Treatment of hypothyroidism in infants, children and adolescents

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Trends in
Endocrinology & Metabolism
Review
Treatment of hypothyroidism in infants, children
and adolescents
Luisa Rodriguez,1 Catherine Dinauer,2 and Gary Francis3,*
Highlights
This review is focused on children for
whom the diagnosis and treatment of
hypothyroidism is problematic.
This includes those with congenital
hypothyroidism, prematurity, Down
syndrome, subclinical hypothyroidism,
and obesity.
In 2014, treatment guidelines from the American Thyroid Association reflected
the general consensus that levothyroxine (LT4), adjusted to maintain a normal
thyrotropin (TSH) level, is the preferred method for treatment of hypothyroidism.
Although this is generally applicable to children, there are subsets of children for
whom the diagnosis and treatment of hypothyroidism are problematic. These
include children with congenital hypothyroidism (CH), low birth weight (LBW) and
very low birth weight (VLBW), Down syndrome (DS), subclinical hypothyroidism,
and obesity. In this Review, we focus on the progress and remaining pitfalls in
diagnosis and treatment of hypothyroidism in these and other groups.
1Assistant Professor of Pediatrics,
Division of Endocrinology and Diabetes,
University of Texas Health Science
Center San Antonio, San Antonio,
TX, USA
2Associate Professor of Pediatrics,
Division of Endocrinology, Yale University,
New Haven, CT, USA
3Professor of Pediatrics, Division of
Endocrinology and Diabetes, University
of Texas Health Science Center San
Antonio, San Antonio, TX, USA
*Correspondence:
francisg@uthscsa.edu (G. Francis).
Introduction
Hypothyroidism is one of the most common endocrine abnormalities, affecting 5.3% of the
population [1]. The prevalence increases with age but even the incidence of CH is increasing
[2]. When subclinical hypothyroidism (SH) is also included, the prevalence of hypothyroidism in
children and adolescents may be as high as 1.7–9.5% [3]. In the USA, Hashimoto thyroiditis
(HT) is the leading cause of acquired hypothyroidism in children and adolescents with a preva-
lence estimate of 3% [4]. Relatives of affected probands have a ninefold increased risk to develop
HT compared to the general population [5]. Over a 5-year follow-up, 57.1% of children with
HT remained euthyroid, while 30.6% developed SH and 12.3% overt hypothyroidism [4]. Poor
outcomes result from either over- or undertreatment [1]. In 2014, guidelines from the American
Thyroid Association reflected the general consensus that LT4, adjusted to maintain a normal
TSH level, is the preferred method for treatment of hypothyroidism [6]. Although this is generally
applicable to children, there are subsets of children for whom the diagnosis and treatment of
hypothyroidism are problematic.
Primary acquired hypothyroidism
The most common cause of acquired hypothyroidism in the USA is autoimmune thyroiditis (HT);
however, ~5% of children (6–11 years old) in the USA are iodine deficient (urine iodine excretion
<50 mg/l) [7]. It is uncommon for children to have secondary hypothyroidism, and even rarer to
have consumptive hypothyroidism [7]. The most sensitive indicator of primary hypothyroidism
is elevation of serum TSH level above the reference range for age (2.59 ± 1.19 mIU/l for female
and 2.74 ± 1.29 mIU/l for male children aged between 2 months and 18 years) [8]. Acquired
hypothyroidism can be subdivided into overt (TSH >10 mU/l) and subclinical (TSH 5.5–10 mU/l)
[9]. The approach to SH is outlined in later sections but for overt hypothyroidism, and regardless
of the cause, treatment requires LT4 supplementation with goals to reduce or eliminate symptoms
of hypothyroidism, restore normal metabolic parameters such as growth and serum cholesterol
levels, and normalize TSH levels. A randomized trial in adults has shown that targeting TSH to levels
<2 mIU/l was not more effective than a normal TSH for reducing symptoms or improving quality of
life [10]. Despite lack of a specific pediatric trial, the data support maintaining TSH levels in the
reference range for children and adolescents of all ages.
