Oto et al.

Thyroid Research (2015) 8:10

DOI 10.1186/s13044-015-0023-5

RESEARCH Open Access

The ratio of serum free triiodothyronine to

free thyroxine in children: a retrospective
database survey of healthy short
individuals and patients with severe thyroid
hypoplasia or central hypothyroidism
Yuji Oto, Koji Muroya, Junko Hanakawa, Yumi Asakura and Masanori Adachi*

Abstract
Background: The ratio of serum free triiodothyronine (FT3) to free thyroxine (FT4) has been shown to be constant
in healthy adults. However, this ratio has been found to be decreased in athyreotic adult patients on levothyroxine
(L-T4) supplementation. In order to better evaluate thyroid-related pathologies in children as well as to establish a
reference range, we investigated the FT3/FT4 ratio in a pediatric population. Furthermore, we evaluated this ratio in
children with congenital hypothyroidism as well as those with central hypothyroidism.
Methods: A reference range for the FT3/FT4 ratio was obtained from 129 Japanese children (3–17 y) with idiopathic
short stature who were designated as the ‘Control’ group. Patients with congenital hypothyroidism due to athyreosis or
severe thyroid hypoplasia (designated as ‘A/Hypoplasia’), as well as patients with central hypothyroidism (‘Central’),
were recruited from the institutional database. For each group, the mean FT3/FT4 ratio was obtained.
Results: In the Control group, the FT3/FT4 ratio was 3.03 ± 0.38 10−2 pg/ng (mean ± standard deviation) with no
age or gender differences. A/Hypoplasia patients showed a significantly decreased mean FT3/FT4 ratio (2.17 ± 0.33,
P < 0.001) compared to Control patients, with decreased FT3 and elevated FT4 levels. The Central group also showed a
significantly decreased FT3/FT4 ratio (2.55 ± 0.45, P < 0.001) compared to the Control group, with decreased FT3 and
equivalent FT4 levels.
Conclusions: The FT3/FT4 ratio appears to be constant between the ages of 3–17 y. Children on L-T4 due to congenital
thyroid a/hypoplasia or central hypothyroidism have a decreased FT3/FT4 ratio compared to short normal children.
Keywords: Congenital hypothyroidism, Deiodinase, L-thyroxine therapy, Hypopituitarism, Triiodothyronine, Thyroxine

Background The ratio of serum free T3 (FT3) over free T4 (FT4)

Triiodothyronine (T3) is the most active form of thyroid (FT3/FT4 ratio) may reflect the degree of extrathyroidal
hormone. While one fifth of net T3 production is per- T4 to T3 conversion activity. Whereas FT3/FT4 ratio
formed by the thyroid gland, the remaining 80 % is derived has been reported to be constant in healthy adult indi-
from the extrathyroidal conversion of thyroxine (T4) to viduals [3], the consistency of this ratio has not yet been
T3, which is mediated by either iodothyronine deiodinase clearly determined in the pediatric population.
1 or 2 (DIO 1 or DIO 2, respectively). In contrast, T4 is Abnormally high or low FT3/FT4 ratios are seen in sev-
produced exclusively in the thyroid gland [1, 2]. eral congenital disorders that may affect peripheral thyroid
hormone economy, such as Allan-Herndon-Dudley syn-
drome (MCT8 deficiency) [4], selenocysteine insertion se-
* Correspondence: madachi@mars.sannet.ne.jp quence binding protein 2 deficiency [5], and thyroid
Department of Endocrinology and Metabolism, Kanagawa Children’s Medical hormone resistance [6, 7]. Therefore, investigating the
Center, Mutsukawa 2-138-4 Minami-ku, Yokohama 232-8555, Japan

