Thyroid and Other Autoimmune Diseases with Emphasis on Type 1 Diabetes Mellitus and Turner Syndrome

Full text

Diseases of the Thyroid in Childhood and Adolescence

Pediatric and Adolescent
Medicine
Vol. 11
Series Editors
Wieland Kiess, Leipzig
David Branski, Jerusalem

Diseases of the
Thyroid in Childhood
and Adolescence
Basel · Freiburg · Paris · London · New York ·
Bangalore · Bangkok · Singapore · Tokyo · Sydney
Volume Editors
Gerasimos E. Krassas, Thessaloniki
Scott A. Rivkees, New Haven, Conn.
Wieland Kiess, Leipzig
62 figures, 6 in color, and 42 tables, 2007

Prof. Gerasimos E. Krassas Prof. Wieland Kiess
Department of Endocrinology, University Hospital for Children and Adolescents
Diabetes and Metabolism University of Leipzig, Leipzig, Germany
Panagia General Hospital,
Thessaloniki, Greece
Prof. Scott A. Rivkees
Yale Pediatric Thyroid Center
Department of Pediatrics
Yale University School of Medicine
New Haven, Conn., USA
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© Copyright 2007 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)
www.karger.com
Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel
ISSN 1017–5989
ISBN-10: 3–8055–8205–6
ISBN-13: 978–3–8055–8205–6
Library of Congress Cataloging-in-Publication Data
Diseases of the thyroid in childhood and adolescence / volume editors,
Gerasimos E. Krassas, Scott A. Rivkees, Wieland Kiess.
p. ; cm. – (Pediatric and adolescent medicine, ISSN 1017–5989 ; v.11)
Includes bibliographical references and index.
ISBN-13: 978-3-8055-8205-6 (hard cover : alk. paper)
ISBN-10: 3-8055-8205-6 (hard cover : alk. paper)
1. Thyroid gland–Diseases. 2. Pediatric endocrinology. I. Krassas, Gerasimos E.
II. Rivkees, Scott A. III. Kiess, W. (Wieland) IV. Series.
[DNLM: 1. Thyroid Diseases. 2. Adolescent. 3. Child.
W1 PE163HL v.11 2007 / WK 200 D61095 2007]
RJ420.H88D57 2007
618.92⬘44–dc22
2006031665

V
Contents
VII Preface
Krassas, G.E. (Thessaloniki); Rivkees, S.A. (New Haven, Conn.); Kiess, W. (Leipzig)
1 Ontogenesis and Anatomy of the
Hypothalamic-Pituitary-Thyroid Axis
Tsoumalis, G.; Tsatsoulis, A. (Ioannina)
25 Thyroid Disease during Pregnancy
Lazarus, J.H. (Cardiff)
44 Thyroid Function in the Newborn and Infant
Spiliotis, B.E. (Patras)
56 Pediatric Aspects of Thyroid Function and Iodine
Knobel, M.; Medeiros-Neto, G. (Sao Paulo)
80 Thyroid Hormone Transport and Actions
Feldt-Rasmussen, U.; Rasmussen, Å.K. (Copenhagen)
104 The Thyroid and Autoimmunity in Children and Adolescents
Weetman, A.P. (Sheffield)
118 Congenital Hypothyroidism
Karges, B. (Ulm); Kiess, W. (Leipzig)
128 Newborn Screening, Hypothyroidism in Infants,
Children and Adolescents
Büyükgebiz, A. (Istanbul)
142 Resistance to Thyroid Hormone in Childhood
Bakker, O. (Amsterdam)
154 Pendred Syndrome
Kassem, S.; Glaser, B. (Jerusalem)

169 Treatment of Hyperthyroidism Due to Graves’Disease in Children
Rivkees, S.A. (New Haven, Conn.)
192 Thyroid-Associated Ophthalmopathy in Juvenile Graves’
Disease: Clinical, Endocrine and Therapeutic Aspects
Krassas, G.E.; Gogakos, A. (Thessaloniki)
210 Differentiated Thyroid Carcinoma in Pediatric Age
Wiersinga, W.M. (Amsterdam)
225 Imaging of the Normal and Affected Thyroid in Childhood
Bennedbæk, F.N. (Herlev); Hegedüs, L. (Odense)
270 Thyroid and Other Autoimmune Diseases with Emphasis on Type 1
Diabetes Mellitus and Turner Syndrome
Kapellen, T.; Galler, A.; Pfäffle, R.; Kiess, W. (Leipzig)
278 Thyroid and Trace Elements in Children and Adolescents
Kahaly, G.J. (Mainz)
287 Author Index
288 Subject Index
Contents VI

Preface
The aim of this volume is to present the latest global knowledge of the thy-
roid in children and adolescents. The book consists of 16 chapters starting with
the ontogenesis and anatomy of the hypothalamic-pituitary-thyroid axis and
ending with the thyroid and trace elements which affect thyroid function in this
age group. Special emphasis has been placed on including novel information
regarding specific topics of thyroid function.
Distinguished experts in the fields of pediatric endocrinology, thyroidol-
ogy and molecular endocrinology review the present knowledge and advances
in pediatric thyroidology. Topics ranging from thyroid disease during pregnancy
to iodine deficiency and excess in childhood, thyroid autoimmunity in pediatric
age, hypothyroidism and hyperthyroidism in pediatric age, thyroid eye disease
in childhood, thyroid cancer in pediatric age, and many others are included.
We believe that this book will become one of the main reference sources for
pediatricians and endocrinologists and provide the reader with further insights
into the pathophysiology, clinical presentation and treatment of thyroid disease.
We wish to thank the whole team at Karger publishers as well as our col-
leagues and the many authors who did the hard work and from whom we have
learned a lot. They all approached their assignments with tremendous enthu-
siasm, met their short deadlines extremely well, and dealt with suggestions and
comments with promptness and restraint. We thank them cordially for their
efforts. We hope the reader is equally enthusiastic.
Gerasimos E. Krassas, Thessaloniki, Greece
Scott A. Rivkees, New Haven, Conn., USA
Wieland Kiess, Leipzig, Germany
VII

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 1–24
Ontogenesis and Anatomy of the
Hypothalamic-Pituitary-Thyroid Axis
Georgios Tsoumalis, Agathocles Tsatsoulis
Department of Endocrinology, University of Ioannina, Ioannina, Greece
Historical Note
Aristotle originally stated that the brain was necessary for the maintenance
of body integrity by regulating food intake and behavior in relation to body
temperature. According to Aristotle, the pituitary was the organ through which
one of the four essential humors of the body, the phlegm or pituita, passed from
the brain into the body.
Five hundred years later Galen of Pergamon described the anatomy of the
third ventricle region, the location of the pituitary gland inside the sella turcica
embodied in a vascular network, the rete mirabilis, and observed nerves adjoin-
ing the ‘soft flesh’ in the neck, i.e. the thyroid gland [1]. He first proposed that
the energy of the body (the vital spirit) was carried through the arteries at the
level of the rete mirabilis, where it was transformed into nerve impulse (the ani-
mal spirit), eventually transferred by the nerves to the periphery of the body,
‘glands’ included, raising implicitly the possibility for a nervous influence over
the thyroid activity. The Galenic model remained virtually unaltered up to the
beginning of the 14th century, when the anatomist Mondino de’ Liuzzi sug-
gested that the thyroid gland interacted with the heat of the blood present in the
internal carotid arteries due to their anatomical relation with the thyroid. He
proposed that the third ventricle serves as an ‘integrator’ of body functions [1].
In the 19th century, Rathke studied the development of the pituitary
(hypophysis) and showed that it consisted of two parts, the anterior pituitary
(or adenohypophysis) and the posterior pituitary (or neurohypophysis). The
importance of the hypothalamic-pituitary region influenced the work of some
of the most famous Renaissance artists including Leonardo da Vinci, and
Michelangelo Buonarroti. Luigi Galvani described that the peripheral nerves

Tsoumalis/Tsatsoulis 2
were carrying electrical impulses supporting the Galenic idea that autonomic
fibers might influence the secretion of ‘humors’ from peripheral glands such as
thyroid gland. The thyroid gland had not been identified until the Renaissance.
The regulation of energy body stores and temperature by the hypothalamic-
pituitary-thyroid axis was suggested again by Claude Bernard in the late 1800s.
The current term ‘hypothalamus’, however, was not actually introduced until
1893 by the Swiss anatomist, Wilhelm His. From these observations, Harris
developed the concept of the control of the adenohypophysis by humoral fac-
tors produced in the hypothalamus. This led to the award of the Nobel Prize to
Schally and Guillemin, who independently isolated the structures of some of
these so-called ‘Releasing hormones’.
The Hypothalamic-Pituitary-Thyroid Axis
Thyroid hormones play an important role in normal growth and develop-
ment of the maturing human. In the adult, thyroid hormones maintain metabolic
homeostasis by regulating oxygen consumption, body weight and intermediate
metabolism. Thyroid function is under hypothalamic-pituitary control. Thus,
thyroid hormones are produced by the thyroid gland in response to stimulation
by thyroid-stimulating hormone (TSH) produced by the anterior pituitary. TSH,
in turn is regulated by the hypothalamic peptide, thyrotropin-releasing hormone
(TRH). The function of the entire complex is modified by the availability of the
thyroid hormones in a typical negative feedback manner leading to the concept
of a functional unit, the hypothalamic-pituitary-thyroid (HPT) axis.
This chapter focuses on the ontogenesis and functional anatomy of the
hypothalamic-pituitary system first, and the thyroid gland itself. Emphasis is
placed on the molecular aspects regarding the morphogenesis of the function-
ally linked endocrine glands constituting the HPT axis.
The Hypothalamic-Pituitary System
Ontogenesis
The components and anatomical organization of the hypothalamus and
pituitary are intimately coupled reflecting their close functional relationship [2].
The hypothalamic-pituitary system is derived from two separate ectodermal
components. The first is Rathke’s pouch, a dorsal outgrowth of the buccal
cavity that detaches itself and develops into the anterior pituitary. The second
component, the infundibulum, develops as a downgrowth from the ventral
diencephalon forming the floor of the third ventricle and developing into the