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Trends in Endocrinology &Metabolism
The optimal daily dose of LT4 for children, as determined by Rezvani and DiGeorge, is generally
104.6 ± 5.2 μg/m2 body surface area [11]. However, consumptive hypothyroidism, resulting
from expression of type-3 deiodinase by certain tumors (hepatic, vascular, or gastrointestinal
stromal tumors), may require higher doses to achieve target TSH levels [12]. A variety of
medications and comorbid conditions affect LT4 absorption and also require higher doses.
Bariatric surgery, and small intestinal diseases such as celiac disease impair absorption of
LT4. Conditions that reduce gastric acidity such as proton pump inhibitor therapy impair
dissolution of LT4 tablets and may require higher doses or substitution of liquid LT4 (see
section below). In addition, calcium, iron, sucralfate, orlistat, bile acid sequestrants, soybean,
and dietary fiber prevent absorption of LT4, whereas vitamin C facilitates absorption of LT4.
Patients taking these medications are advised that at least 1 h should elapse between admin-
istration of these medicines and LT4.
Treatment may be lifelong, but according to DeLuca et al., children with HT remain or become
euthyroid in about 50% of cases suggesting that LT4 therapy may eventually be discontinued
[13]. The presence of goiter, or rising levels of thyroid peroxidase antibody or serum TSH suggest
continued need for LT4.
Secondary hypothyroidism
Hypothyroidismmay also be caused by pituitary or hypothalamic dysfunction. In this case, serum
TSH is no longer valid for diagnosis or management. The goal of therapy is to maintain serum free
thyroxine (fT4) in the upper half of the reference range for age [6]. However, due to the risk of
additional pituitary hormone deficiencies, one should either ensure adequate cortisol production
or begin hydrocortisone replacement 24 h prior to initiation of LT4 [14].
Liquid thyroxine
Levothyroxine tablets (LT4-tabs) contain LT4 salt compressed into a tablet that must dissolve
prior to absorption. This can be facilitated by crushing the tablet [15] but the solubility of LT4
decreases with increasing gastric pH as encountered with proton pump inhibitors, atrophic
gastritis, Helicobacter pylori infection, delayed gastric emptying, and intake of food or drinks
other than plain water [16]. In contrast, liquid levothyroxine (LT4-liq) preparations are well
absorbed regardless of gastric pH [17]. LT4-liq may be an appropriate formulation for patients
who are unable to maintain normal TSH with LT4-tab therapy. Two important studies showed
that LT4-liq achieved and maintained normal TSH in a greater proportion of infants with con-
genital hypothyroidism than could be achieved with LT4-tabs [18,19]. Similarly, Cappelli et al.
found that LT4-liq achieved TSH targets in more patients treated for differentiated thyroid
cancer than could be achieved with LT4-tabs [20]. These data support the use of LT4-liq for
patients with severe hypothyroidism if TSH targets cannot be achieved with conventional
LT4-tab therapy (Table 1).
Table 1. Treatment for primary hypothyroidism in children
Usual (first-line) therapy LT4 fails to normalize TSH in patient with
low gastric acidity or malabsorption
LT4 fails to normalize TSH in CHa
LT4-tab (100 μg/m2/day)
Adjust to TSH target in
reference range for age
Ensure dose and timing are appropriate
Ensure no interfering medicines
Consider LT4-liq
Ensure dose and timing are appropriate
Ensure no interfering medicines
Consider LT4-liq or combination LT4 + LT3
aSome newborns with CH develop central thyroid hormone resistance and do not normalize TSH for months to years despite
fT4 above the reference range for age [23]. Treatment must be individualized and the benefit and risk of fT4 elevation must be
weighed [101,102].
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Combined levothyroxine and triiodothyronine therapy
The thyroid produces 100% of T4 and ~20% of triiodothyronine (T3) found in the circulation [14].
The majority of T3 is generated by deiodination of T4 in peripheral tissues [6]. When athyreotic
patients are treated with LT4 monotherapy, T3 levels decrease and, in 15% of patients, may
drop below the normal reference range [21]. This has generated suspicion that some patients
might have better symptom resolution with combined LT4 + LT3 therapy. However, large con-
trolled trials in adults fail to support this hypothesis [22]. Nevertheless, studies in CH support
the use of combined LT4 + LT3 therapy for some infants and children. As many as 43% of infants
and 10% of older children with CH develop a form of thyroid hormone resistance and fail to
normalize TSH with LT4 monotherapy [23]. In these children, Paone et al. showed that addition
of LT3 normalized TSH and significantly reduced the proportion of children with TSH >10 mIU/l
(35% vs 8%) [23]. Likewise, following total thyroidectomy in patients with differentiated thyroid
cancer (DTC), combined LT4 + LT3 therapy achieved TSH suppression targets without elevation
in T4 levels above the normal range [24,25].
