findings and normal TSH levels.
By analyzing only the 34 patients submitted to hormone level measurements,
thyroid ultrasound and iodine-131 scintigraphy, we found the following
diagnoses: five (14.7%) cases of goiter; three (8.8%) cases of hypoplasia;
Hashimoto's thyroiditis in two patients (5.9%), and iodine organification
defect in one patient (2.9%).
Among 10 children with elevated TSH levels, submitted to all tests,
no diagnosis could be established in five (50%).
Table 1 shows the results regarding the association of sex, US
findings, scintigraphy findings, and positive anti-TPO with elevated
TSH levels. In this analysis, 45 children were placed in two groups:
Group 1 - those with normal TSH levels and Group 2 - those whose
TSH levels were still greater than 5 U/ml. The child who presented
with suppressed TSH and positive anti-TPO was excluded from this
Table 1 -
Comparison of the results regarding the association of sex, US findings,
scintigraphy findings, and positive anti-TPO with elevated TSH levels
of children with Down's syndrome
No association was observed between sex and elevated TSH levels.
Abnormal US findings were not correlated with the persistence of
elevated TSH levels in any of the 39 children evaluated.
The 36 patients submitted to scintigraphic examination did not
show any association between abnormal results in this exam and elevated
However, when we compared the presence of anti-TPO with TSH values,
we noted that high serum levels of this antibody (> 35 U/ml)
were correlated with persistently high TSH levels (p = 0.0270).
Group 1 was compared to Group 2 in terms of TSH levels described
on the medical records. The mean TSH level found on the medical
records was 7.91±2.90 µU/ml (range of 5.1 to 15.9 µU/ml)
for the children whose TSH levels returned to normal (Group 1) and
11.37±7.60 µU/ml (range of 5.6 to 29.9 µU/ml)
for those whose TSH remained high (Group 2), with no statistical
difference between the means (p = 0.22). Therefore, the variation
of previous TSH levels was not related to a tendency towards persistent
The close relationship between thyroid disorders and DS has been
largely described in the literature. The present study showed a
significant prevalence (39.6%) of thyroid dysfunction in DS patients,
which concurs with other studies that regard elevation in TSH levels
as a thyroid dysfunction. TSH levels were not so elevated (5.1 to
29.9 U/ml), as observed in several studies ().
There was no difference in sex distribution in our patient population,
similarly to what has been described in other studies (.
The fact that only eight (4.7%) of 169 patients were following a
treatment suggests that most of them had an isolated elevation of
TSH levels - hyperthyrotropinemia; corroborating the results found
by several authors who studied DS patients ().
Of the children who showed elevated TSH levels sometime during
the follow-up period, 67.4% returned to normal levels after new
tests. This demonstrates that hyperthyrotropinemia in DS patients
is often transient. This result is consistent with studies on DS
pointed out the inappropriate release of TSH resulting from a central
dysfunction, production of a less active type of TSH or some form
of unresponsiveness of the thyroid gland to TSH as possible explanations
for this transient elevation. However, the study carried out by
Konings et al. ()
showed normal bioactivity of TSH in the plasma of children with
DS who had subclinical hypothyroidism. An increased response of
TSH to TRH is observed in DS patients ().
In the cross-sectional study by Sharav et al. (),
this increased response of TSH to TRH showed a gradual decrease,
returning to normal at the age of three years. This was explained
as being a consequence of delayed maturation of the hypothalamic-pituitary-thyroid
axis in children with DS, which might be the cause for isolated
elevation of TSH levels in a large number of these patients. Other
reasons for this transient elevation in TSH levels have been suggested
by other studies, namely, low serum levels of zinc (),
which is implicated in some endocrine and immunological processes;
and low serum levels of selenium, which is found in proteins responsible
for thyroid hormone synthesis ().
In this study, no significant difference was observed between the
means of initial TSH serum levels of patients who normalized their
TSH levels and of those in whom these levels were persistently high
during the reassessment. Among the patients with totally normal
thyroid function, three presented goiter and one Hashimoto's thyroiditis
after a more comprehensive evaluation using ultrasound and scintigraphy.
