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Acquired hypothyroidism in childhood and adolescence
Author
Stephen LaFranchi, MD
Section Editors
Douglas S Ross, MD
Mitchell Geffner, MD
Deputy Editor
Alison G Hoppin, MD
Disclosures:Stephen LaFranchi, MD Nothing to disclose. Douglas S Ross, MD
Grant/Research/Clinical Trial Support: Genzyme [thyroid cancer (rhTSH)].
Mitchell Geffner, MD Grant/Research/Clinical Trial Support: Genentech; Ipsen;
NovoNordisk; Pfizer; Versartis (for all-growth [somatropin]). Consultant/Advisory
Boards: Daiichi-Sankyo (T2DM [Colesevelam]); Endo (puberty [Histrelin
acetate]); Ipsen (growth [Mecasermin (IGF-I) Increlex]); Pfizer (growth
[Somatropin (GH) Genotropin]). Alison G Hoppin, MD Employee of UpToDate,
Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial
group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to
support the content. Appropriately referenced content is required of all authors
and must conform to UpToDate standards of evidence.
Conflict of interest policy
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Mar 2014. | This topic last updated: Jun 12,
2013.
INTRODUCTION Hypothyroidism is the most common disturbance of thyroid
function in children; acquired hypothyroidism is most often caused by
autoimmune thyroiditis [1]. As in adults, acquired hypothyroidism can be
caused by both thyroid disease (primary hypothyroidism) and hypothalamicpituitary disease (central hypothyroidism); furthermore, primary
the optic chiasm, it rarely causes symptoms or signs (in contrast to a pituitary
tumor or craniopharyngioma), and it is reversible with T4 therapy. Thus,
primary hypothyroidism must be excluded in any child with an enlarged sella
turcica.
ETIOLOGY The causes of hypothyroidism in children are listed in the table
(table 1). They are similar to those in adults, but iatrogenic hypothyroidism is
relatively less common. Most can be identified from the history and physical
examination. (See "Disorders that cause hypothyroidism".)
Chronic autoimmune (Hashimotos) thyroiditis The most common cause of
hypothyroidism in children is chronic autoimmune (Hashimoto's) thyroiditis,
resulting in either thyroid atrophy or goiter. It is more common in girls than
boys and in whites than blacks. Among all children with this disorder, euthyroid
goiter is more common than hypothyroidism [3,6,7]. The changes in the thyroid
gland may not be detectable on physical examination. (See "Congenital and
acquired goiter in children", section on 'Chronic autoimmune (Hashimoto's)
thyroiditis'.)
In the National Health and Nutrition Examination Survey (NHANES III) from
1988 to 1994, 6.3 percent of adolescents (12 to 19 years of age) had positive
anti-thyroglobulin antibodies (Tg Ab) and 4.8 percent had positive anti-thyroid
peroxidase antibodies (TPO Ab) [8]. The likelihood of detecting Tg Ab and TPO
Ab was two times greater in female versus male adolescents. The incidence of
antithyroid antibodies was highest in Hispanic-American adolescents and
lowest in black non-Hispanic adolescents; non-Hispanic whites had an
incidence between these two groups. Approximately 2 percent of surveyed
adolescents had a serum TSH >4.5 mU/L, a value indicating hypothyroidism.
The natural history of euthyroid autoimmune thyroiditis was illustrated in a
report of 160 children (mean age 9.1 years) [9]. Among 105 children with
elevated thyroid antibodies and normal thyroid stimulating hormone (TSH)
followed for five years, 65 percent remained euthyroid, 10 percent developed
mild elevation in serum TSH concentrations (typically 5 to 10 mU/L), and 26
percent developed serum TSH levels twofold above the upper limit of normal
(usually >10 mU/L). In a subsequent study of 87 children with elevated thyroid
antibodies and mild TSH elevation (5 to 10 mU/L) followed for three years, 41
percent reverted to euthyroidism (TSH <5 mU/L), 20 percent had persistent
mild TSH elevation (5 to 10 mU/L), while 39 percent developed more overt
hypothyroidism (TSH >10 mU/L) [10].
Pathogenesis Different mechanisms can be responsible for thyroid atrophy or
goiter formation in these patients [11]. (See "Pathogenesis of Hashimoto's
thyroiditis (chronic autoimmune thyroiditis)".)