For most patients, however, the reasons for failure of LT4 monotherapy are poor adherence with
daily dosing or failure of LT4 absorption [16]. Once those are excluded, combined LT4 + LT3
therapy may be appropriate for children and adolescents who fail to meet TSH targets with
LT4 monotherapy (Table 1).
Congenital hypothyroidism
Newborn screening for CH identifies between 1/3000 and 1/2000 affected infants/live births but
the incidence is increasing in part due to lower TSH diagnostic thresholds [26]. Recent guidelines
have been published by the European Society for Paediatric Endocrinology [27,28], the Japanese
Society for Pediatric Endocrinology [29], and the American Academy of Pediatrics [30]. The most
sensitive test for detection of primary CH is measurement of the serum TSH. Abnormal results
of CH screening should be confirmed by measures of serum fT4 and TSH. CH is stratified into
mild (fT4 = 10–15 pmol/l, 0.78–1.17 ng/dl), moderate (fT4 = 5–10 pmol/l, 0.39–0.78 ng/dl), and
severe (fT4 <5 pmol/L, <0.39 ng/dl). According to recent European guidelines, treatment with
LT4 (10–15 μg/kg/day) should begin if any of the following criteria are met (Table 2). (i) LT4
should be given without delay if the screening whole blood TSH ≥40 mIU/l while awaiting
confirmatory laboratory results. (ii) LT4 should be given for infants with screening TSH
<40 mIU/l and confirmatory TSH >20 mIU/l. (iii) LT4 should be given for infants with screening
TSH <40mIU/l and confirmatory TSH 6–20 mIU/l with low fT4. (iv) LT4 should be given if the fT4
is low and the TSH is greater than the age-adjusted range. (v) LT4 should be given if the serum
TSH is >20 mIU/l (beyond 1 week of age), even if fT4 is normal. (vi) Although treatment remains
controversial, LT4 should be considered if the serum TSH remains 6–20 mIU/l despite normal
fT4 beyond 21 days of age [31,32]. In those cases, imaging by ultrasound or radionuclide scan
will help identify infants with an abnormal thyroid gland for whom LT4 therapy is indicated [28].
In most cases, the fT4 will normalize within 1 week and TSH within 4 weeks of life. However, as
noted above, some infants develop thyroid hormone resistance and fail to normalize TSH with
Table 2. Criteria for LT4 therapy in newborn infants [27,28]
Abnormal screening
TSH ≥40 mIU/la
Abnormal screening TSHb
and confirmatory TSH
>20 mIU/l
Abnormal screening TSHb
and confirmatory TSH
6–20 mIU/l and low fT4
fT4 low + TSH >
age-adjusted normal
TSH >20 mIU/l
and > 1 week old
Consider if TSH 6–20 mIU/l
and normal fT4 and
>21 days oldc
aLT4 should be given without delay if the screening TSH ≥40 mIU/l while awaiting confirmatory laboratory results.
bRefer to State Guidelines for definition of abnormal TSH.
cAlthough treatment remains controversial, LT4 should be considered if serum TSH remains 6–20 mIU/l despite normal fT4 beyond 21 days of age [31,32].
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LT4 monotherapy [23]. For them, addition of LT3 may be considered, although the impact on
neurodevelopmental outcome is not yet known [14] (see Outstanding questions).
Thyroid function in premature infants
Organogenesis and differentiation of the hypothalamus, pituitary, and thyroid occur during the
first trimester [33]. Each is hormonally active by 10–12 weeks, but coordinated secretion is not
established until 18–20 weeks’ gestation [33]. Once the fetal thyroid produces thyroid hormone,
fetal T4 levels serially increase to achieve adult levels by 36 weeks [34–36]. Although total and free
T3 concentrations also increase, placental deiodinase converts T4 to the inactive reverse T3 (rT3)
generating less T3 in the fetus [34–36]. Serum TSH rises gradually throughout gestation resulting
in similar cord blood levels in preterm and term infants [36,37].