These facts suggest that the persistence of elevated TSH levels
or progression to thyroid disease is not related to serum TSH levels.
Autoimmune factors might be implicated in the pathogenesis of hyperthyrotropinemia
in DS. Some mechanisms have been suggested, such as greater sensitivity
of cells in trisomy 21 to interferon; presence of a certain HDR
antigen closely associated with autoimmune thyroiditis in cells
of DS patients; or the presence of three superoxide dismutase-1
genes. This enzyme is believed to cause excessive production of
hydrogen peroxide and to be involved in high levels of anti-TPO,
since peroxidase is the substrate for peroxidase iodine ().
However, the studies conducted by Zori et al. ()
did not find any correlation between HLA (human leukocyte antigen)
system and the presence of thyroid autoantibodies. The pathogenetic
mechanism of subclinical hypothyroidism without anti-TPO still remains
unclear in DS patients.
The fact that TSH levels in eight children who had been previously
treated for hypothyroidism returned to normal after discontinuation
of levothyroxine therapy for four weeks stresses the fact that hypothyroidism
may be transient. Therefore, it has been suggested that hormone
replacement therapy should be discontinued during the clinical follow-up
of these patients in order to determine whether it is necessary
to maintain it or not.
The present study allowed demonstrating that children with positive
anti-TPO have a higher probability of showing persistently elevated
TSH levels, whereas those with negative anti-TPO tend to normalize
their TSH levels. It was also observed that anti-TPO proved to be
an isolated factor, since other variables such as sex, ultrasound
or scintigraphy findings were not associated with the persistence
of elevated TSH levels. It should be considered that the absence
of detectable anti-TPO in many of these children (including those
presenting only goiter) could result from the fact that low serum
levels were not detected by the laboratory methods used or from
the fact that it could be a case of Hashimoto's thyroiditis with
negative autoantibodies commonly observed in children. Rubello et
in a longitudinal study about patients with DS and subclinical hypothyroidism
without anti-TPO, found that the isolated elevation of TSH levels
does not seem to predispose to the development of a clinically overt
thyroid disease, since spontaneous normalization of TSH levels was
frequently observed in these cases.
Congenital hypothyroidism (CH) also is observed more often in DS
patients (1-2%) than in the general population ().
In an extensive study on the prevalence of CH in neonatal screening
by van Trotsenburg et al., DS patients showed a higher frequency
of thyroid dysfunctions. These dysfunctions show significantly high
TSH levels and low T4 levels, compared to newborns without DS ().
In the present study, we detected four cases (8.7%), three of them
concerned hypoplasia of the thyroid gland and one constituted an
iodine organification defect. Also, a significant number of cases
of goiter (14.3%) of unknown etiology was observed. CH due to hormone
synthesis defect, which causes enlargement of the thyroid gland,
cannot be ruled out in these patients.
One patient with elevated anti-TPO levels developed hyperthyroidism,
probably due to Graves' disease. This indicates that, although this
thyroid dysfunction is less frequent in DS patients (),
hyperthyroidism may be present. Occurrence of asymptomatic transient
hyperthyroidism also has been reported in DS patients without detectable
antibodies. The mechanism of this thyroid dysfunction has not been
clarified yet ().
The results of the present study show a high prevalence of thyroid
dysfunctions in children with DS, the most common of which is the
transient elevation of TSH levels without evident pathological consequences.
It was not possible to establish a clear etiology for these dysfunctions.
However, children with higher anti-TPO levels had greater difficulty
in spontaneously normalizing their TSH levels. Therefore, it is
important to perform a regular thyroid examination, at least once
a year, in children with DS, focusing on those with positive anti-TPO,
due to their increased risk of developing clinically overt thyroid
Thanks to Dr. Letícia Lima Leão, physician and geneticist
at Policlínica Antônio Cândido, in Belo Horizonte,
for explaining the importance of the study to the patients. Also
thanks to Foundation for the Support of Research of the state of
Minas Gerais - FAPEMIG - for the financial support.