[Tc]-99m Thyroid Scintigraphy in Congenital Hypothyroidism

Screening Program
by R. Iranpour,a M. Hashemipour,b M. Amini,b S. M. Talaei,c R. Kelishadi,c S. Hovsepian,b S. Haghighi,b and Kh. Khatibib
a
Division of Neonatology, Department of Pediatrics and
b
Endocrine & Metabolism Research Center, Isfahan University of Medical Sciences & Health Services, Iran
c
Isfahan University of Medical Sciences, Isfahan, Iran

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Summary
The aetiology of congenital hypothyroidism (CH) may be important in determining disease severity,
outcome and treatment schedules because athyroid patients need higher treatment doses and close
monitoring particularly early in life. The aim of this study was to evaluate thyroid scintigraphy (TS)
findings in infants with CH and to determine the relationship of serum TSH and T4 values with thyroid
agenesia, in an attempt to identify factors that may detect thyroid agenesia before treatment. Since
August 2002 to April 2005, screening program for CH was carried out in the Isfahan University of
Medical Sciences and Health Services, Isfahan, Iran. Screening was performed by measuring both the
serums T4 and TSH concentration at day 3–7 of birth. Full-term newborns were recalled based on a
serum TSH >20 mIU/l or serum T4 < 6.5 mg/dl and premature newborns based on T4 level by weight
and TSH level by age. After repeating the laboratory test and clinical evaluation, Tc-99m TS was
recommended for all infants with suspected CH before thyroxin replacement therapy. On the basis of
Tc-99m TS, the thyroid gland was classified as normal scan, ectopic, goiter and athyrosis. TS results
were compared with serum T4 and TSH levels. Of 93 381 newborns screened over a period of nearly
3 years, 262 neonates were found to have CH. The overall incidence of CH was 1 : 357 live births with a
female/male ratio (F/M) of 1.4/1. Thyroid scan was performed on 116 (54%) of the infants with CH;
of them, 33 cases (28.4%) were athyrotic (F/M ¼ 0.8/1) while seven infants (6%) had ectopic thyroid
(F/M ¼ 1.3/1) and 76 cases (65.6%) had a normal thyroid scan (F/M ¼ 1.5/1). Infants with the absence
of thyroid in TS had significantly higher TSH value in comparison with those with ectopic or normal TS
(116.3
109.64 vs. 108.10
62.92 or 55.35
48.26 mIU/l, respectively, P < 0.0001). Although not
statistically different, the mean T4 level was higher in normal TS group than in ectopic and athyrotic
groups (8.03
3.48 vs. 6.36
5.57 or 5.04
3 mg/dl, respectively, P ¼ 0.09). We conclude that Tc-99m
TS is a useful diagnostic tool for the initial investigation of suspected CH and considering the
correlation of TS results with blood TSH levels, proper management and close monitoring of
hypothyroid infants with severe hormonal alterations is necessary for the detection of thyroid agenesia.

Key words: congenital hypothyroidism, Tc-99m thyroid scintigraphy, thyroid agenesia, screening.

Introduction neurodevelopment impairment [1, 2]. The prevalence

Congenital hypothyroidism (CH) is the most of CH is occurring in approximately one in
common congenital endocrine disorder and it is 3000–4000 live births in North America and Europe
well-documented that without thyroxin replace- [3]. Whereas in Iran, it is detected at a rate of 1 : 914
ment from early life, it causes irreversible live births in Tehran, 1 : 1423 live births in Fars
province and 1 : 370 live births in Isfahan [4]. CH is
most commonly caused by developmental defects of
Acknowledgements thyroid gland (85%); which in turn consists of either
This project was funded by the Research Bureau, thyroid agenesia (40% of all cases) or incomplete
Isfahan University of Medical Sciences and Health or aberrant migration (40%), or hypoplasia of a
Services, Isfahan, Iran. eutopic gland [1]. Thyroid dysgenesis is commonly
sporadic with unknown mechanisms. However,
Correspondence: Ramin Iranpour, MD, Assistant Professor recent studies estimate that approximately 2% of
of Neonatology, Isfahan Endocrine & Metabolism
the cases with thyroid dysgenesis are familial [1].
Research Center, Sedigheh Tahereh Medical Research
Complex, Khorram Street, Jomhouri Square, Isfahan The remaining 10–20% of the infants with CH
8187698191, Iran. E-mail <iranpour@med.mui.ac.ir>. have dyshormonogenesis that is transmitted by an

ß The Author [2006]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org 411
doi:10.1093/tropej/fml038 Advance Access Published on 30 August 2006
 R. IRANPOUR ET AL.