Ontogenesis of the HPT Axis 3
pituitary stalk and the posterior lobe of the pituitary gland. The remainder of
this ventral neuroectoderm forms the median eminence, while the hypothalamic
nuclei differentiate in its lateral walls to form the sides of the third ventricle.
The hypothalamus emerges from the ventral diencephalon, during the 6th week
of gestation in humans and between embryonic (E) days E-11 and E-18 in rats.
The anterior pituitary appears at about day E-8.5 and detaches from the ecto-
derm at E-12.5. Thus, the pituitary gland originates from two embryonic tis-
sues. The anterior lobe (adenohypophysis) is derived from the oral ectoderm
and the posterior lobe (neurohypophysis) from the neural ectoderm. However,
during this process there is a direct association between the neuroectoderm of
the diencephalon and Rathke’s pouch. The close apposition of these tissues sug-
gests that cell to cell contact and tissue interactions may be important for their
determination and differentiation. Indeed, recent studies indicated that several
genes expressed in the ventral diencephalon are involved in the development of
Rathke’s pouch, providing evidence that the infundibulum has a critical role in
pituitary organogenesis [3]. During pituitary organogenesis, signaling mole-
cules and transcription factors are expressed in overlapping but distinct spatial
and temporal patterns controlling pituitary development as well as cell determi-
nation and specification. As mentioned earlier, the primordium of the anterior
pituitary, Rathke’s pouch can be identified by the third week of gestation in
humans. It forms an upward invagination of the oral ectoderm that comes in
contact with the neuroectoderm of the primordium of the ventral hypothalamus.
Eventually, cell proliferation within Rathke’s pouch and cell differentiation
results in the formation of the anterior pituitary lobe that becomes populated
by highly differentiated cell types. Ultimately, transcription factors are also
involved in the cell-specific expression of the gene products of these cells, the
pituitary hormones.
Functional Anatomy
Hypothalamic Nuclei
During development of the hypothalamus, neurosecretory cells are orga-
nized into several nuclei, including the paraventricular, supraoptic and arcuate
nuclei. Functionally, two different neurosecretory systems are organized in the
hypothalamus. One is composed of the supraoptic and paraventricular nuclei
formed of magnocellular neurons, whose axons migrate into the posterior lobe
of the pituitary gland. The other group, referred to collectively as the hypothalamic-
hypophysiotropic nuclei, is formed of parvocellular neurons and synthesizes
the hypophysiotropic neuropeptides. The neurons of this region terminate in the
median eminence, in close proximity to the capillaries of its primary plexus and
release neurosecretory peptides into the hypothalamic-pituitary portal venous
system.

Tsoumalis/Tsatsoulis 4
TRH-secreting neurons release TRH, a tripeptide which is synthesized as a
pre-pro TRH in the hypothalamus. The gene for TRH in humans is on chromo-
some 3. The TRH neuron bodies are densely innervated by catecholamine and
NPY-containing axons, which also regulate the secretion of the pre-pro TRH
molecule. Somatostatin-containing axons regulate in a negative manner the
secretion of TRH. Regulation of the synthesis and processing of pre-pro TRH
appears to be tightly controlled. Apart from its known actions on TSH and PRL
secretion, TRH influences cell division and differentiation in the pituitary
and may also be critical in development. In fetal rat pituitary cells in vitro, TRH
has been shown to influence the differentiation of thyrotrophs, gonadotrophs
and lactotrophs [4]. In vivo, TRH has a mitogenic effect on thyrotrophs and
somatotrophs.
After its secretion, TRH binds to a specif ic G-protein coupled receptor in
the plasma membrane of the thyrotrophs to induce the synthesis and release of
TSH, and in this way the production of thyroid hormones. TRH may also induce
the release of prolactin from lactotroph cells in the anterior pituitary.
Anterior Pituitary
In the adult, the pituitary gland lies in a bony cavity, the sella turcica or
pituitary fossa, in the sphenoid bone. The human adult pituitary gland weighs
about 0.5 g, but this can double during puberty or pregnancy. The anterior pitu-
itary accounts for about three quarters of its weight. The pituitary is connected
to the hypothalamus by the pituitary stalk which carries axons for the posterior
lobe as well as blood vessels for the anterior lobe. Blood flows from the primary
capillary plexus in the median eminence down the portal veins to the sinusoidal
vessels in the anterior pituitary.
The secretory cells of the anterior pituitary are arranged in cords separated
by the sinusoidal capillaries arising from the hypophyseal portal vessels. Using
light-microscopy techniques, the cells of the anterior pituitary are classif ied as
chromophobes (poorly stained) and chromophils (well stained), which are fur-
ther subdivided into those that stain with acid dyes (acidophilic) and those that
stain with basic dyes (basophilic). Using immunocytochemical stains for
particular hormones, acidophilics can be divided into two subgroups, the soma-
totrophs, which secrete GH and the lactotrophs which produce prolactin. The
basophilics can be divided into three populations of cells, the gonadotrophs
producing LH and FSH, the corticotrophs, producing ACTH and the thyro-
trophs producing TSH.
TSH is a 118 amino acid glycoprotein composed of two noncovalently
bound and subunits. The gene for the subunit is in chromosome 6 and the
gene for the  subunit in chromosome 1 [5]. The subunit is common among
glycoprotein hormones TSH, LH, FSH and hCG, whereas the subunit is

Ontogenesis of the HPT Axis 5
specific for the TSH molecule being responsible for its biologic and immuno-
logic specificity.
Pituitary Organogenesis – Molecular Aspects
Morphogenic Signals Involved in Early Pituitary Development
The development of the anterior pituitary depends on the competency of
the oral ectoderm to respond to inducing signals from the neural epithelium, the
ventral diencephalon. One of the early extrinsic signals required for the initial
commitment of cells of the oral ectoderm to form the pituitary gland is the bone
morphogenic protein (Bmp-4) signal from the ventral diencephalon. Members
of the fibroblast growth factor (Fgf) family (Fgf-8 and Fgf-10) and Wnt-5are
also expressed in the ventral diencephalon in distinct overlapping patterns with
Bmp-4 to control pituitary proliferation and positional determination of pitu-
itary cell lineage [6].
Fgf signaling plays an instructive role by inducing the gene encoding the
LIM homeodomain transcription factor Lhx3/P-Lim which is required for pro-
gression of pituitary development beyond the initial invagination of Rathke’s
pouch [7]. Bmp-4 is also required for continued organ development after pouch
formation. These extrinsic ventral diencheplalic signals are required for initial
organ commitment, proliferation and progression. Subsequent patterning of
Rathke’s pouch is determined by intrinsic and ventral mesenchymal signals,
including Bmp-2 and Wnt-4 expressed in the developing gland. These, together
with sonic-hedgehog (Shh) establish the positional identity and stimulate pro-
liferation of specific ventral cell types.
The ventral →dorsal Bmp-2 signals and the dorsal →ventral Fgf-8
signals appear to create opposing activity gradients that dictate the expression
of specific transcription factors underlying cell lineage specif ication. Thus,
the Fgf-8 gradient determines the dorsal cell phenotypes and dorsally exp-
ressed transcription factors, whereas Bmp-2 controls the expression of differ-
ent, ventrally expressed pituitary transcription factors required for terminal
differentiation of ventral cell types [8]. However, for progression of terminal
differentiation of pituitary cell types, attenuation of Bmp signaling is also
required.
Transcription Factors Controlling Early Pituitary Development and
Pituitary Cell Type Determination
The transient signaling gradients result in the induction of expression of
transcription factors in spatially overlapping patterns, which are thought to be
cell-autonomous determinants of pituitary cell fate. These factors may act as
molecular memory of prior signals in the positional determination of specific
cell types. They include members of the LIM homeodomain family of transcription