At delivery, term infants exhibit a dramatic surge in TSH within 30–60 min, resulting in robust
levels during the first 24 h of life. TSH then declines to plateau around 7 days of age. This TSH
surge leads to increases in T4 and T3 that are sustained over the first week. In contrast, prema-
ture infants have an attenuated and shorter TSH surge generating lower peak levels that correlate
with gestational age [37,38]. As a result, the subsequent T4 rise is less robust but still correlates
with gestational age. Infants born between 24 and 27 weeks show a small rise in T4, lasting for
only a few hours, whereas infants born after 28 weeks show a greater and more sustained rise
of at least 24 h [39].
Normative ranges for TSH and thyroid hormone levels in premature infants beyond the first week
of life are limited. One study examined a cohort of over 3000 infants born at <32weeks’ gestation.
Median TSH changed little from birth to 10 weeks of age [38]. At 3–4 weeks of age, the median
TSH (2.5–2.6 mIU/l) was similar across the cohort. However, the 95th percentile TSH was higher
(11–11.8 mIU/l) for infants born extremely prematurely (22–27 weeks) when compared to those
born very prematurely (28–31 weeks, TSH = 8.2–9.0 mIU/l). Similar results were reported in a
recent study of infants born at <36 weeks’ gestation. Median TSH levels (2.806–3.667 mIU/l)
changed little across all subgroups between 7 and 300 days of life [40]. Median free T4 levels
increase throughout the postmenstrual age (PMA, gestational age at birth + postnatal chronological
age). Free T4 levels increased from 0.70 ng/dl in infants at <28 weeks PMA to 1.15 ng/dl in those at
>40 weeks PMA. The data suggest that reference ranges for fT4 should be 0.42–0.91 ng/dl for the
25–26 + 6/7-week PMA infants and 0.87–1.32 ng/dl for infants at >40 weeks PMA (Table 3). These
data support the notion that infants born prematurely often have hypothyroxinemia of prematurity,
reflecting immaturity of the hypothalamic–pituitary–thyroid (HPT) axis, which resolves over time
(Outstanding questions).
The incidence of permanent CH, for example, due to thyroid agenesis, dysgenesis, or
dyshormonogenesis, is the same for premature as for term infants [41]. However, VLBW infants
have a greater incidence of transient CH [41,42]. The diagnosis of primary CH in a premature
infant is challenging since screening in the early neonatal period (24–72 h of life) may show a normal
TSH even in true hypothyroidism. This can occur regardless of whether TSH was measured as a
Table 3. Reference ranges (central 95%) for TSH and fT4 in preterm infantsa
Age
(weeks PMA)
25–27 + 6/7 28–30 + 6/7 31–33 + 6/7 34–36 + 6/7 37–39 + 6/7 ≥40
TSH (mIU/l) 0.340–9.681 0.709–7.105 0.954–7.278 1.782–6.983 0.889–6.896 1.090–7.627
fT4 (ng/dl) 0.42–0.91 0.68–1.23 0.67–1.38 0.82–1.38 0.78–1.53 0.87–1.32
aAdapted from [40].
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reflex test in response to a low T4 screen or as part of a TSH-based screening program. There are
multiple reasons for this including an immature HPT axis; comorbidities such as intrauterine growth
retardation or respiratory distress syndrome; treatment with medications affecting the HPT axis
(dopamine or glucocorticoids); twin gestation; and/or blood transfusion. Therefore, repeat screening
at 2–4 weeks of life is recommended for infants born prematurely or those weighing <1500 g [43].
The decision to initiate thyroid hormone replacement in premature infants is difficult but is
predominantly based on the clinical condition of the baby. Serum TSH is primarily used to
detect hypothyroidism and a level >95th percentile for PMA is considered abnormal (generally
TSH >10 mIU/l). If the TSH is high and free T4 is low, LT4 should be prescribed despite the fact
that CH may be transient (typically resolving by 2 years of age) [44]. If the TSH is mildly elevated
but the fT4 is normal for PMA, thyroid function tests (TFT) can be serially followed (generally
every 2 weeks). For infants with hypothyroxinemia of prematurity (free or total T4 are low and
TSH is normal or low), LT4 therapy has not been proven to offer neurocognitive benefit [45].