autosomal recessive mode of inheritance [5]. There Recalls were implemented based on the level of T4
are gender and ethnic variations in CH. Overall, and TSH. In the case of T4 < 6.5 mg/dl or TSH
there is a 2/1 female/male ratio and higher prevalence >20 mIU/l on 3rd–7th days after birth, and
in Caucasians and Hispanics than in White infants T4 < 6.5 mg/dl or TSH >10 mIU/l after the 7th day
[6]. Although neonatal thyroid screening programs of birth, the neonates were recalled. Immature
have been extremely successful in the prevention of neonates with low level of T4 for their weight or with
neurodevelopmental deficit, some studies have high TSH levels for their age were recalled, as well [15].
reported subtle neuropsychological disturbance in Considering the first TSH values (3rd–7th day of
severely affected infants despite early detection and birth), the proper approach was selected. If TSH
treatment [7–9]. The aetiology of CH may be level was between 20 and 39 mIU/l, T4 and TSH
important in determining the disease severity, measurements were repeated, but if TSH level was

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outcome and treatment schedules. Patients with >40 mIU/l, then treatment was initiated as well as
athyrosis have shown the greatest hormonal altera- repeating lab test. If the result of the second test
tion and they need higher treatment doses and close was within the normal limits, the neonate was
monitoring particularly early in life [10–11]. considered to have transient CH, in which the
Thyroid imaging with technetium TC-99 m treatment was halted and the neonate was excluded
provide information about the size and the location from the study; otherwise, the treatment was
of thyroid gland [12]. Thyroid Scintigraphy (TS) is continued.
not routinely used to determine different forms of All recalled neonates were examined clinically by a
CH prior to the thyroxin replacement therapy [13]. pediatric endocrinologist. According to the results of
Patients with a non-visualized gland or with secondary measurements (on 7th–28th days of birth),
images suggesting dyshormonogenesis should be neonates were considered as hypothyroid when
re-evaluated at 3–4 years of age, after withdrawal having TSH > 10 mIU/l and T4 < 6.5 mg/dl. In both
of levothyroxin therapy [14]. premature and full-term neonates whose T4
Considering the high prevalence of CH in our measurements were low according to their weight,
country (Iran) and the importance of its proper complimentary tests including T3 resin uptake
treatment in preventing developmental and intellec- (T3RU) and free T4 index (FTI) were performed
tual impairment, this study was conducted to and treatment was started if these results were
evaluate the TS findings in infants with CH and abnormal.
to determine the relationships of serum TSH and In order to determine the aetiology of CH, all
T4 values with thyroid agenesia, in an attempt to infants were recommended to perform TS before
identify factors that may detect thyroid agenesia. treatment. A 99m-pertechnetate scintigraphy of
thyroid was performed. On the basis of Tc-99m TS,
Material and Methods the thyroid gland was classified as normal scan,
Since August 2002 to April 2005, the screening ectopic, goiter and athyrosis. Athyrosis was diag-
program for CH was carried out in the Isfahan nosed in infants whose thyroid scans did not show
Endocrine and Metabolism Research Center, Isfahan any radionuclide uptake. According to our screening
University of Medical Sciences and Health Services, strategy, CH newborns with normal thyroid scan and
Isfahan, Iran. All neonates were born in 17 maternity dyshormonogenesis had to be re-evaluated on their
hospitals of Isfahan and were referred for screening. 3rd–4th years of age, after interruption of treatment
The neonates’ sex, weight, height, head circumfer- for at least 4 week. The serum T4 & TSH values
ences, maternal age and parents’ consanguinity were (first measurement) in confirmed hypothyroid
recorded. Venous blood samples were obtained on patients were compared between athyrotic, ectopic
the day of referral (3rd–7th day of birth) by trained and normal thyroid scan groups.
nurses, from the cubital vein, and serum T4 and TSH
levels were measured. Serum T4 and TSH were Statistical analyses
measured by radioimmunoassay (RIA) and immu- Data were recorded on questionnaires and trans-
noradiometric assay (IRMA) methods, respectively, ferred to coding sheets in a computer database. Data
using Iran Kavoshyar Co. kits (Tehran, Iran) and by analyses were performed using SPSS version 10.5
gamma counter of Isfahan Endocrine and Metabolism (Chicago Inc., USA). Frequency, mean and SD for
Research Center (Berthold LB 2111-12). The sensitivity demographic data, T4 and TSH levels in neonates
of T4 and TSH tests were 0.38 mg/dl and 0.05 mIU/l, are presented. We compared the mean T4 and TSH
respectively. A 99m-pertechnetate scintigraphy of values between the athyrotic, ectopic and normal
thyroid was performed by using a gamma camera scan groups by one-way analysis of variance
equipped with a parallel hole collimeter. (ANOVA) and post hoc Tukey test. Gender and
A pediatric endocrinologist and a general practi- consanguinity differences between groups were
tioner evaluated the results of laboratory tests to analyzed by chi-square test. Statistical significance
determine neonates who needed to be recalled. was considered to be at the 5% probability level.