Tsoumalis/Tsatsoulis 6
factors expressed in Rathke’s pouch such as Lhx-3, Lhx-4 and Isl-1. These fac-
tors appear to control the earliest phases of pituitary development [9].
Two pituitary homeobox (Pitx) genes are expressed throughout the pitu-
itary, with distinct overlapping patterns of expression. Pitx-1 interacts with the
pituitary-specific POU domain protein Pit-1 and is expressed in the early stages
of pituitary organogenesis in the oral ectoderm. Targeted disruption of Pitx-1
leads to decreased expression of terminal differentiation markers of gonadotrophs
and thyrotrophs [10]. The Pitx-2 gene appears to collaborate with Lhx-3 to
regulate the same pituitary specific genes. Both factors act synergistically to
activate the expression of the subunit gene. Thus, the induction of Lhx-3
expression in response to infundibular Fgf signals is a critical step in the selec-
tion of oral ectoderm for development into the pituitary gland and it acts syner-
gistically with Pitx-2 to direct the expression of pituitary-specific genes.
The paired homeodomain factor Prop-1 (prophet of Pit-1) and Rpx
(Rathke’s pouch homeobox) expressed in an overlapping spatial and temporal
pattern are required for Rathke’s pouch cell types to produce the anterior lobe of
the pituitary. The expression of Prop-1 is coincident with the closure of
Rathke’s pouch and it is down regulated at the time of terminal differentiation
of the pituitary specific cells. Prop-1 appears to be important for the expression
of all pituitary cell lineages. Mutations in the Prop-1 gene can be the cause of
combined pituitary hormone deficiency in humans [11].
The expression of Rpx is restricted to the oral ectoderm and Rathke’s
pouch and down-regulation of this gene is required for the progression of pitu-
itary development and the appearance of terminal differentiation markers for
anterior pituitary cell types. The Rpx gene can dimerise with Prop-1 to inhibit
Prop-1 activity, suggesting that Rpx acts to antagonize Prop-1 function [12].
An additional paired-domain factor important in the early development of
Rathke’s pouch is Pax-6. This gene is transiently expressed in the dorsal part of
the pouch and is down-regulated when cell-type differentiation starts. In the
absence of Pax-6, the ventral lineages, particularly thyrotrophs become dorsally
extended at the expense of somatotroph and lactotroph cell-types and Pax-6
null mice are GH and prolactin def icient. Thus, Pax-6 is required for delineat-
ing the dorsal/ventral boundaries between the thyrotroph/gonadotroph and the
somatotroph/lactotroph progenitor regions of the pituitary gland.
Transcription Factors Controlling Terminal Differentiation of
Specific Cell Types
Anterior pituitary cell types are initially positionally determined as they
emerge from proliferation zones, with the somatotroph cells arising caudomedi-
ally, gonadotrophs more ventrally and corticotrophs ventrally. For each cell type
to progress beyond initial patterns, by transient signaling gradient, induction of

Ontogenesis of the HPT Axis 7
additional specific transcription factors is required. These transcription factors
include Pit-1 (somatotrophs, lactotrophs, thyrotrophs); the orphan receptor SF-1
and Egr-1 (gonadotrophs); and T-pit and possibly STAT-3 (corticotrophs).
Pit-1, a member of the family of POU domain-containing transcription
factors was originally identified through analysis of the nuclear proteins regu-
lating the transcription of GH and prolactin. Later, Pit-1 was found to be
required for generation and cell- type specification of three pituitary cell- lin-
eages: somatotrophs, lactotrophs and thyrotrophs [13]. Pit-1 binds to the pro-
moter region of the genes for GH, prolactin, the subunit of TSH, the receptor
of GHRH, the type-1 somatostatin receptor 1 and the TRH receptor, interacting
with other transcription factors to form functionally active heterodimers [14].
Pit-1 also interacts with members of the nuclear-receptor family including thy-
roid hormone receptors (TRs) and retinoid acid receptors (RARs).
Finally, the interaction between Pit-1 and the zinc f inger protein GATA-2
is a critical determinant of the development of both thyrotrophs and gonadotrophs.
In the thyrotrophs, this interaction leads to synergistic activation of thyrotroph-
specific genes such as the genes for the subunit of TSH. In the absence of
Pit-1, GATA-2 expression appears suff icient to induce the entire set of tran-
scription factors that are required for gonadotroph cell type specification.
Conversely, the absence of GATA-2 dorsally is critical for differentiation of
Pit-1-positive cells to somatotroph/lactotroph phenotypes [15].
In conclusion, coordination between signal molecules and transcription
factors is necessary for the early pattering, proliferation and specification of
pituitary cell types including the thyrotrophs.
The Thyroid Gland
Ontogenesis
In the human embryo, the thyroid gland is the first endocrine gland to
develop. The thyroid gland consists of two distinct cell types, the thyroid
follicular cells (TFCs) and the parafollicullar or C cells responsible for the dual
endocrine function of the gland, the production of thyroid hormones and calci-
tonin, respectively. The TFCs, the most abundant cell type form the thyroid fol-
licles, whereas the C cells are scattered in the interfollicullar space, mostly in a
parafollicular position.
The two cell types originate from two separate embryological structures:
the TFCs originate from the thyroid anlagen, whereas the C cells from the ulti-
mobranchial bodies. The thyroid anlagen is a thickening consisting of embry-
onic endodermal cells in the floor of the primitive pharynx. The ultimobranchial
bodies are a pair of embryonic structures derived from the fourth pharyngeal

Tsoumalis/Tsatsoulis 8
pouch and located on the sites of the developing neck. Precursors of C cells
migrate from the neural crest and colonize the ultimobranchial bodies. The thy-
roid anlagen appears as a visible bud on embryonic days 16–17 in humans.
Subsequently, the bud expands ventrally as a diverticulum, with rapid prolifera-
tion of cells but it remains attached to the pharyngeal floor by a tubular stalk the
thyroglossal duct. The progenitor thyroid cells continue to proliferate distally
and then laterally, leading to the formation of a bilobed structure connected by
an isthmus. This caudal migration occurs from E-24 to E-32 in humans and is
accompanied by elongation and eventually degeneration of the thyroglossal
duct. The thyroid reaches its final position in the base of the neck at about E-40
to E-50 and, at this time, it merges with the two lateral anlagen, the ultimo-
branchial bodies, resulting in the incorporation of C cells in the thyroid
parenchyma. In the adult thyroid, the C cells disperse either singly or in small
groups in the interfollicullar space and their contribution to thyroid mass is
minimal (10%). The merging of the two populations is complete at about E-50
in humans, at which time the thyroid gland exhibits the def initive external form
with an isthmus connecting the two lateral lobes. The foramen cecum of the
base of the tongue is a remnant of the origin of the thyroid gland in the floor of
the primitive pharynx. The pyramidal lobe, a vestige of the embryonic thryo-
glossal tract, is a narrow projection of thyroid tissue extending upward from the
isthmus and lying on the surface of the thyroid cartilage. The timing of events
during human thyroid development is shown in table 1.
It appears that most of the critical events in thyroid morphogenesis take
place in the f irst 60 days of gestation in humans. For this reason, morphogenic
errors during this period result in developmental thyroid abnormalities. These
may cause displacement of cells derived from the thyroid anlagen leading to
abnormal thyroid migration and ectopic thyroid tissue. Mutations in thyroid
transcription factors may also lead to abnormalities in thyroid development
resulting in congenital hypothyroidism [16, 19, 36]. Also, the thryroglossal
duct may not degenerate but persist as a fistulous tract containing some thyroid
follicular cells from which thyroglossal cysts or rarely thyroid carcinoma
may arise.
Functional Anatomy and Ultrastructure of the Thyroid Gland
The gross anatomy of the thyroid gland is well defined. The gland is
located in the neck region just caudal to the larynx and adherent to the front of
the trachea. Its name derives from the Greek word ‘thyreos’ meaning shield and
was proposed by Thomas Warton in 1656. It is believed that the name was given
because it describes its gross morphology resembling an ancient Greek shield
or because of its topographic association with the laryngeal thyroid cartilage

Ontogenesis of the HPT Axis 9
whose shape resembles a shield. The thyroid is the largest endocrine gland in
humans weighing 1–2 g after birth and 10–20 g in adulthood.
The structure of the thyroid gland is unique in that it is the only endocrine
gland in which the hormone products are stored in an extracellular location
[2, 20]. The functional unit of the thyroid gland is the thyroid follicle, a spheri-
cal structure of varying size that consists of an outer layer of thyroid follicular
cells (TFCs) which enclose a lumen that contains thyroglobulin-rich colloid.
The follicular organization and the polarity of the thyrocytes are essential for
the specialized function of the organ. The follicular cells are surrounded by a
basement membrane and the colloid lumen is sealed by various cell to cell
junctions which are linked to the cytoskeleton. The extracellular matrix plays a
role in the adhesion, proliferation, differentiation and migration of thyroid
follicular cells and the molecules involved in these processes include type I and
IV collagen, fibronectin, laminin and cadherin.
The TFCs have the machinery for thyroglobulin (TG) biosynthesis, transport
and storage as well as iodide uptake, organification and thyroid hormonogenesis.
Thus, TFCs have long prof iles of rough endoplasmatic reticulum and a large
Golgi apparatus in their cytoplasm for the synthesis, packaging and transport of
Table 1. Timing of events during human thyroid development [18]
Developmental stage according to Carnegie staging (CS) and the anatomical or morphological events in
thyroid development. Estimated age in parentheses.
CS10 (22 days) thickening of the floor of the primitive pharynx between the
diverging aorta
CS12 (26 days) outgrowth and budding of the median thyroid primordium
from the floor of the primitive pharynx. The inferior part
of the fourth pharyngeal pouch forms the ultimobranchial body
CS13 (28 days) the median primordium grows caudally and appears bilobed. It is
connected to the primitive pharynx by the thyroglossal duct
CS14 (32 days) migration of the median primordium, still connected to the
epithelium of the primitive pharynx
CS15 (33 days) the thyroglossal duct starts to break down
CS16 (37 days) the median primordium consists of two lobes, an isthmus and
a pedicle remnant. the continuity with the primitive pharynx is lost
CS18 (44 days) median primordium fuses with the lateral components derived
from the ultimobranchial bodies
CS19 (48 days) the thyroid reaches its final position in front of the trachea just
inferior to the cricoid cartilage; it begins to form follicles
10–12 weeks follicles containing colloid become visible; the thyroid is able to
incorporate iodine into thyroid hormones