For that reason, therapy can be deferred as long as serial measures confirm improvement in
T4 and no increase in TSH. Adequate iodine intake (>30 μg/kg/day for a premature infant)
should be ensured but excess iodine should be avoided as this may induce hypothyroidism
through the Wolff–Chaikoff effect, from which premature infants cannot readily recover [46–48].
A common example is the preterm infant who undergoes cardiac catheterization and may receive
an iodinated contrast load that is sufficient to induce overt hypothyroidism. Although likely to be
transient, this nonetheless requires LT4 treatment [46]. It may be difficult to determine if abnormal
TFTs are due to hypothyroxinemia of prematurity, nonthyroidal illness (NTI), and/or medications.
With time and improvement in the overall clinical condition, TFTs should normalize if these are
the cause.
Thyroid hormone suppression therapy for thyroid cancer
Most children with DTC are treatedwith total thyroidectomy and require thyroid hormone replace-
ment. DTC, including papillary and follicular variants, arises from thyroid follicular cells that
respond to TSH [49]. Suppression of TSH with LT4 is a universal strategy to reduce the risk of
recurrent or progressive disease [50,51]. The dose is initially estimated using weight and/or
body surface area (full replacement dose is ~100 μg/m2/day) and then titrated to achieve a
TSH level consistent with the ATA Pediatric Risk category (low, intermediate, or high) based on
the extent of disease [51]. Stringent TSH suppression (<0.1 mIU/l) is advised for ATA Pediatric
High-Risk patients, while a low but detectable TSH (0.1–0.5 mIU/l) is recommended for ATA
Pediatric Intermediate-Risk patients. For ATA Pediatric Low-Risk patients, the recommended
TSH target is at the lower end of the reference range (0.5–1.0 mIU/l) (Table 4) [51]. Over time,
with no evidence for disease, suppression may be relaxed, but a TSH in the lower half of the
reference range (generally <1.5 mIU/l) remains the goal for all patients, regardless of initial ATA
Pediatric Risk category. Overly aggressive TSH suppression may result in clinical thyrotoxicosis.
If this occurs, the LT4 dose should be decreased to minimize adverse effects while still maintain-
ing a low TSH. For patients with DTC who are initially treated with lobectomy, the residual lobe
may produce adequate thyroid hormone. However, if the TSH is in the upper half of the reference
range, LT4 should be prescribed to reduce the TSH into the lower end of the reference range
(e.g., 0.5–1.0 mIU/l).
Table 4. TSH suppression targets for thyroid cancer [51]
ATA risk category for DTC High Intermediate Low
TSH target (mIU/l) < 0.1 mIU/l 0.1–0.5 mIU/l 0.5– - 1.0 mIU/l
Medullary thyroid cancer For all patients TSH in reference range for age
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Patients with medullary thyroid cancer (MTC) require thyroid hormone replacement following
thyroidectomy, but TSH suppression is not warranted since MTC is derived from parafollicular
C cells that do not respond to TSH. TSH should thus be targeted to the age appropriate reference
range (Table 4).
LT4 monotherapy provides effective replacement for most patients. However, there is a subset
who do not feel well on LT4 alone, even if thyroid hormone levels are normal. In these patients,
the addition of liothyronine (LT3) may be considered and given at a low dose (5 μg twice daily)
[24,25]. Clinical benefit from combined LT4 and LT3 therapy is based on the individual’s sense
of improvement rather than laboratory testing. If a patient does not feel better on combination
therapy, LT3 should be discontinued and LT4 continued alone.
Considerations in critical illness and depression
Abnormal TFTsmay develop during serious illness (includingmultisystem inflammatory syndrome
in children, due to SARS-CoV-2), trauma, burn, surgery (e.g., cardiac surgery requiring cardiopul-
monary bypass), or fasting, and termed NTI [33,52,53]. In mild or moderate illness, findings
include low T3 and high rT3 with normal TSH. If the illness is prolonged or severe, T4 declines,
due to decreased TSH secretion. During recovery from illness, TSH rises and may be transiently
elevated, leading to an increase in T4. NTI was initially postulated to be an adaptive response to
the metabolic demands of severe physiologic stress [54] but research shows that inflammatory
cytokines play a central role in disrupting the HPT axis [53,55,56].