Some children diagnosed with Graves disease who are treated with antithyroid
drugs have relatively rapid resolution of their hyperthyroidism, typically within
six months of diagnosis. After discontinuation of antithyroid drug treatment,
they remain hypothyroid. In hindsight, such children are recognized to have
Hashitoxicosis rather than Graves disease [42]. Other children with Graves
disease who are treated with antithyroid drugs may achieve a true remission,
remaining euthyroid after discontinuation of antithyroid drugs. About 10
percent of such children later become hypothyroid, caused by chronic
autoimmune thyroiditis, either with destruction of the thyroid or due to
production of a TSH receptor blocking antibody [43].
Late-onset congenital hypothyroidism Late-onset congenital hypothyroidism
that develops during childhood may appear to be acquired hypothyroidism.
This may occur with some forms of thyroid dysgenesis, such as an ectopic
gland, or with inborn errors of thyroid hormone synthesis (dyshormonogenesis).
Children with high TSH and normal free T4 during neonatal screening are more
likely to have subclinical hypothyroidism during early childhood [44]. (See
"Clinical features and detection of congenital hypothyroidism", section on
'Etiology' and "Reduced sensitivity to thyroid hormone".)
Williams syndrome Subclinical hypothyroidism is common among young
patients with Williams syndrome (caused by a deletion of genes in the 7q11.23
region, including elastin). In a report of 92 patients with Williams syndrome, 32
percent had subclinical hypothyroidism; none had thyroid autoantibodies [45].
In most cases, thyroid function improves with age. (See "Williams-Beuren
syndrome" and "Microdeletion syndromes (chromosomes 1 to 11)", section on
'7q11.23 deletion syndrome (Williams syndrome)'.)
Hepatitis C infection In a report of 36 children with chronic hepatitis C
infection acquired from their mother, 11.1 percent had subclinical
hypothyroidism [46]. This did not appear to be autoimmune thyroiditis because
antithyroid antibodies were negative.
Hemangiomas Hypothyroidism can occur in young children with large
hemangiomas of the liver [47]. The tumors contain very high levels of type 3
deiodinase activity, which catalyzes deiodination of T4 to reverse
triiodothyronine (rT3) and triiodothyronine (T3) to diiodothyronine (T2),
resulting in low serum T4 and T3 concentrations. Thyroid secretion is increased,
but not sufficiently to compensate for the large increase in T4 and T3
degradation.
Thyroid hormone resistance Children with generalized thyroid hormone
resistance may have some tissue-specific clinical manifestations of
hypothyroidism if they cannot sufficiently increase their serum thyroid hormone
8AM:4PM ratio >1.5), when serum free T4 is in the lower third of the normal
range. (See "Laboratory assessment of thyroid function" and "Central
hypothyroidism".)
Chronic autoimmune thyroiditis can be confirmed as the cause of
hypothyroidism by measuring antithyroid antibodies, best done by measuring
TPO Ab. Approximately 85 to 90 percent of children with chronic autoimmune
thyroiditis have high serum TPO Ab concentrations, while 30 to 50 percent have
positive Tg Ab levels [55]. In one study, 8 of 83 children (9.2 percent) with
autoimmune thyroiditis had positive TSH receptor blocking antibodies; all had
associated overt hypothyroidism [56].
Pendrin, an apical protein on thyroid follicular cells, is another antigen in
autoimmune thyroid disease. Pendrin antibodies were found in 81 percent of
patients with autoimmune thyroid disease compared with 9 percent of controls
[57]. Measurement of pendrin antibodies is not yet commercially available.
Other studies, such as thyroid ultrasonography or radionuclide scanning, are
rarely indicated in children with primary hypothyroidism. In a study of 105
children with antibody positive Hashimoto's thyroiditis, only one-third showed
typical ultrasound changes (scattered hypo- and hyperechogenicity) at
diagnosis [58]. During 7 to 14 month follow-ups, more than half of the
remaining children developed typical ultrasound changes. Children with central
hypothyroidism should undergo cranial imaging with contrast, preferably
magnetic resonance imaging, and tests for other pituitary hormone
deficiencies. If the patient has a markedly asymmetric goiter or a prominent
nodule, or a smaller nodule that enlarges during follow-up, fine-needle
aspiration biopsy is indicated. (See "Diagnosis of hypopituitarism" and "Thyroid
nodules and cancer in children".)