Tsoumalis/Tsatsoulis 10
TG into the colloid lumen. The cytoplasm also contains lysosomal bodies, which
are important in the secretion of thyroid hormones. The surface characteristics of
the apical and basolateral surfaces are different according to their particular role
in thyroid hormonogenesis. Thus, the apical surfaces have numerous microvilli
that protrude into the follicular lumen increasing the surface area in contact with
the colloid. The base of the cell abuts on a capillary and is separated from it by a
two layer basement membrane. There are pores in the endothelial lining of the
capillaries that may allow plasma to come in direct contact with the basement
membrane. There is an extensive network of interfollicullar capillaries providing
the follicular cells with an abundant blood supply. The stroma also contains nerve
fibers, most of which are sympathetic and some parasympathetic.
The height of the follicular cells varies, depending on the degree of stimu-
lation by TSH, ranging from cuboidal to tall columnar. When TSH secretion is
high, the f irst response is the formation of numerous pseudopodes resulting in
increased endocytosis of TG-rich colloid from the follicular lumen. If the TSH
secretion is sustained, TFCs become more columnar and the lumen of the folli-
cles become smaller because of the increase in endocytosis of the colloid.
A sustained increase in TSH secretion, whether due to iodine deficiency or due
to goitrogens results in thyroid cell hyperplasia and enlargement of the entire
thyroid gland. The opposite changes occur when TSH secretion is inhibited. The
thyroid cells become flat, their microvilli disappear and the follicular lumen
increases due to the accumulation of colloid.
In addition to TG, a number of other proteins are involved in the synthesis
and secretion of the thyroid hormones, T4and T3, by the thyroid follicles.
Important among these are the sodium/iodide symporter (NIS) located at the
basolateral membrane of the cells, which actively transports iodide into the cells
against a steep iodide concentration gradient [21]. From inside the cell, the
iodide is transported through the apical membrane into the follicular lumen by
anion transporter proteins, among which is pendrin. Subsequent iodide oxida-
tion and binding to the tyrosine residues of TG, as well as the coupling of
iodotyrosines to form T3and T4are catalyzed by the enzyme thyroid peroxidase
(TPO) in the presence of hydrogen peroxide (H2O2). The latter is generated by a
membrane system composed of at least two NADPH-thyroid oxidases, THOX-
1 and THOX-2 localized in the apical membrane. Finally, for the production of
T4and T3, TG from the follicullar lumen is absorbed across the apical surface
by endocytosis in the form of colloid droplets. These fuse with lysosomes,
where most of the TG-thyroid hormone complex is hydrolyzed by proteolytic
enzymes, freeing T4and T3 molecules that are released into the bloodstream.
The same process of proteolysis also releases mono- and diiodotyrosine (MIT
and DIT) molecules which are deiodinated by a dehalogenase. The iodide
released locally is used for a new cycle of thyroid hormonogenesis.

Ontogenesis of the HPT Axis 11
The main regulator of all steps in thyroid hormonogenesis is TSH acting
through its specific G-protein coupled receptor on the plasma membrane of
thyroid cells. TSH action is largely mediated by an increase in intracellular
cAMP, which not only regulates thyroid hormone synthesis and secretion but
also contributes to thyroid cell differentiation and proliferation.
The genes encoding the above enzymes and proteins are expressed either
specifically in thyroid cells for example, TG and TPO, or in a very limited num-
ber of tissues, such as NIS and the TSH receptor. These genes become
expressed in a coordinate way during thyroid hormonogenesis and are all pre-
sent in the fully differentiated thyroid cells. The regulation of thyroid function
by the hypothalamic-pituitary system is depicted in figure 1.
Molecular Aspects of Thyroid Development – Thyroid-Specific
Transcription Factors
The development of the embryonic thyroid gland and its normal migration
is dependent on the interplay between several transcription factors. The tran-
scription factors Titf-1/Nkx2-1, Foxe1, Pax8 and Hhex are expressed simultane-
ously in the cells of the primitive pharynx that will become TFCs. The
Fig. 1. Regulation of thyroid function. TRH is synthesized in the hypothalamus,
reaches the thyrotrophs of in the anterior pituitary via the hypothalamic-hypophysial-portal
system and stimulates TSH synthesis and release. TSH binds to its receptor in the thyroid
gland, stimulating the synthesis and release of thyroxine (T4) and triothyronine (T3). The thy-
roid gland secrets predominantly T4. The peripheral deiodination of T4to T3in the liver and
kidney supply roughly 80% of the circulating T3. Both circulating T3 and T4directly inhibit
TSH synthesis and release independently; T4via its rapid conversion to T3(although a direct
negative effect of T4has been recently reported on TSH-gene expression) and T3via bind-
ing to the thyrotroph nuclear T3receptor. Thyroid hormones also inhibit indirectly TSH syn-
thesis via their negative effects on the synthesis of TRH. SRIH Somatostatin.
Hypothalamus
T4T3
TSH ()
Thyroid
Liver,
Kidney
T4→T3 ()
T3 ()
T4 (T3)
T4→T3
Pituitary
T4T3
TRH ()
SRIH ()

Tsoumalis/Tsatsoulis 12
formation of the thyroid diverticulum and the beginning of its migration is
accompanied by the exclusive expression of these factors in thyroid pri-
mordium. In mice, the expression of Ttf-1, Ttf-2, and Pax-8 begins at the onset
of thyroid migration on day 9.5 of gestation and these factors continue to be
expressed throughout embryonic development [22–24]. The onset of thyroid
differentiation is heralded by the expression of Tshr, TPO, and TG. For the rest
of its life, a thyroid cell will be hallmarked by the simultaneous presence of
Titf-1/Nkx2-1, Foxe1, Pax-8, and Hhex. The chromosomal localization of the
genes of these transcription factors are presented in table 2 and their gene
expression patterns in mice and humans in table 3. A summary of the different
phases of thyroid development and the expression of relevant genes is presented
in table 4. The specific role of these transcription factors in thyroid develop-
ment have been confirmed by the generation of mouse knock-outs.
Genes Involved at Early Stages of the Morphogenesis
(a) Titf-1/Nkx2-1. The transcription factor Titf/Nkx2-1, responsible for thy-
roid specific expression of TG and TPO, is a homeobox transcription factor of
the NK-2 gene family. The factor was originally called Ttf-1 (for thyroid
transcription factor-1) and after reisolation as a protein binding to the enhancer
of TPO, Ttf-1 has also been renamed T/EBP [25]. The official name for the
mouse genetic locus is Titf-1 (Titf-1 for humans). The Titf/Nkx2-1 protein is
encoded by a single gene (table 2). Human Ttf-1 is a single polypeptide 371
amino acids long and has two independent transcriptional activation domains
located at the amino-terminal (N domain) and the carboxy-terminal (C domain)
regions with respect to the DNA-binding homeodomain.
Table 2. Chromosomal localization of genes expressed during thyroid development and molecular
features of the corresponding product
Gene Chromosome Features of the gene product
mouse human
Titf-1/Nkx2-1 12 C1–C3 14q13 homeodomain transcription factor
Pax-8 2 2q12–14 paired domain transcription factor
Foxe1 4 9q22 forkhead domain transcription factor
Hhex 19 10 homeodomain transcription factor
Tshr 12 14q31 G-protein coupled receptor
Fgfr2 7 10q26 tyrosine kinase receptor
Nkx2-5 17 5q34 homeodomain transcription factor
NIS 8 19p13 NIS; membrane protein with 13 putative transmembrane
domains

Ontogenesis of the HPT Axis 13
Table 3. Human and murine Pax-8, Titf-1, and Foxe1 gene expression patterns
Features shared between human and mouse Features observed in human or mouse only
Pax-8
Thyroid 4th pharyngeal pouch in human
Brain and spinal cord ureteric bud and derivatives in human
Otic vesicle
Metanephric blastema and derivatives
Titf-1
Thyroid 4th pharyngeal pouch in mouse
Lung
Ventral part of forebrain
Foxe1
Thyroid later onset in the median thyroid primordium in human
Foregut thymus in human
Table 4. Summary of the different phases of thyroid development, indicating the morphological features, the
expression of relevant genes, and the capacity to produce thyroid hormones
Embryonic Morphology Functional Thyroid Controller
day (terminal) hormones genes
differentiation
TG, TPO, Tshr NIS Titf-1/Nkx2-1, Fgfr-2,
Foxe1, Pax-8,
Hhex
E-8 undifferentiated endoderm – – – – –
E-8.5 thyroid anlagen – – – –
E-9.5 thyroid bud – – – –
E-11.5–13.5 expansion of thyroid – – – 
primordium
E-14.5–15 definitive bilobated shape –– 
E-16 folliculogenesis –
E-16.5 completion of organogenesis 
Present; – absent.