412 Journal of Tropical Pediatrics Vol. 52, No. 6

R. IRANPOUR ET AL.

Results Iran (Tehran, Fars province) have been lower than

Of the 93 381 newborns who were screened over a our area [4], but are 3–4 times more than that
period of nearly 3 years, 262 neonates were found reported from some Western countries [2]. Indeed,
with CH. The overall incidence of CH was 1 : 357. the prevalence of permanent CH has to be deter-
Among hypothyroid neonates, 110 (42%) were males mined by the exclusion of transient hypothyroid
and 152 (58%) were females leading to a female : cases after withdrawal of L-T4 therapy at 3–4 years
male ratio of 1.4 : 1. There was no parental con- of age.
sanguinity among 158 (61%) hypothyroid neonates, The main cause of compensated or transient
whereas the parents of 74 (28%) of them had primary hypothyroidism is iodine deficiency [16],
first-cousin consanguinity and 27 (11%) had however, from many years ago, this problem has
been solved in Iran [17]. A previous study in Isfahan

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second-degree consanguinity.
The mean
SD serum T4 and TSH levels of has shown that urinary iodine excretion was in the
hypothyroid newborns were 6.58
3.47 mg/dl and optimal range in neonates and their mothers [18]. The
48.79
62.93 mIU/l, respectively. other causes of transient hypothyroidism are transfer
Of the 262 infants with CH, TC-99m TS was of blocking antibodies or antithyroid drugs and
performed on 116 (54%) infants and the parents of iodine exposure [19–22]. Despite of our suggestion to
the remainder neonates accepted to perform TS on gynecologists and delivery room nurses about not
the third year of age. TS revealed ectopia in 7 (6%), using povidone iodine for delivery, we are not sure
thyroid agenesia in 33 (28.4%) and normal TS in about their compliance, so this may be a cause of
76 (65.5%) cases. high CH found in our area. None of the mothers of
The demographic data and TS results in infants neonates with CH had a history of antithyroid drug
with CH are summarized in Table 1. Normal scan intake but blocking antibodies were not measured,
was predominated in females than males (60.5 vs. this was a limitation in our study. Other variables
39.5%, respectively), and athyroid gland was more such as environmental, genetic, ethnic variation and
frequent in males than females (54.5 vs. 45.5%, familial factors are involved in increased prevalence
respectively), but no statistical gender difference was rate of CH in some population [23, 24]. We suggested
found between the two groups (P ¼ 0.4). There was that these factors may be the cause of high CH in our
no difference in the prevalence of parental consan- community that should be evaluated within the next
guinity among athyrotic, ectopic and normal TS years. One study from Saudi Arabia performed on
infants (P ¼ 0.3). 147 infants with CH detected a prevalence of 21.8%
The mean T4 and TSH values in hypothyroid athyrosis, 42.2% ectopic gland and 36% eutopic
neonates based on TS results are shown in Table 2. gland [25]. Another trial in Chile showed that
There was no difference between normal scan, neonates with CH had 47% ectopic, 29.1% eutopic
and 24.3% athyrotic gland [26]. The result of our
athyroid and ectopic groups in the mean T4 values
study was nearly similar to these studies. In our
(P ¼ 0.09), but significant difference was found in the
study, the high percentage of normal TS before
mean TSH values between the three groups
treatment may be due to transient hypothyroidism
(P ¼ 0.002). Athyroid infants had significantly
or dyshormonogenesis. Consequently, as recom-
higher TSH values compared with those with
mended, definite diagnosis has to be confirmed at
normal TS (116
109.64 vs. 55.35
48.26 mIU/l,
third to fourth years of age, after the interruption of
respectively, P < 0.0001).
replacement therapy for at least 4 weeks [14].
When the diagnosis of CH is confirmed, some
Discussion clinicians do not recommend routine thyroid imaging
This study revealed the incidence of CH in Isfahan, prior to starting levothyroxin therapy, because they
Iran, to be one case per 357 newborns which is about believe that the imaging results would not alter
10 times higher than that reported from America and their management [27]. Subtype of primary CH has
Europe [3]. The prevalence of CH in other regions of shown different degrees of impairment of thyroid

TABLE 1
Demographic characteristics and thyroid scan results in infants with congenital hypothyroidism

n (%) Sex Parents’ consanguinity

Male n (%) Female n (%) Yes No
1st degree n (%) 2nd degree n (%) n (%)

Normal scan 76 (65.5%) 30 (39.5%) 46 (60.5%) 26 (34.2%) 9 (11.9%) 44 (53.9%)

Ectopic gland 7 (6.1%) 3 (42.9%) 4 (57.1%) 3 (42.8%) 1 (14.3%) 3 (42.9%)
Athyrosis 33 (28.4) 18 (54.5%) 15 (45.5%) 10 (30.3%) 1 (3%) 22 (66.7%)