In critically ill children, serum T4 levels inversely correlate with mortality [33,55,57,58]. Based on this,
multiple studies, mainly in adults, have investigated whether thyroid hormone therapy is beneficial
during acute illness. However, LT4 therapy does not generate normal T3 levels (conversion of T4
to T3 is impaired in NTI) nor does it reducemortality [33,55,59,60]. Treatment with LT3may possibly
benefit some parameters in patients undergoing cardiac surgery, but may not impact mortality
[33,55]. Data in children are sparse but one study of young children undergoing cardiac surgery
showed that treatment of patients <5 months of age with intravenous LT3 (Triostat) beginning at
surgery and continuing postoperatively had a shorter time to extubation and needed less inotropic
support than a placebo group [61]. However, LT3 therapy did not show benefit in infants >5months
to 2 years of age [61]. The data are not conclusive and further studies, especially in children, are
needed. In addition, adverse effects (such as arrythmia) are possible if LT3 treatment results in T3
toxicosis [55]. Clinical benefit of LT3 therapy in other scenarios has not been demonstrated [33].
There is debate about when or whether to obtain TFTs during inpatient hospitalization. A
retrospective study of hospitalized children (n = 20 907) found that 5.7% had TFTs obtained, of
which, 17.1% were abnormal [62]. The most common abnormality was SH (mildly elevated
TSH with normal thyroid hormone levels) followed by subclinical hyperthyroidism (TSH of
0.1–0.5 mIU/l with normal thyroid hormone levels). There was no correlation between TFTs and
the cause of hospitalization. Treatment with LT4 would have been considered in few cases.
Elevated TSH with low fT4 accounted for only 0.6% of abnormal TFTs, while low or normal TSH
with low fT4 accounted for just 1.7%. No patient with SH was treated with LT4 and all had normal
TSH on outpatient testing. Of the TFTs ordered by endocrinology (14.9%), 58.1% were drawn on
patients with new-onset type 1 diabetesmellitus (T1DM) and ~20%were abnormal. However, TSH
normalized in all during outpatient follow-up. These data indicate thatTFTs are often abnormal
during acute illness but rarely impact diagnosis or management [62].
TFTs are frequently obtained during evaluation of T1DM. One study examined TFTs in children at
diagnosis with T1DM and found that ~50% had abnormal TFTs, most commonly low T3 [63]. NTI
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was a more common cause than underlying thyroid autoimmunity. With insulin treatment, TFTs
normalized. However, patients with autoimmune thyroiditis (AIT) were more likely to develop
overt thyroid dysfunction. The authors recommend checking for thyroid antibodies at diagnosis
of T1DM rather than TFTs. Antibody status is then used to guide recommendations for subse-
quent TFT measurement.
Depression is associated with a spectrum of thyroid abnormalities, including low TSH, mildly
elevated TSH, low T3, elevated T4, elevated rT3, and a blunted TSH response to thyrotropin
releasing hormone (TRH), as well as positive antithyroid antibodies [64]. The pathophysiology is
not well understood and data in children are limited. A recent study of adolescents with depression
found increased TSH, normal fT4, and increased cortisol levels [65]. The data suggested the HPT
and adrenal axes were not tightly connected and seemed to function differently than in adults.
SH is common in adults with treatment-resistant depression [66,67]. A study of adolescents found
a higher prevalence of SH in those with depression compared to a cohort without mental health
disease [68]. In addition, teens with depressionweremore likely to have positive thyroid peroxidase
antibody but neither SH nor positive antibody correlated with the degree of depression.