Tsoumalis/Tsatsoulis 14
Titf-1/Nkx2-1 Knock-Out. Heterozygous animals were initially described
as having a normal euthyroid phenotype but were later found to have reduced
motor coordination skills when compared with wild type mice. Kimura [26]
announced in 1996 a mutant mouse lacking Ttf-1. Homozygous animals were
stillborn, apparently owing to lack of a normal lung. Mutant mice may contain
a rudimentary bronchial tree with severely abnormal epithelium. There is a
reduction of the number of cartilage rings of the trachea probably due to the
control of the expression of Bone morphogenetic protein (Bmp)-4 by Titf-1/
Nkx2-1. In knock-out animals, thyroid follicular cells and C cells are com-
pletely absent. The latter feature, which is not shared by humans with thyroid
dysgenesis, is consistent with the expression pattern of this factor in neuroecto-
dermal tissue, as are the severe defects of the forebrain and hypothalamus in
these animals. As concerns the pituitary gland, Titf-1/Nkx2-1 is exclusively
detected in the posterior bud. The developing posterior pituitary expresses two
growth factors, Bmp-4 and fibroblast growth factor (Fgf )-8, and is adjacent to
Rathke’s pouch, which expresses Fgfr-2, an Fgf receptor. In mice deprived of
Ttf-1/Nkx2-1, Bmp-4 is still expressed and thus its expression is Titf-1/Nkx2-1
independent in the posterior pituitary. The Fgf-8 expression is abolished in the
posterior pituitary and the apoptosis of the anterior bud has been attributed to
this fact. Later in development, no pituitary, either anterior or posterior, is pre-
sent, thus showing that Titf-1/Nkx2-1 is required both for the development of
the posterior bud and for controlling the expression of a signaling molecule,
perhaps Fgf-8, that is essential for the survival of the anterior portion.
The appearance of Titf-1/Nkx2-1 in the thyroid anlagen coincides with the
proliferation of the cells that give rise to the primitive thyroid bud. Titf-1/Nkx2-
1 remains expressed in the TFC during all stages of development and in adult-
hood. This factor has been shown to function as a potent transcriptional
activator of thyroid- and lung-specific genes [22]. In humans and rats, Titf-1
transcripts are detected during lung development. It is known to regulate the
transcription of TG and TPO genes, the Tshr gene in thyroid follicular cells, and
the surfactant protein B (SPB) gene in epithelial lung cells (table 3). Titf-1/
Nkx2-1 mRNA was also identified in parafollicular C cells and in the epithelial
cells of the ultimobranchial body. This transcription factor is first expressed in
epithelial cells and becomes progressively restricted to distal branches. The
absence of expression in main bronchial epithelial cells or in the proximal res-
piratory compartments of the fetal lung and its restriction to the distal part of
the lung is also consistent with its role in surfactant production and regulation.
Apart from lung and thyroid, this factor is expressed in the ventral forebrain.
After birth and in adult organisms, Titf-1/Nkx2-1 is still present in the thyroid
and lung epithelium and in the posterior pituitary, whereas its expression is
reduced in the brain and is restricted to the periventricular regions and some

Ontogenesis of the HPT Axis 15
hypothalamic nuclei. However there is a transient increase before the first
endocrine manifestations of puberty.
In conclusion, Titf-1/Nkx2-1 controls survival of thyroid cells at the begin-
ning of organogenesis and the expression of TFC-specific genes in adult life,
a role that cannot be investigated in knock-out mice because thyroid cells dis-
appear before the onset of functional differentiation [22].
(b) Pax-8. Pax-8 (paired box gene 8) is a transcription factor, member of a
family of 9 transcription factors and is also involved in the early stages of
organogenesis [27]. In the endoderm Pax genes are essential for the differentia-
tion of endocrine cells in the pancreas and follicular cells in the mature thyroid
gland [27]. Pax-8 has a DNA binding domain at the amino terminal end, a car-
boxy terminal transcriptional activation domain, and a central homeodomain
[27]. The gene encoding Pax-8 (called Pax8 in mice and Pax-8 in humans) is
located on chromosome 2 in both species (table 2) and the Pax-8 gene in
humans consists of 11 exons. Pax-8 is expressed, as Titf/Nkx2-1, in the thyroid
diverticulum and in the developing neural tube and excretory system. Like Titf-1/
Nkx2-1, Pax-8 is detected in the developing thyroid from E8.5, i.e. at the time
of specification. Expression of Pax-8 is maintained in TFCs during all stages of
development and in adulthood. In the mature TFC, Pax-8 regulates the expres-
sion of thyroglobulin and TPO genes [28, 29].
Pax-8 Knock-Out. Heterozygous Pax-8 mice show no specific pheno-
type. Pax8 mice have a higher prevalence of elevated plasma TSH than wild-
type littermates, but their thyroid gland appears histologically normal.
Homozygous Pax8 mice present with growth retardation and die within 2–3
weeks. Only the formation of the endoderm-derived follicular cells is affected
(31 days) and thyroid glands are hypoplastic with absent median anlagen deriv-
atives (i.e., follicular cells), whereas lateral anlagen derivatives (parafollicular
calcitonin-producing C cells) are present [27]. The thyroid is composed com-
pletely of calcitonin producing cells. The early neonatal death of Pax-8/mice
is due to their severe hypothyroidism (the administration of T4to Pax-8 mice
allows the animals to survive), and to the retarded development of other organ
systems (such as bone, spleen and intestine). The absence of Pax-8 is still com-
patible with very early stages of thyroid development (appearance of the thyroid
diverticulum from endodermal cells of the primitive pharynx) but precludes
further differentiation events to the mature TFC. The brain and kidneys, in
which this transcription factor is expressed during development are normal.
Furthermore, in the thyroid anlagen of Pax-8/mice, the expression of Foxe1
and Hhex is strongly down-regulated.
The function of Pax-8 appears similar to that of Titf-1, i.e. it is not required
for the initial specif ication of the thyroid anlagen, but is critical at later steps of
development. It has been shown that Titf-1 and Pax-8 interact physically and

Tsoumalis/Tsatsoulis 16
they might similarly cooperate to control thyroid differentiation [27] but the data
are conflicting. The Pax-8 gene has been implicated in the development and
maintenance of the follicular cell phenotype by activating thyroperoxidase,
sodium/iodide symporter, and thyroglobulin genes without apparent effect on
C cell development. The expression of Pax-8 gene expression observed in the
thyroglossal duct cells suggests that this structure represents a cellular track left
by the migrating thyroid anlagen rather than a pre-established pathway for
thyroid migration, and its expression may explain the capacity of these cells to
differentiate into follicular cells. During normal development, the thyroglossal
duct disappears, but remnants may persist and form cysts anywhere along the
course of thyroid migration. On the other hand, the expression pattern of the
Pax-8 gene in the central nervous system in human is similar to that observed in
the mouse, i.e. restricted to the midbrain-hindbrain boundary, then to the mye-
lencephalon and the spinal cord. In addition to being expressed in the condensed
mesenchyme of the developing kidney, human Pax-8 is expressed in the
mesonephric duct, the ureteric bud, and the collecting ducts (but not at their
tips). This is different from what has been described in the mouse.
(c) Foxe1. Foxe1 (formerly called Ttf-2 for thyroid transcription factor-2)
was originally identified as a thyroid-specific nuclear protein that recognizes a
DNA sequence present on both TG and TPO promoters under hormone stimu-
lation [30]. It is a phosphoprotein that consists of an N-terminal region, a highly
conserved forkhead domain, a helical polyalanine tract, and unique C terminal
residues. The official name for the mouse genetic locus is Foxe1 (Foxe1 for the
human locus). Foxe1 is located on mouse chromosome 4 and the human gene is
on chromosome 9q22 and consists of a single exon (table 2). Foxe1 mRNA is
detected at E-8.5 in all the endodermal cells of the floor of the foregut, includ-
ing the thyroid anlagen. The expression of Foxe-1 is limited posteriorly.
Expression of Foxe1 in the thyroid cell precursors is maintained during devel-
opment and persists in adult TFCs.
Foxe1 (Ttf-2) Knock-Out. Heterozygous Foxe1 knock-out mice are euthy-
roid, with no visible phenotype. In 50% of Foxe1 null mice the thyroid disap-
pears indicating that this gene, too, is implicated in the control of the survival of
thyroid cells at a step different from those controlled by Titf-1/Nkx2-1 and
Pax-8. Homozygous null mice have cleft palate and thyroid dysgenesis, consist-
ing of either thyroid agenesis or an ectopic sublingual gland, which is often
lethal in the neonatal period [22]. However their thyroid phenotype is complex
[22]. Although they display no thyroid in its normal location and an absence of
thyroid hormones, the elevated TSH levels suggests normal pituitary function.
Death occurs within 48 h. In mouse embryos, Foxe1 is known to be expressed
not only in the thyroid gland but also in the craniopharyngeal ectoderm
involved in palate formation and in Rathke’s pouch. In contrast to what is

Ontogenesis of the HPT Axis 17
observed in Titf/Nkx2-1/mice, C cells develop normally in Foxe1/mice.
The budding of the thyroid primordium does not require Foxe1. However, at
E-9.5 in Foxe1 null embryos, thyroid precursor cells are still on the floor of the
pharynx, whereas in wild-type embryos they are detached from the pharynx
cavity and begin to descend. At later stages of development, in the absence of
Foxe1, mutant mice exhibit either a small thyroid remnant still attached to the
pharyngeal floor or no thyroid gland at all.
The role of Foxe1 in the adult gland is still a matter of study. In the adult,
Foxe1 is still present in the thyroid, whereas the expression in the esophagus is
faint. In ectoderm-derived structures, at an early stage of development, Foxe1 is
present in the posterior stomatodeum, in the buccopharyngeal membrane, and
in the cells of the roof of the oral cavity indenting to constitute Rathke’s pouch,
which will form the various components of the anterior pituitary. At later
stages, Foxe1 mRNA expression in the pituitary is downregulated [30], whereas
it appears in the secondary palate, in the definitive choanae, and in the whiskers
and hair follicles [31]. In humans, Foxe1 mRNA is also detected in adult testis
and several other tissues.
In conclusion, Foxe1 plays an essential role in promoting migration of TFC
precursors, a role quite different from the previously mentioned transcription
factors Tift-1/Nkx2-1 and Pax-8, which seem to be involved in the survival
and/or differentiation of these cells [22].
(d) Hhex. Hhex (hematopoietically expressed homeobox) is a homeodomain-
containing transcription factor that was first identified in hematopoietic cells.
The genomic locus encoding Hhex is called Hhex in mice (located on chromo-
some 19) and Hhex in humans (located on chromosome 10q23.32) (table 2). The
gene is split into four exons and codes for a protein 271 amino acids long in mice
and 270 amino acids long in humans. Hhex mRNA is expressed in early mouse
development in the primitive endoderm and at later stages in the ventral gut.
From E8.5 onward it marks the primordium of several organs derived from the
foregut, among which, both developing and adult thyroid express Hhex at the
highest level. Hhex function is essential in definitive endoderm for normal
development of the forebrain, liver and thyroid gland [32].
The role of Hhex in the adult thyroid gland cannot be studied in Hhex null
mice because thyroid cells disappear at an early stage. In Hhex embryos, at
E-9.5 the thyroid primordium is absent or hypoplastic, still connected to the
floor of the pharynx; notably, no expression of Titf-1/Nkx2-1 and Foxe1 mRNA
is observed in the thyroid bud. A small thyroid primordium can nevertheless be
identified in some Hhex/embryos before E-9 [33]. In the absence of Hhex,
the thyroid anlagen is properly formed and expresses Titf-1/Nkx2-1, Foxe1,
and Pax-8; at later stages, the expression of all these transcription factors is
downregulated.