The diagnostic studies that should be performed in children suspected of
having a late-onset form of congenital hypothyroidism are reviewed elsewhere.
(See "Clinical features and detection of congenital hypothyroidism".)
Skeletal maturation is delayed, and therefore bone age, like height age, is less
than chronologic age [59]. Indeed, because bone age increases so little after
the onset of hypothyroidism, it may indicate the age of onset.
TREATMENT AND PROGNOSIS Levothyroxine (T4) is the treatment of choice
in children with hypothyroidism. The goals of treatment are to restore normal
growth and development, including pubertal development. There is some
controversy about the need to treat children with mild subclinical
hypothyroidism, characterized by TSH elevations between 6 and 10 mU/L.
There is general agreement to treat children with subclinical hypothyroidism
and TSH levels >10 mU/L, to prevent any subtle effects on growth and
development. (See 'Diagnosis' above.)
T4 dose Children clear T4 more rapidly than adults; as a result, the daily
replacement dose on a weight basis is higher:
Age 1 to 3 years 4 to 6 mcg/kg body weight
Age 3 to 10 years 3 to 5 mcg/kg
Age 10 to 16 years 2 to 4 mcg/kg
Alternatively, the replacement dose can be calculated as a function of body
surface area, in which case the dose at any age is approximately 100
mcg/m2/day. Body surface area can be determined from height and weight
using a calculator (calculator 1).
In children with primary hypothyroidism, the recommended target range for
TSH is in the lower half of the reference range (optimally 0.5 to 2.0 mU/L) and
for T4 or free T4 is in the upper half of the reference range [60]. The optimal T4
range is between 9 and 13 ug/dL (116 to 167 nmol/L). Because the normal free
T4 reference range varies according to the assay method, clinicians need to
determine the range for their specific laboratory. As an example, if the normal
free T4 reference range is 0.6 to 1.8 ng/dL (8 to 23 pmol/L), the corresponding
optimal free T4 range would be between 1.2 and 1.8 ng/dL (15 to 23 pmol/L).
In children with central hypothyroidism, only measurement of serum free T4 or
T4 is useful for dosage monitoring. The target serum free T4 or T4 in these
children should be the same as in children with primary hypothyroidism.
Adult height may be diminished among children treated just before or during
puberty as compared with children treated earlier [61]. Although
hypothyroidism may cause weight gain, this is typically attributable to fluid
retention rather than adiposity. Treatment does not lead to substantial changes
in weight or body mass index for most children [62].
For most children, therapy should be initiated with a T4 dose in the middle of
the appropriate range for age. Severe long-standing hypothyroidism is
associated with a significant height deficit after treatment, ranging from 8 to 14
cm in one study, and use of a lower initial dose of T4 has been suggested as a
strategy to avoid overly rapid acceleration of skeletal maturation, which could
lead to loss of adult height [59]. However, the efficacy of this strategy is
challenged by a study that reported no correlation between slow or rapid
correction of hypothyroidism and skeletal maturation [63]. In the same study,
use of other growth-promoting therapies such as gonadotropin-releasing
hormone agonists and growth hormone also failed to improve adult height
outcome. Children with more chronic (or severe) hypothyroidism also are at
higher risk of poorer school achievement and hyperactivity during treatment
[64].
Rallison ML, Dobyns BM, Meikle AW, et al. Natural history of thyroid
abnormalities: prevalence, incidence, and regression of thyroid diseases in
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Demirbilek H, Kandemir N, Gonc EN, et al. Hashimoto's thyroiditis in children
and adolescents: a retrospective study on clinical, epidemiological and
laboratory properties of the disease. J Pediatr Endocrinol Metab 2007; 20:1199.
Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid
antibodies in the United States population (1988 to 1994): National Health and
Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;
87:489.
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Radetti G, Maselli M, Buzi F, et al. The natural history of the normal/mild
elevated TSH serum levels in children and adolescents with Hashimoto's
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Matsuura N, Konishi J, Yuri K, et al. Comparison of atrophic and goitrous autoimmune thyroiditis in children: clinical, laboratory and TSH-receptor antibody
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Pueschel SM, Pezzullo JC. Thyroid dysfunction in Down syndrome. Am J Dis Child
1985; 139:636.
Grueiro de Papendieck L, Iorcansky S, Coco R, et al. High incidence of thyroid
disturbances in 49 children with Turner syndrome. J Pediatr 1987; 111:258.