Since both thyroid and psychiatric disorders may present with changes in cognition, mood, and/or
behavior, TFTs are frequently included during psychiatric intake [62,69,70]. However, the utility is
debated as true thyroid dysfunction appears to be rare [33,62,71,72] and abnormal TFTs often
normalize after discharge [62]. In a pediatric study of patients admitted for mood disorder, 6%
had elevated TSH but <1% had true thyroid disease [71]. Increased TSH was associated with
recent weight gain, treatment with benzodiazepines or lithium, irregular menstrual bleeding in
females, and a history of prior thyroid disease. The authors suggest TFTs should be obtained in
select patients whose history includes risk factors for thyroid dysfunction. Lithium impairs thyroid
hormone synthesis; therefore, TFTs should be monitored in patients on lithium. LT4 therapy
may be necessary. The hypothyroidism usually remits if lithium is discontinued. The presence of
goiter will inform thyroid treatment decisions since primary thyroid disorders (hypothyroidism and
hyperthyroidism) are typically associated with goiter.
Although the relationship between the H{T axis and mood disorders is not fully elucidated, a
variety of studies have examined T3, T4, TRH, or TSH treatment for depression in adults. Only
T3may have clinical benefit and only to accelerate response to treatment with tricyclic antidepres-
sants (but not SSRIs), or to augment antidepressant monotherapy [64]. The use of T3 in depres-
sion is currently at the discretion of the treating psychiatrist and not based on specific TFT results.
There are currently no data on the utility of T3 as part of a treatment regimen for depression in
pediatric patients.
Down syndrome
Children with DS are at high risk to develop thyroid disorders of broad spectrum including CH,
SH, overt hypothyroidism, HT, and Graves’ disease [73]. The clinical diagnosis of thyroid disor-
ders in DS can be difficult because clinical features of DS such as growth failure, umbilical hernia,
dry skin, hypotonia, and developmental delay can be confused with thyroid hormone deficiency
[74]. The American Academy of Pediatrics recommends routine screening for thyroid disorders
in DS beginning with the newborn screen and then at 6 and 12 months of age, followed by annu-
ally thereafter [73]. It is estimated that 10–32% of infants with DS and CH go undiagnosed due to
false-negative newborn screening results [75]. A retrospective review of 508 patients with DS
found that 20% of infants with CH were diagnosed after the newborn period but before 6 months
of age [76]. The authors suggested that an additional screen for thyroid disease should be
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performed between the newborn screen and the 6-month well-child visit in all children with DS
[76]. A recent study found that 13% of CH in DS was missed by the newborn screen and also
suggested more frequent testing for children with DS [77].
CH is more common in infants with DS than the general population with an incidence estimated
between 1:113–114 live births [78]. Approximately 70% require lifelong treatment for permanent
CH, while 30% are treated for transient hypothyroidism [77]. Thyroid hypoplasia is the most com-
mon cause of CH in DS, while ectopy and agenesis are rare [79]. Infants with DS and CH aremore
likely to have congenital heart disease and gastrointestinal malformations. Early LT4 treatment
(before age 2 years) is associated with significant improvements in growth and motor develop-
ment. When treated early, children with DS and TSH >5 mIU/l are significantly taller at 8 years
of age [80].
SH occurs in 7–40% of children with DS but is transient and self-limited in >70% of cases.
Spontaneous resolution is more common in the absence of goiter and thyroid autoimmunity.
To avoid unnecessary lifelong treatment, close follow-up and serial TFTs are recommended.
SH is not a precursor or predictor of permanent hypothyroidism later in life. If antithyroid anti-
bodies are present, TSH and fT4 levels should be monitored more frequently (every 3–6 months).
Treatment with LT4 is advised if the TSH rises above 10 mIU/l.
AIT is common in DS, resulting in both hypo- and hyperthyroidism. Antithyroid antibodies are
found with equal prevalence in 13–46% of males and females with DS [76,81,82]. HT is the
most common AIT in DS but family history of AIT is frequently absent. Furthermore, HT presents
at an earlier age in DS and commonly begins as SH that is more likely to progress to overt hypo-
thyroidism than in the general population [76,83]. Possible mechanisms for the association of AIT
with DS include: thymic atrophy; diminished expansion of T and B lymphocytes; altered expres-
sion of genes located on chromosome 21 that regulate immune function such as AIRE [84]; MHC
class II DQA 0301 alleles; and altered regulation of pro- and anti-inflammatory cytokines, perhaps
due to increased gene dose expression and enhanced autoimmune response [85].
Children with DS are more likely to transition from hypo- to hyperthyroidism than are children
without DS [86]. The mechanism is poorly understood and for that reason, routine monitoring
of TFTs and antibody testing are recommended for children with DS.