Tsoumalis/Tsatsoulis 18
Hhex is an early marker of thyroid cells. The role of Hhex could me to
maintain the expression of Titf/Nkx2-1, Foxe1 and Pax-8 mRNA in the thyroid
anlage. On the other hand, Titf/Nkx2-1 and Pax-8 are both required to maintain
the expression of Hhex. This regulatory network between transcription factors
seems to be in place in differentiated TCFs also showing that Titf-1/Nkx2-1 reg-
ulates the activity of Hhex promoter in thyroid cell lines.
Genes Involved in the Late Stages of Thyroid Organogenesis
(a) Tshr. Tshr is localized on chromosome 14q31 in humans and chromo-
some 12 in mice. Tshr is a protein of 765 amino acids in humans and in mice
and belongs to the superfamily of G-protein coupled receptors. The initiation
of expression of the Tshr on day 14 of mouse embryogenesis, at the onset of
thyroid differentiation after completion of gland migration [24] suggests that
alterations in TSH signaling pathways could result in defective thyroid develop-
ment. Alterations in the Tshr gene [34] may cause hypothyroidism. Both the
Tshrhyt/hyt mice, characterized by a loss-of-function mutation in the fourth trans-
membrane domain of the Tshr and the Tshr null mice display severe hypothy-
roidism, associated with thyroid hypoplasia in adult life. However, at birth, in
both these mutants, the size of the thyroid does not appear to be affected, and
the gland displays only some alterations in its structure. The amount of TG does
not change, whereas the expression of both TPO mRNA and NIS is strongly
downregulated. During embryonic life the TSH/Tshr signaling is probably
required to complete the differentiative program of the TFC, but, unlike what
happens during adult life, this signaling is not relevant in controlling the growth
of the gland. In contrast to mouse models, where an intact TSH-Tshr signaling
pathway does not appear to be a prerequisite for the development of a normal
sized thyroid gland in utero, this pathway is clearly important for the develop-
ment of a normally sized fully differentiated gland in utero in humans. While
the action of TSH through its receptor (Tshr) is essential for the proliferation
and maintenance of differentiated function of thyroid follicular cells, it plays no
role in the migration of the thyroid anlagen and the growth of thyroid gland.
Tshr is therefore a candidate gene for thyroid hypoplasia, but not for thyroid
ectopy.
(b) Hoxa3 and Eya1. The Hox genes belong to a large gene family in both
mice and humans distributed in four different chromosomal complexes. Hoxa3
is detected in the floor of the pharynx, in the developing thyroid, and in the mes-
enchymal, endodermal, and neural crest-derived cells of the fourth pharyngeal
pouch [17].
Hoxa3 Null Mice. Hoxa3 is present both in thyroid diverticulum and the
utimobranchial body and thus their products are defective in mutant mice [17].
Hoxa3 mutant mice are athymic and show thyroid hyoplasia [17]. A more

Ontogenesis of the HPT Axis 19
detailed analysis of Hoxa3 mice revealed a variable expressivity and pene-
trance of the thyroid phenotype. The embryos show severe alterations in the
development and migration of the ultimobranchial bodies, which do not fuse
with the thyroid primordium (persistent ultimobranchial bodies), and a reduced
or absent C cell population in the thyroid. Thus the ability of the neural crest
population that is about to differentiate into C cells and migrate to its final
position is affected. Both Hoxb3 and Hoxd3 single mutant mice have
a thyroid gland that appears normal. However, both the double mutants
Hoxa3 Hoxb3 and Hoxa3 Hoxd3 mice show a 100% penetrance of
the thyroid and ultimobranchial body phenotype. Although Hox3 paralogs do
not play a direct role in the morphogenesis of the thyroid, they could have an
important role in the normal development and migration of the ultimobranchial
bodies [22].
In Hox3/mice, hemiagenesis occurs (absence of one of the thyroid
lobes and, sometimes, of the isthmus) and defective fusion of the C cells with
the thyroid lobes [17]; the latter feature is also seen in Eya/mice [33].This
hypothesis is supported by the study of the phenotype of mouse embryos
deprived of a functional Eya1 gene [33]. Eya1 control is critical in early induc-
tive events involved in the morphogenesis of thymus, parathyroid and thyroid
[33]. At an early stage of embryonic life, Eya1 is expressed in the pharyngeal
arches’ mesenchyme, in the pouches’ endoderm, and in the surface ectoderm of
the clefts. Later, it is clearly evident in the thymus, parathyroid, and ultimo-
branchial bodies but is not detected in the developing thyroid. In Eya1 null
mice, the thyroid phenotype is almost identical to the phenotype displayed from
Hoxa3 mutants. Indeed, the embryos show persistent ultimobranchial bodies,
hypoplasia of the lobes, absence of the isthmus, and a reduced number of fol-
licular cells.
Other Genes
(a) Fgfr2. The Fgf family includes at least 22 peptide growth factors that
bind and activate specific tyrosine kinase receptors (Fgfr). One of the receptors,
the Fgfr2-IIIb isoform, is expressed in many types of epithelial cells and is acti-
vated by Fgfs (like Fgf-10) that are present in the surrounding mesenchyme. In
many cases it has been shown that the activation of Fgfr-2-IIIb mediates the
epithelium-mesenchyme cross-talk required for the development of different
organs. In the thyroid Fgfr activation appears to be essential only after budding
and initiation of migration. Both mutated mice expressing a soluble dominant
negative form of Fgfr-2-IIIb receptor and mice deficient for the same isoform
show absence of the thyroid. Furthermore, in Fgf10 null mice the thyroid is
missing. These data strongly suggest that the interaction of Fgf-10 with
its receptor Fgfr-2-IIIb is relevant for thyroid organogenesis. It is possible that

Tsoumalis/Tsatsoulis 20
Fgf-10/Fgfr signaling is required for the progression of already established dif-
ferentiative programs [22].
(b) Nkx2-6, Nkx2-3 and Nx2-5. Other genes of the Nkx2 family, such as
Nkx2-6, Nkx2-3, and Nkx2-5, are expressed in the endodermal layer of the
developing pharynx, including the thyroid anlagen, as well as in other tissues.
Nkx2-3 null mice the gland appears histologically normal despite the expression
of Nkx2-3 in the thyroid. Because of the early mortality of Nkx2-5 embryos,
it is not easy to identify the role of this factor in thyroid morphogenesis. In the
developing thyroid, the specific role of Nkx2-3 or Nkx2-5 has not yet been
identified.
(c) Hepatic Nuclear Factor 3b(Hnf-3b). Hnf-3bhas a wide and early
expression in embryonic tissue including the developing thyroid. It is hard to
identify the relevance of Hnf-3during thyroid morphogenesis because the dis-
ruption causes an embryo-lethal phenotype at a stage preceding that of thyroid
bud formation [22].
Thyroid-Specific Genes and Mature Thyroid Cell
The term ‘thyroid-specific genes’ applies to genes that encode proteins
exclusively found in the thyroid (e.g. thyroglobulin and thyroperoxidase) or pri-
marily involved in thyroid function (e.g. TSH receptor and sodium/iodide sym-
porter). The transcription of these genes in the thyroid appears to rely on the
coordinated action of transcription factors that includes at least Ttf-1, Pax-8, and
perhaps also Ttf-2 [24]. TSH and the increase in intracellular cAMP, upregulates
the expression of transcription factor Pax-8 as well as other transcription factors
but it cannot account for the observed control on thyroglobulin gene transcription.
TSH may also influence some post-transcriptional steps, as in the case of thy-
roglobulin. A positive in vivo effect of TSH on general protein synthesis, with
stimulation of transcription and translation, has been well documented, an effect
mimicked by cAMP agonists.
Ttf-1 and Pax-8 proteins exert a major control on thyroglobulin gene tran-
scription [29] individually and in synergism, but other factors may contribute.
The thyroglobulin gene is expressed in cells devoid of Ttf-2 protein. After the
TSH receptor gene, the thyroglobulin gene is the most affected in its expres-
sion by a reduced Ttf-1 availability. There is probably a synergistic action of
Ttf-1 and Pax-8 on gene transcription of TPO, but thyroperoxidase gene tran-
scription is more rapidly and tightly controlled by TSH and cAMP. TSH sig-
naling is indispensable for sodium/iodide symporter gene transcriptional
activation in vivo [34], and iodide downregulates the expression of the gene.
The control of Tshr gene seems to be quite complex. Additionally, growth fac-
tors, such as TGF-and FGF, seem to be involved in the regulation of thyroid-
specific genes [35].