© 2015 Oto et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://
creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Oto et al. Thyroid Research (2015) 8:10 Page 2 of 6

consistency of the FT3/FT4 ratio in the pediatric popula- chronological year, the mean FT3/FT4 ratio for that
tion, as well as the establishment of a reference range, is of age was used.
vital importance. Finally, patients with central hypothyroidism, whether
Decreased FT3/FT4 ratios has been observed in postop- congenital or acquired, were enrolled; these were desig-
erative athyreotic adult patients under oral levothyroxine nated as ‘Central’. As for patients with growth hormone
(L-T4) supplementation [3, 8]. This presents the thera- (GH) deficiency, only GH-replaced patients were included.
peutic problem of setting a target thyroid-stimulating hor- In each patient, the FT3/FT4 ratio was selected only when
mone (TSH) range when treating athyreotic populations the FT4 level was adequate (0.80–1.80 ng/dL). As with
with L-T4. It also indicates the potential benefit of com- congenital hypothyroidism patients, the mean FT3/FT4
bination therapy with L-T4 and liothyronine (L-T3). It is ratio at each age was obtained.
therefore probable that these same challenges may apply During the study period, serum FT3 and FT4 levels
to children with congenital hypothyroidism, especially were determined by electrochemiluminescence immuno-
those with athyreosis. Additionally, we anticipated that the assay (ECLIA) kits: FT3 by Elecsys® FT3II and FT4 by
FT3/FT4 ratio may be unbalanced in children with central Elecsys® FT4 (Roche Diagnostics, Tokyo, Japan). Anti-
hypothyroidism, owing to diminished TSH stimulation on bodies used for FT3 and FT4 determination were ovine
thyroidal T3 production. monoclonal and polyclonal antibodies, respectively.
The purpose of this study was twofold: First, to investi- Serum TSH levels were determined via the ECLIA kit
gate any age-dependent variations in the FT3/FT4 ratio in Elecsys® TSH (Roche Diagnostics).
the pediatric population without thyroidal morbidity; and
second, to evaluate this ratio in children with congenital
Statistical analysis
hypothyroidism owing to athyreosis or severe thyroid hy-
Statistical analysis was performed using the SPSS software
poplasia, and in those with central hypothyroidism of any
(Version 16.0; SPSS, IL, Chicago, USA). Data were com-
etiology.
pared using paired t-tests with normal distributions. Dif-
ferences between groups were evaluated by the covariance
Methods
analysis test. FT3/FT4 ratios lower than −2 SD or higher
This study was conducted as a retrospective database
than +2 SD were regarded as outliers. A P value less than
survey of the patients who attended the endocrine unit
0.05 was considered significant.
in Kanagawa Children’s Medical Center, the regional
children’s hospital near metropolitan Tokyo between
April 2004 and March 2010. The Ethics Committee of Results
Kanagawa Children’s Medical Center reviewed and ap- The profiles of the 129 children with idiopathic short
proved the study protocol. Informed consent from the stature (the Control group) are shown in Table 1. Table 2
patients and/or their caregivers was not required. shows the reference ranges for the FT3/FT4 ratio in
To obtain a reference range for the FT3/FT4 ratio, 129 each age group, together with individual FT3 and FT4
patients who were diagnosed with idiopathic short stat- values, obtained from the Control group. The FT3/FT4
ure without any underlying morbidities were selected. ratio was constant across each age interval, although a
Hereafter, this category is referred to as the ‘Control’. significant decrease of FT3 was observed in the 12–14 y
They were divided into 5 groups according to their age group compared to the 6–8 y age group (P = 0.037).
chronological ages: 3–5 y, 6–8 y, 9–11 y, 12–14 y, and There was no significant difference between males and
15–18 y. For each interval, mean and standard deviation females in the Control group (Table 3).
(SD) of the FT3/FT4 ratio, expressed as 10−2 pg/ng, was There were 22 patients with congenital hypothyroidism
obtained. due to A/Hypoplasia with neonatal TSH levels greater
Next, we searched for patients with congenital than 100 μIU/mL (Table 1). A total of 101 sets of FT3 and
hypothyroidism due to athyreosis or severe thyroid hypo- FT4 values obtained with adequate TSH levels (0.30–5.0
plasia (designated as ‘A/Hypoplasia’). Thyroid morphology μIU/mL) from these patients were utilized for FT3/FT4
was evaluated by ultrasound imaging and/or scintigraphy ratio calculation.
with 123I or 99mTcO−4 . Among all candidate patients, only Results of FT3/FT4 ratio analysis in A/Hypoplasia pa-
those who presented with a TSH value greater than 100 tients, with their respective FT3 and FT4 values, are pre-
μIU/mL during the neonatal period were selected. For sented in Table 2 and Fig. 1. For all age intervals, the FT3/
each patient, the FT3/FT4 ratio obtained at various FT4 ratio was significantly lower than that of the respective
ages throughout childhood was extracted from the Control, whereas the FT4 levels in A/Hypoplasia were sig-
database only when the concurrently determined TSH nificantly higher than that of the Control. Although there
level was adequate (0.30–5.0 μIU/mL). If a patient had was no difference in FT3 levels between A/Hypoplasia and
measured FT3 and FT4 more than once during a Control when comparing within each age interval, the
Oto et al. Thyroid Research (2015) 8:10 Page 3 of 6