Journal of Tropical Pediatrics Vol. 52, No. 6 413

 R. IRANPOUR ET AL.

TABLE 2
The mean T4 and TSH values in hypothyroid neonates based on TS results

TSHa (mIU/l) T4b (mg/dl)

Mean (SD), Range Mean (SD), Range

Normal scan, n ¼ 76 55.35 (48.26), 8–240 8.03 (3.48), 0.60–13.20

Ectopic gland, n ¼ 7 108.10 (62.92), 34.80–224 6.36 (5.57), 1.30–15.30
Athyrosis, n ¼ 33 116.3 (109.64), 10.20–492 5.04 (3.9), 0.60–11.50
a
The normal range in serum TSH is considered to be 0.6–20 mIU/l and 0.6–10 mIU/l on the 3rd–7th days and 8th–28th days
of birth, respectively [15].

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b
The normal range in serum T4 is considered to be 6.5–15.0 mg/dl in term neonates [15].

function [28]. There are limited data available on probable, but in athyrotic or ectopic patients, life-
patterns of hormonal concentration for T4 and TSH in long therapy with higher dose might be needed.
children with different etiologies of CH. A previous Therefore, TS also provide useful prognostic infor-
study, in which the disease severity was related to mation for counseling with parents of CH patients
etiological category, reported that despite rapid and their follow-up program.
normalization of mean T4 levels in different etiologies According to the results of the present study, in
category of CH, the mean TSH level at screening and infants with athyrosis, the mean TSH level was
during the first 6 months of follow-up were consistently significantly higher than the normal scan group. No
higher in those with athyrosis than in those with dys- statistical differences were found between ectopic and
genetic or dyshormonogenetic etiologies. The percentage athyrotic patients or ectopic and normal TS groups
of patients who required a dose increase in the first 6 in the mean TSH values, but athyrotic patients when
months was significantly higher in athyrotic group compared with ectopic and ectopic when compared
than in other groups [11]. In our study, the mean with normal scan group had an increasing TSH level.
TSH level was significantly higher in the athyrotic However, no statistical difference was detected
group. Accumulating data from this and other between the groups in the mean T4 levels, but the
studies provide strong support for the view that the mean T4 values in athyrotic patients were lower than
aetiology should be considered as an important in other groups. Some studies also showed that
determinant of severity of disease and treatment newborns with normal TS had less hormonal
schedules in patients with CH. The follow-up alterations than those with athyrosis [11, 26, 28].
schedules for CH may differ in the three aetiological Our findings were consistent with the study of
categories (athyrosis, dysgenesis, dyshormonogenesis) Hanukoglu et al. [11], who examined the patterns
based on the different hormonal patterns and of TSH and T4 in the three groups based on their
responses to therapy [11]. Generally, CH children thyroid scans (athyrosis, dysgenesis and dyshormo-
with most severe and prolonged disease at diagnosis nogenesis). They reported that the mean TSH levels
have the worst outcome [29]. It is established that the at screening and during the first 6 months of follow-up
outcome is better in infants with severe hypothyroid- were consistently higher in those with athyrosis
ism if thyroxin replacement therapy would be started than in those with dysgenesis or dyshormonogenesis
on a high dosage due to the reduced period of post- aetiologies. The athyrotic group also had lowest total
natal hypothyroidism. However, the efficacy of a T4 levels at diagnosis and at 3 months of age. They
high dosage for milder forms of CH is yet to be concluded that CH patients without thyroid gland
confirmed [30]. Thus, the Tc-99m TS can add useful (agenesia) need close monitoring and prompt treat-
information in the clinical evaluation of infants with ment particularly early in life. Contrary to the
CH for choosing the better treatment strategies findings of these studies [11, 26, 28], in our patients
especially in patients with athyrosis. We suggest with athyrosis, T4 levels were not lower than in the
that performing TS, as soon as possible before other two groups but with a larger sample size there
starting replacement therapy would be useful. Due is a probability to find a statistical difference.
to higher mean screening TSH levels in infants with Conversely, one study showed that the initial T4
athyrosis than in the other two groups, TS especially levels correlated with the degree of skeletal matura-
in CH patients with severe hormonal alteration can tion and aetiology, but initial TSH level could not
determine the athyrotic group for the beginning of predict the nature of CH [31]. Further confirming
higher dose of L-T4 as well as closer monitoring. studies, with large sample size and longer period are
If the thyroid gland is present in the normal position necessary to prove definite relationship of hormonal
in TS, later discontinuation of treatment is more alteration and aetiology in CH.

414 Journal of Tropical Pediatrics Vol. 52, No. 6

R. IRANPOUR ET AL.

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