Ontogenesis of the HPT Axis 21
In conclusion, it has been shown that, in mice, the thyroid anlagen,
although distinguished by early expression of Titf-1/Nkx2-1, Foxe1, Pax-8, and
Hhex, does not require these factors for the initial steps of morphogenesis [22].
Titf-1, Foxe1, Pax-8, and Hhex are transcription factors regulating the
expression of downstream genes that ultimately activate the organogenesis of the
gland. These thyroid specific genes are mentioned here because of their con-
nection with congenital hypothyroidism. Nevertheless mutations of Ttf-1, Ttf-2
and Pax- 8 are found in 10% of patients with congenital hypothyroidism and
these predominately have orthotopic hypoplasia, often associated with other
malformations. The possibility of underestimation, considering that mutations
have been searched mostly in the coding region, cannot be excluded.
Additionally the discordance of more than 90% of monozygotic twin pairs sug-
gests that isolated thyroid ectopy or athyreosis most often results from early
somatic mutations, epigenetic modif ications or stochastic developmental
events [19].
Two more genes are worth mentioning, in respect to their relation with
congenital hypothyroidism: (1) The stimulatory G-protein subunit gene
(GNAS1) is located on chromosome 20q13 and contains over 13 exons that
encode Gsa, the subunit of the heterotrimeric stimulatory G-protein. This
protein has intrinsic GTPase activity. Apart from TSH receptors, TRH and LH
and PTH receptors use these G-proteins for their signal. (2) The PDS gene is on
chromosome 7q, contains 21 exons and is found to be expressed in the cochlea
as well as in the thyroid. It encodes pendrin, 4,780 amino acid protein (molecu-
lar weight 86 kDa) with 11 transmembrane domains which functions as a chlo-
ride-iodide transporter.
The Maturation of Hypothalamic-Pituitary Axis – The Role of Placenta
At 10–12th week of gestation tiny follicle precursors can be seen, iodine
binding can be identified and thyroglobulin detected in follicular spaces.
Thyroid hormones (T4and T3) are detectable in fetal serum by gestational age
of 12 weeks, probably of maternal origin. Thyroid hormones and thyroxine-
binding globulin (TBG) continue to increase gradually over the entire period of
gestation. The serum TBG concentrations are higher in the infant than in adult
humans (⬃300 nmol/l) as a consequence of placental estrogen effects on the
fetal liver. In addition to the increase in total T4, however, there is also a pro-
gressive increase of free T4concentrations between 18 and 36 weeks of gesta-
tion, indicating a maturation of the hypothalamic-pituitary-thyroid axis. While
thyroglobulin can be identified in the fetal thyroid as early as the 5th week, and
is certainly present in follicular spaces by 10–11 weeks, maturation of thy-
roglobulin secretion takes much longer and it is not known when circulating
thyroglobulin first appears in the fetal serum. By the time of gestational age

Tsoumalis/Tsatsoulis 22
27–28 weeks, however, thyroglobulin levels average approximately 100 ng/ml
and remain approximately stable until the time of birth. Iodide concentrating
capacity can be detected in the thyroid of the 10- to 11-week fetus, but the
capacity of the fetal thyroid to reduce iodide trapping in response to excess
iodide (the Wolff-Chaikoff effect) does not appear until 36–40 weeks of gesta-
tion. TSH is detectable at levels of 3–4 mU/l at the 12th week of gestation. It
increases moderately over the last two trimesters to levels of 6–8 mU/l at the
time of delivery. The fetal thyrotroph responds to TRH as early as the 25th week
of gestation. The maturation of the negative feedback control of thyroid hor-
mone synthesis, occurs by approximately mid-gestation. The increase in serum
TSH concentrations have been noted in infants as early as the 28th week of ges-
tation. Serum levels of TRH are higher in the fetal circulation than in maternal
blood, due to extrahypothalamic TRH production (placenta and pancreas) and
the decreased TRH degrading-activity in fetal serum. All three iodothyronine
deiodinases involved in the activation and inactivation of thyroid hormone are
coordinately regulated during gestation for the proper supply of T3to develop-
ing tissues. Type 1 iodothyronine deiodinase (D1) is low throughout gestation.
Consequently circulating T3concentrations in the fetus are quite low. The type 2
deiodinase (D2) is detectable by the 7th week of gestation. The type 3 or inner
ring deiodinase (D3) is also expressed in fetal brain by the 7th week of gesta-
tion. D2 and D3 are the major isoforms present in the fetus and are especially
important in defining the level of T3in the brain and pituitary [37]. The matura-
tion of D2 activity in brain is tightly linked to thyroid hormone receptor
ontogeny [37]. D2 expression with a precise timing is fundamental during criti-
cal periods of mammalian development. D3 is present in many fetal tissues and
has a key role in protecting fetal tissues against high maternal T4concentrations
present either in the placenta or in amniotic fluid.
The fetal hypothalamic-pituitary-thyroid axis develops relatively indepen-
dent of maternal influence. The placenta is freely permeable to iodide which is
essential for fetal thyroid hormone synthesis. On the other hand, maternal TSH
does not cross the placenta, nor does thyroglobulin. Maternal thyroid function
can play a critical role in the fetus and normal maternal T4concentrations seem
to be important. T4is present in cord serum at concentrations between 25 and
50% of normal. Maternal-fetal T4transfer may occur in the first half of preg-
nancy, when fetal thyroid hormone levels are low prior to the onset of fetal thy-
roid function. An appropriate thyroid hormone level is critically important for
the coordination of developmental processes in all vertebrate species. During
embryogenesis, thyroid hormone acts primarily to promote differentiation and
thus attenuate proliferation. As a result, either insufficient levels of T3or the
premature exposure of the embryo to adult T3concentrations can be detrimental
and can result in abnormal development [38]. In conclusion, the provision of

Ontogenesis of the HPT Axis 23
sufficient iodine from the placenta, probably appropriate maternal thyroid
hormone levels and the normal maturation of the hypothalamic-pituitary-thy-
roid axis during gestation are important elements for the development of human
embryos.
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Agathocles Tsatsoulis, MD, PhD, FRCP
Department of Endocrinology, University of Ioannina
GR–45110 Ioannina (Greece)
Tel. 30 26510 99625, Fax 30 26510 46617, E-Mail atsatsou@uoi.gr

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 25–43
Thyroid Disease during Pregnancy
John H. Lazarus
Centre for Endocrine and Diabetes Sciences, University Hospital of Wales,
Cardiff University, Cardiff, UK
Thyroid disorders are common. The prevalence of hyperthyroidism is
around 5 per 1,000 and hypothyroidism about 3 per 1,000 in women. As the
conditions are generally much more common in the female it is to be expected
that they will appear during pregnancy. Developments in our understanding of
thyroid physiology [1] and immunology [2] in pregnancy as well as improve-
ments in thyroid function testing [3] have highlighted the importance of recog-
nising and providing appropriate therapy to women with gestational thyroid
disorders.
Before considering the clinical entities occurring during and after preg-
nancy it is useful to briefly review thyroid physiology and immunology in rela-
tion to pregnancy.
Fetal-Maternal Relationships
Thyroid Function during Pregnancy
Iodine Metabolism
Pregnancy affects thyroid homeostasis. An increased excretion of iodine in
the urine accounts for the increase in thyroid volume even in areas of moderate
dietary iodine intake [4]. Some studies, however, do not show an increase in uri-
nary iodine during pregnancy. In either case the increase in thyroid volume is
the result of imbalance between the intake and increased requirements of iodine
during pregnancy [5]. Iodine def iciency during pregnancy is associated with
maternal goitre and reduced maternal thyroxine (T4) level. While thyroid size
increases in areas of iodine deficiency it does not do so in those regions that are
iodine sufficient; even in moderate iodine-deficient regions urinary iodine
excretion is higher in all trimesters than in non-pregnant women and may be

Lazarus 26
causative in maternal goitre formation as assessed by ultrasound. The increase
in thyroid volume already referred to is substantially greater in iodine-deficient
areas. This gestational goitrogenesis is preventable by iodine supplementation
not only in areas of severe iodine deficiency (24-hour urinary iodine less than
50 g) but in areas such as Belgium and Denmark [6] where trials have shown
clear beneficial effects on maternal thyroid size. The aim of these studies
should be to increase the iodine supply to pregnant and lactating women to
at least 250 g/day, a level agreed by a recent concensus WHO meeting on iodine
requirements in pregnancy and lactation [7]. Clinical studies of children born to
mothers with known iodine deficiency clearly showed impaired neurointellec-
tual development, sometimes to the extreme of cretinism in severe deficient
states. These defects can be corrected by iodine administration before and even
during gestation [8]. Urinary iodine excretion in pregnancy is characterised by
maximum excretion in the first trimester followed by a decline in the second
and third trimesters. Often there is an increase in urinary iodine in the first
trimester compared to control non pregnant women but where the population
has a high median iodine concentration this difference may not occur.
Thyroid Hormones
Thyroid hormone transport proteins particularly TBG (thyroxine-binding
globulin) increase due to enhanced hepatic synthesis and a reduced degradation
rate due to oligosaccharide modification. Serum concentration of free thyroid
hormones has been reported to be decreased, increased or unchanged during
gestation by different groups depending on the assays used [9]. However, there
is general consensus that there is a transient rise in free thyroxine (FT4) in the
first trimester due to the relatively high circulating hCG concentration and a
decrease of FT4 in the second and third trimester albeit within the normal ref-
erence range. Recently, it has become apparent that there is a need for norma-
tive trimester-specif ic reference ranges for thyroid hormones [10]. Ideally these
should be derived from iodine sufficient women who do not have any evidence
of thyroid autoimmunity [11]. Changes in free triiodothyronine (FT3) concen-
tration are also seen in which they broadly parallel the FT4, again within the
normal range. The precise reason for the decline in free thyroid hormones is not
clear. In iodine-deficient areas (including marginal iodine deficiency seen in
many European countries) the pregnant woman may become significantly
hypothyroxinaemic with preferential T3 secretion. The thyroidal ‘stress’ is also
evidenced by a rise in the median TSH and serum thyroglobulin.
Thus, pregnancy is associated with significant, but reversible changes in
thyroid function (table 1). The findings associated with the hypermetabolic
state of normal pregnancy can overlap with the clinical signs and symptoms of
thyroid disease.