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Topic 5838 Version 14.0
GRAPHICS
Causes of hypothyroidism in children and adolescents
Chronic autoimmune (Hashimoto's) thyroiditis
Iodine
Deficiency
Excess ingestion (eg, nutritional supplements, drugs [amiodarone,
expectorants])
Drugs
Antithyroid drugs (eg, methimazole, propylthiouracil)
Anticonvulsant drugs (eg, phenytoin, phenobarbital, valproate)
Tyrosine kinase inhibitors
Interferon alfa
Thyroid injury
External radiation therapy
Radioactive iodine treatment
Thyroidectomy
Infiltrative diseases
Langerhans cell histiocytosis
Cystinosis
Late-onset congenital hypothyroidism
Williams syndrome
Hemangiomas
Thyroid hormone resistance
Central hypothyroidism (hypothalamic-pituitary disease)
Graphic 55456 Version 9.0
Normal ranges for thyroid function tests in infants and children
Age
Free
T4*(ng/dL
)
T4(g/
dL)
Free
T3(pg/dL
)
T3(ng/
dL)
TSH(mU
/L)
TBG(mg/
dL)
1.4-9.4
Cord
blood
0.9-2.2
7.813.1
20-240
15-75
2.2-10.7
1 to 4
days
2.2-5.3
9.320.9
180-760
100740
2.7-26.5
4 to 30
days
0.9-3.4
8.021.8
293-508
105387
1.2-13.1
1.9-4.5
1 to 12
months
0.9-2.3
7.215.7
267-521
105245
0.6-7.3
1.9-4.4
1 to 5
years
0.8-1.8
6.413.5
273-495
105269
0.7-6.6
1.6-4.2
6 to 10
years
1.0-2.1
6.012.8
273-469
94-241
0.8-6.0
1.4-3.7
11 to 18
years
0.8-1.9
4.712.4
267-462
80-210
0.6-5.8
1.2-2.9
>18
years
0.9-2.5
5.310.5
210-440
70-204
0.4-4.2
1.5-3.4
* Because the normal free T4 reference range varies according to the assay
method, clinicians need to determine the range for their specific laboratory,
which may differ from the data presented in the table.
Data adapted from the following sources:
Nelson JC, Clark SJ, Bonut DL, et al. Age-related changes in serum free
thyroxine during childhood and adolescence. J Pediatr 1993; 123:899.
Elmlinger MW, Khnel W, Lambrecht HG, et al. Reference intervals from birth to
adulthood for serum thyroxine (T4), triiodothyronine (T3), free T3, free T4,
thyroxine binding globulin (TBG) and thyrotropin (TSH). Clin Chem Lab Med
2001; 39:973.
Mutlu M, Karagzel G, Alyaziciolu Y, et al. Reference intervals for thyrotropin
and thyroid hormones and ultrasonographic thyroid volume during the neonatal
period. J Matern Fetal Neonatal Med 2012; 25:120.
Strich D, Edri S, Gillis D. Current normal values for TSH and FT3 in children are
too low: evidence from over 11,000 samples. J Pediatr Endocrinol Metab 2012;
25:245.
Lem AJ, de Rijke YB, van Toor H, et al. Serum thyroid hormone levels in healthy
children from birth to adulthood and in short children born small for gestational
age. J Clin Endocrinol Metab 2012; 97:3170.
Esoterix (Endocrine Sciences).
Graphic 60095 Version 8.0
Disclosures
Disclosures:Stephen LaFranchi, MD Nothing to disclose. Douglas S Ross, MD
Grant/Research/Clinical Trial Support: Genzyme [thyroid cancer (rhTSH)].
Mitchell Geffner, MD Grant/Research/Clinical Trial Support: Genentech; Ipsen;
NovoNordisk; Pfizer; Versartis (for all-growth [somatropin]). Consultant/Advisory
Boards: Daiichi-Sankyo (T2DM [Colesevelam]); Endo (puberty [Histrelin
acetate]); Ipsen (growth [Mecasermin (IGF-I) Increlex]); Pfizer (growth
[Somatropin (GH) Genotropin]). Alison G Hoppin, MD Employee of UpToDate,
Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial
group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to
support the content. Appropriately referenced content is required of all authors
and must conform to UpToDate standards of evidence.
Conflict of interest policy