Table 1 Profiles of the three categories of patients enrolled in this study

Categorya n (male) Age range at study Median latest L-T4b Total number of FT3 and Mean TSHd level
in years dose (range) FT4 measurementsc (range)
Control 129 (81) 3.1–17.1 Not applicable 129 2.16 ± 1.03 (0.56–4.96)
A/Hypoplasia 22 (11) 3.0–18.4 125 (25–200) 156 1.81 ± 1.19 (0.30–4.96)
Central 27 (13) 3.0–18.9 100 (50–200) 366 Not applicable
a
See text for the definition of each category
b
L-T4: L-thyroxine, in μg per day
c
These numbers represent all the individual FT3 and FT4 measurements taken before averages were calculated. In A/Hypoplasia and Central, the values exceed
the number of patients owing to repetitive measurements
d
Values are μIU/mL; mean ± standard deviation

difference was significant when compared as a whole group Discussion

(P = 0.004, Table 2). We observed a marked consistency in the FT3/FT4 ratio
There were 27 patients in the Central group who were (mean, 3.03 ± 0.38) among healthy short Japanese chil-
GH sufficient or replete (Table 1). Of these, 11 patients dren between 3–17 years of age, with no differences
had congenital hypopituitarism (including 5 with septo- owing to gender. This finding is in line with a previous
optic dysplasia) and 16 had acquired hypopituitarism (11 study conducted in an adult population by Gullo et al.
with craniopharyngioma, 4 with germinoma, and 1 with [3], which reported a consistent FT3/FT4 ratio with a me-
ROHHADNET syndrome). A total of 145 sets of values dian molar ratio of 0.32 (corresponding to 2.71 10−2 pg/ng),
for FT3 and FT4 (where FT4 levels were 0.80–1.80 ng/ in 3,875 euthyroid subjects (with minor age and gender
dL) were utilized for FT3/FT4 ratio calculation. variability). The difference in the absolute value of the ratio
In Table 2 and Fig. 1, the FT3 and FT4 values, as well between Gullo et al.’s data [3] and ours may be multi-
as the FT3/FT4 ratio, in the Central group are also pre- factorial, owing to both the methodological differences
sented. The total FT3/FT4 ratio was significantly lower in hormone detection (particularly the types of the
than that of the Control group, as was the case in all in- antibodies used) and ethnic differences that influence
dividual age groups except for the youngest. The FT4 iodine sufficiency.
value in the Central group was not different than that of Our report is the first to specifically investigate the FT3/
the Control group, whereas the total FT3 value of the FT4 ratio in the pediatric population. While reference
Central group was significantly lower than that of the values for FT3 and FT4 in children have been reported
Control group (P = 0.02). [9–13], these reports did not refer to the FT3/FT4 ratio.
Table 4 depicts a schematic summary of the FT3/FT4 Additionally, most studies provided only the ranges or
ratio, as well as the levels of FT3 and FT4, in the A/Hy- centile values of FT3 and FT4, and calculation of the FT3/
poplasia and Central groups compared to the Control FT4 ratio was therefore impractical. More research is
group. needed to evaluate the distribution of the FT3/FT4 ratio