Graves' disease is also more common and without gender preference in DS compared to the
general population [82]. Symptoms present at a younger age and are frequently associated
with other autoimmune diseases and family history of autoimmune disease. Treatment response
to methimazole is usually favorable. Fortunately, compared to children without DS, relapse rates
after methimazole withdrawal are lower, and the need for surgery or radioactive iodine ablation is
reduced [87]. Life-long monitoring of thyroid function is recommended for all patients with DS to
facilitate early evaluation and treatment.
Obesity
Obesity affects 20% of children and adolescents in the USA, and TFTs are routinely performed as
thyroid hormone plays an important role in energy balance and regulation of metabolic rate [88].
However, abnormal TSH concentration (generally below the level expected for SH) is reported in
up to 23% of obese children [89–93]. In adults, serum TSH and leptin levels correlateindepen-
dently of BMI, suggesting an association between TSH signaling and energy balance [94].
Such alterations in TSH generally normalize with weight loss [89,90]. Evaluation of antithyroid
antibodies is indicated for goiter or a family history of AIT. By ultrasound, the thyroid of obese
Trends in Endocrinology & Metabolism, July 2022, Vol. 33, No. 7 529
Trends in Endocrinology &Metabolism
Outstanding questions
What is the optimal treatment for infants
with thyroid hormone resistance from
CH?
Is there a role for thyroid hormone
analogs in the treatment of obesity?
Are there metabolic parameters
that could assist in distinction of
hypothyroxinemia of prematurity from
central hypothyroidism?
children is hypoechoic, consistent with inflammation [91]. Cytokines, generated by peripheral
adipose tissue, are speculated to induce thyroid inflammation in the absence of AIT. In summary,
hyperthyrotropinemia is common in obese children and usually reversible with weight loss. In
randomized clinical trials, LT4 therapy for obese children failed to reduce BMI [95,96]. For this
reason, LT4 therapy is discouraged in the absence of AIT (see Outstanding questions).
Subclinical hypothyroidism
SH is defined as a mild elevation of serum TSH (generally <10 mIU/l), normal fT4 and T3, and
few or no signs or symptoms. Clinically, SH is difficult to diagnose as signs and symptoms are
nonspecific. The most common causes are HT, medications, syndromic (i.e., DS), or pseudo-
hypoparathyroidism [97]. Medications including amiodarone, antiretrovirals, and anticonvulsants
(phenobarbital, phenytoin, carbamazepine, and valproic acid) commonly affect the thyroid resulting
in SH [97]. The mechanisms are poorly understood but the effects are transient and TSH normal-
izes when medications are discontinued. Serum TFTs that suggest SH also result from laboratory
interference (recent blood transfusion, immunization, autoimmune disease, and monoclonal
antibody therapy). When that occurs, TFTs should be repeated in 4–8 weeks to confirm SH.
The probability that SH will progress to overt hypothyroidism in children with HT is increased for
those with higher TSH, younger age, higher antithyroid antibody titers, history of another autoim-
mune disease, or presence of a genetic syndrome [98,99]. In otherwise healthy children who lack
antithyroid antibodies, SH is considered benign and with good prognosis. A 5-year longitudinal
study showed that 74% of children with SH normalized over time, while only 9% required
LT4 therapy [99]. LT4 was more commonly required for those of female sex and those with
TSH >7 .5 mIU/l [99]. TSH is less likely to normalize in children with SH and HT (20%) compared
to those with SH alone (48%) [98]. The long term effects of SH on growth and cardiovascular
outcomes are still under investigation. Mild SH is associated with normal linear growth, bone
health, and neurodevelopment. However, recent studies show that serum TSH >75th percentile
is associated with higher cardiometabolic risk, insulin resistance, and nonalcoholic fatty liver
disease independent of BMI [100].
Conclusion
LT4, adjusted to maintain a normal TSH level, is the preferred method for treatment of hypothy-
roidism in most children. Although this is generally applicable, there are subsets of children for
whom the diagnosis and treatment of hypothyroidism are problematic. Serial measures of thyroid
function help to identify cases in which disease is transient or may require alternate thyroid
hormone preparations.
Declaration of interests
No interests are declared.
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