Table 2 FT3 and FT4 levels, as well as their ratios, in patient groups according to age
3–5 y 6–8 y 9–11 y 12–14 y 15–18 y Total
Control (n = 129) n 24 19 31 36 19 129
FT3 4.11 ± 0.56 4.29 ± 0.43α 4.14 ± 0.38 3.89 ± 0.50α 3.93 ± 0.56 4.06 ± 0.50
FT4 1.36 ± 0.14 1.38 ± 0.11 1.36 ± 0.14 1.33 ± 0.16 1.31 ± 0.10 1.35 ± 0.14
FT3/FT4 3.02 ± 0.38 3.12 ± 0.31 3.07 ± 0.38 2.95 ± 0.35 3.01 ± 0.50 3.03 ± 0.38
b
A/Hypoplasia (n = 22) n 14 20 22 21 24 101
FT3 4.15 ± 0.51 3.86 ± 0.42 3.91 ± 0.45 3.84 ± 0.60 3.52 ± 0.60 3.82 ± 0.55*
FT4 1.95 ± 0.20** 1.81 ± 0.31** 1.76 ± 0.26** 1.85 ± 0.59** 1.90 ± 0.69** 1.85 ± 0.47**
FT3/FT4 2.15 ± 0.25** 2.18 ± 0.30** 2.25 ± 0.39** 2.23 ± 0.34** 2.03 ± 0.30** 2.17 ± 0.33**
b
Central (n = 27) n 11 31 46 31 26 145
FT3 3.50 ± 0.48 3.49 ± 0.53** 3.51 ± 0.64** 3.63 ± 0.64 3.46 ± 0.54 3.52 ± 0.58**
FT4 1.24 ± 0.23 1.31 ± 0.17 1.43 ± 0.29 1.45 ± 0.30 1.49 ± 0.25 1.41 ± 0.27
FT3/FT4 2.94 ± 0.58 2.68 ± 0.51* 2.49 ± 0.37** 2.52 ± 0.37* 2.37 ± 0.40** 2.55 ± 0.45**
Values are pg/mL (FT3) and ng/dL (FT4); mean ± standard deviation
α
P < 0.05, *P < 0.05; **P < 0.01, compared to control, respectively
b
In A/Hypoplasia and Central, patients underwent repetitive measurements of FT3 and FT4. All the values are averaged according to the chronological age of the
patients. The same patients may have average independent measurement values in more than one age category if they were evaluated over multiple years
Oto et al. Thyroid Research (2015) 8:10 Page 4 of 6

Table 3 Gender difference of FT3/FT4 ratio in Control

3–5 y 6–8 y 9–11 y 12–14 y 15–18 y Total
Male n 10 11 19 29 12 81
FT3/FT4 3.03 ± 0.27 3.23 ± 0.32 3.06 ± 0.30 3.02 ± 0.34 3.09 ± 0.37 3.06 ± 0.32
Female n 14 8 12 7 7 48
FT3/FT4 3.02 ± 0.0.46 2.97 ± 0.25 3.08 ± 0.50 2.83 ± 0.16 3.11 ± 0.23 3.02 ± 0.40
Values are mean ± standard deviation

in both the longitudinal and cross-sectional aspects. The The FT3/FT4 ratio in patients with A/Hypoplasia,
influence of pubertal development on this ratio also ought which is defined by extremely high neonatal TSH levels
to be investigated, because FT3 levels in the 12–14 y (>100 μIU/mL), was significantly lower than that in the
groups were found to be lower than in the younger age Control group (Table 2 and Fig. 1). As depicted in
groups. Table 4, this decrease is mainly due to the elevation of
The consistency of the FT3/FT4 ratio during childhood the denominator (FT4 level), although a slightly de-
is useful for the screening of several genetic disorders re- creased numerator (FT3 level) also contributed. This
lated to peripheral thyroid hormone metabolism, includ- finding is consistent with recent studies conducted in adult
ing Allan-Herndon-Dudley syndrome (MCT8 deficiency) populations. For example, Ito et al. found that athyreotic
[4], selenocysteine insertion sequence binding protein 2 adult patients (n = 51) who underwent total thyroidectomy
deficiency [5], thyroid hormone resistance [6, 7], and for papillary thyroid carcinoma and who are on L-T4 ther-
others. apy with normal TSH level (0.3–5 μIU/mL) had increased
Furthermore, evaluating the FT3/FT4 ratio in patients FT4 and slightly decreased FT3, resulting in a decreased
on L-T4 supplementation due to various thyroidal disor- FT3/FT4 ratio [8]. Additionally, Gullo et al. reported that
ders may be a method of assessing the sufficiency of the 29.6 % of 1,811 patients who were thyroidectomised be-
L-T4 therapy. Observing differences of FT3/FT4 ratios cause of thyroid cancer and were on L-T4 therapy with
in pathological situations was the main feature of this TSH levels of 0.4–4.0 μIU/mL, had FT3/FT4 ratios below
study, which is the first to evaluate this ratio in pediatric the lower limit of euthyroid controls [3].
patients with congenital hypothyroidism and central Elevated FT4 levels in our A/Hypoplasia group and
hypothyroidism. athyreotic adult patients is expected because, in athyreo-
tic patients, thyroid hormone is solely derived from ex-
ogenous L-T4 whereas thyroidal T3 production is
P< 0.01 FT3/FT4 almost absent. Thus, normalization of TSH is achieved
P< 0.01
(10-2 pg/ng) at the expense of higher FT4 levels. This is the inverse
4.0 situation of the increased FT3/FT4 ratio in untreated or
refractory Graves’ disease, where thyroidal T3 produc-
tion is predominant [14].
3.5 Ito et al. explained the pathophysiology of decreased
FT3 levels in their athyreotic adult patients as follows
3.0 [8]: First, TSH secreting cells have T3 in their cytoplasm
transported directly from the circulation. Second, these
cells also have T3, which is generated from T4 by intracel-
2.5
lular deiodinase. Third, referring to a classical study [15],
it was shown that the proportion of the latter T3 is in-
2.0 creased in hypothyroid patients on L-T4. Thus, when tar-
get TSH levels are set to approximate the physiologically
1.5
A/Hypoplasia Central Control Table 4 Summary of FT3/FT4 ratio and individual levels in
Fig. 1 Serum free triiodothyronine (FT3) to free thyroxine (FT4) ratio congenital hypoplasia and central hypothyroidism
distribution in the Control, A/Hypoplasia, and Central groups. In the Congenital thyroid hypoplasiaa Central hypothyroidisma
A/Hypoplasia and Central groups, the number of dots exceeds the
FT3/FT4 ratio ↓↓ ↓
patients’ number because all the individual FT3/FT4 measurements
with averaging per chronological age groups are included. Note the FT3 ↓ ↓↓
significantly decreased FT3/FT4 ratio in both the A/Hypoplasia and FT4 ↑↑ →
Central groups compared to the Control group a
Compared to the control group
Oto et al. Thyroid Research (2015) 8:10 Page 5 of 6

normal range, circulating FT3 will be maintained at lower Conclusions

level. As Gullo et al. pointed out, the reason for this The FT3/FT4 ratio appears to be constant between 3–17
phenomenon is the inadequacy of peripheral T3 produc- y. Pediatric populations with congenital hypothyroidism
tion, which cannot compensate for the absent thyroidal due to severe thyroidal hypoplasia and with central
T3 production [3]. This same scenario likely applies to our hypothyroidism with exogenous L-T4 supplementation
A/Hypoplasia patients. were found to have decreased FT3/FT4 ratios compared
The Central group was also found to have a signifi- to short normal children. The clinical significance of this
cantly decreased FT3/FT4 ratio compared to the Control finding should be further investigated.
group. This decrease is mainly due to grossly decreased
FT3 levels with maintained FT4 levels, resulting in a less Abbreviations
prominent decrease of the ratio than that found in the TSH: Thyroid stimulating hormone; T3: Triiodothyronine; FT3: Free triiodothyronine;
T4: Thyroxine; FT4: Free thyroxine; L-T3: Liothyronine; L-T4: Levothyroxine;
A/Hypoplasia group (Table 2 and Fig. 1). There does not SD: Standard deviation.
appear to be a precedent study investigating the FT3/
FT4 ratio in subjects with central hypothyroidism in ei- Competing interests
ther adult or pediatric populations. The authors declare that they have no competing interests.
The explanation for decreased FT3/FT4 values in the
Central group is straightforward: As TSH level cannot Authors’ contributions
MA conceptualized and designed the study. MA and YO contributed to the
be used as a therapeutic guide in patients with central data collection, analysis, and writing the manuscript. JH, KM, and YA contributed
hypothyroidism [16], they instead undergo L-T4 therapy to preparation of the manuscript by critically analyzing it. All authors read and
to achieve normal FT4 levels. Thus, FT3 levels must be approved the final manuscript.
lower because T3 is generated mainly from the peripheral Received: 9 June 2015 Accepted: 30 June 2015
conversion of exogenous L-T4 to T3, and thyroidal T3 pro-
duction is diminished under attenuated TSH stimulation.
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