Thyroid Disease during Pregnancy 27
Immunological and Hormonal Aspects of Normal Pregnancy
Pregnancy has a significant effect on the immune system, in order to main-
tain the fetal-maternal allograft, which is not rejected despite displaying pater-
nal histocompatability antigens [12]. While there is no overall immunosuppression
during pregnancy, control or tolerization of anti-fetal T cells is critical [13].
Clinical improvement usually occurs in patients with immunological disorders
such as rheumatoid arthritis [RA] when they become pregnant [14]. Clinical
improvement occurs as well in psoriatic arthritis and Graves’ disease. On the
other hand, systemic lupus erythematosus (SLE) may flare during pregnancy.
The trophoblast does not express the classical major histocompatibility
complex (MHC) class Ia or II which are needed to present antigenic peptides to
cytotoxic cells and T helper cells, respectively. Instead HLA-G, a non-classical
MHC Ib molecule is expressed which may be a ligand for the natural killer
(NK) cell receptor so protecting the fetus from NK cell damage; it may also
activate CD8T cells that may have a suppressor function. Human trophoblasts
also express the Fas ligand abundantly, thereby contributing to the immune
privilege in this unique environment possibly by mediating apoptosis of acti-
vated Fas expressing lymphocytes of maternal origin [15].
T cell subset studies in pregnancy are discrepant, as peripheral blood
CD4and CD8cell levels have been variously reported to decline, remain
unchanged and increase during pregnancy. Although, the distinction between
Th1 (T cell helper 1) and Th2 (T cell helper 2) immune responses in humans
remains less clear than in the mouse the general agreement is that in pregnancy
there is a bias towards a Th2 response [16]. This seems to be achieved by the
fetal/placental unit producing Th2 cytokines, which inhibit Th1. Th1 cytokines
are potentially harmful to the fetus as, for example, interferon alpha is a known
abortifacient.
Table 1. Physiologic changes in pregnancy that influence thyroid function tests
Physiologic change Thyroid function test change
↑Thyroid-binding globulin (TBG) ↑Serum total T4 and T3 concentration
First-trimester hCG elevation ↑Free T4 and ↓TSH
↑Plasma volume ↑T4 and T3 pool size
↑Type III 5-deiodinase (inner ring ↑T4 and T3 degradation resulting in requirement
deiodination) due to increased for increased hormone production
placental mass
Thyroid enlargement (in some women) ↑Serum thyroglobulin
↑Iodine clearance ↓Hormone production in iodine-deficient areas

Lazarus 28
Sex steroids are powerful negative regulators of B cell activity. Oestrogen
alone is effective in reducing B cell lymphopoiesis in pregnancy. Although proges-
terone is not effective on its own, it reduced the amount of oestrogen required for
suppression by up to 90% in a mouse pregnancy model. The high concentrations
of oestrogen produced in normal pregnancy almost certainly contribute to the fall
in autoantibody levels observed in pregnant patients with autoimmune thyroid dis-
ease (AITD). Despite the fall in autoantibodies, there are no significant changes
reported in the number of B cells in the circulation in normal human pregnancy.
While progesterone may favour Th2 cells, evidence has indicated that oestrogen
delivers a negative signal to B cell function during pregnancy and this showed a
slow reversal in the postpartum period. In keeping with these observations,
autoantibody titres and inflammation fall throughout pregnancy as observed in all
autoimmune diseases investigated [17]. However, after most pregnancies, there is
a marked increase in many different types of autoantibody secretion and an exac-
erbation of autoimmune diseases in the months after delivery. Recent data sug-
gests that cortisol, norepinephrine and 1,25-dihydroxyvitamin-induced inhibition
and subsequent rebound of interleukin-12 (IL-12) and tumour necrosis factor-
(TNF) production may represent a major mechanism by which pregnancy and
postpartum alters the course of or susceptibility to various autoimmune disorders
[18]. Table 2 summarises relevant immunological changes in gestation.
Fetal Thyroid Development and Function
The fetal thyroid begins concentrating iodine at 10–12 weeks of gestation
and is under control of fetal pituitary thyroid-stimulating hormone (TSH) by
about 20 weeks of gestation [19]. Despite the fetus not possessing a functioning
thyroid in early pregnancy there is good evidence that thyroid hormone is
Table 2. Immunological and hormonal features of pregnancy
Clinical: Improvement in Graves’ hyperthyroidism
Rheumatoid arthritis
Psoriatic arthritis and other autoimmune diseases
Trophoblast: HLA G expression
Fas ligand expression
Lymphocytes: Th2 response
Th2 cytokines produced by the fetal/placental unit
Hormones: Progesterone increase – reduction in B cell activity
Oestrogen increase – fall in autoantibody levels
Cortisol, 1, 25-vitamin D and norepinephrine all affect the immune response

Thyroid Disease during Pregnancy 29
important in the development of many organs including the brain. It is now well
accepted that maternal circulating T4 crosses the placenta into the fetus at all
stages of pregnancy, first shown by Vulsma et al. [20]. The precise mechanism
of placental T4 transport is not clear but the important role of both the type 2
and type 3 deiodinase enzymes, both expressed in the placenta, has been recog-
nised. Type 2 deiodinase is also located in the uterus and other parts of the
genital tract and may have a role in fetal implantation [21]. In the fetus it is
expressed in the brain and its action supplies that developing organ with T3.
Type 3 deiodinase (D3), which degrades thyroid hormones, is also expressed in
pregnant uterus, placenta, fetal and neonatal tissues. Analysis of a D3 knock out
mouse has revealed a critical role for this enzyme in the maturation and func-
tion of the thyroid axis [22]. As thyroid hormone receptors have been localised
in different brain areas well before fetal thyroid function occurs the supposition
is that brain T3 derived from maternal T4 is active in promoting growth and dif-
ferentiation in neural and other tissues [23]. Further understanding in relation to
delivery of T3 to neurones following the deiodination of T4 in other nervous
system cells has come from the discovery that, while there is absence of the
type 2 deiodinase in neurones, a thyroid hormone transporter (MCT8) has been
found to affect the entry of T3 into these neurones [24].
Thyroid Antibodies and Pregnancy Failure
Fertility is impaired in hypothyroid women with autoimmune thyroid disease
and if such patients do achieve pregnancy the hypothyroid state is associated with
a higher incidence of miscarriage early in pregnancy [reviewed in 14]. Thyroid
autoimmunity, as evidenced by the presence of anti-thyroid antibodies, present
during early pregnancy even in the euthyroid situation, is associated with an
increased risk of subsequent miscarriage [25]. Thyroid autoantibody positive
women miscarry at a rate of between 13 and 22% compared to 3.3–8.4% in
control euthyroid antibody negative women [14]. While the association between
thyroid antibodies and miscarriage is strong that between these antibodies and
recurrent abortion is less so. In the euthyroid woman with thyroid antibodies no
specific treatment can be offered to reduce the antibody titres; one uncontrolled
study in euthyroid thyroid antibody positive women with recurrent abortion
reported a significant success rate with thyroxine administration [26].
Hyperthyroidism and Pregnancy
Etiology
While the commonest cause of hyperthyroidism in pregnancy (which
affects up to 0.2% of pregnant women) is Graves’ disease (85–90%), other

Lazarus 30
causes such as hyperemesis gravidarum, toxic multinodular goitre, toxic ade-
noma and subacute thyroiditis may occur. It should be noted that most women
with nausea and vomiting in pregnancy do not have hyperthyroidism. Rarer
causes include struma ovarii, hydatidiform mole and one reported case of a
TSH receptor mutation activated only during pregnancy [27] (table 3).
Diagnosis
The clinical suspicion of hyperthyroidism may not be obvious as symp-
toms of tachycardia, sweating, dyspnoea and nervousness are seen in normal
pregnancy as are cardiac systolic flow murmurs. The diagnosis should always
be confirmed by estimation of circulating thyroid hormone concentrations. It
should be noted that serum thyroxine (both total and free) varies during normal
gestation. Recent national and internationally agreed guidelines suggest that
laboratories should be encouraged to develop normal ranges for total but more
particularly free T4 and T3, as well as TSH after the 1st trimester during preg-
nancy, all of which may change during the course of gestation. Normally the
TSH is suppressed in hyperthyroidism but in early pregnancy (approx. 9–12
weeks) TSH is usually suppressed by human chorionic gonadotrophin and may
also be lowered due to non-specific illness such as vomiting as well as multiple
pregnancy. This may lead to uncertainty in differentiating Graves’ hyperthy-
roidism from gestational thyrotoxicosis due to hyperemesis gravidarum. The
diagnosis of Graves’ disease may be conf irmed however by demonstrating the
presence of TSH receptor stimulating antibodies which are also useful markers
in the management of the condition.
Effects of Hyperthyroidism on Mother and Child
Several reviews of this subject are available [27–29]. Maternal complica-
tions of hyperthyroidism include miscarriage, placenta abruptio and preterm
Table 3. Causes of hyperthyroidism in pregnancy
Graves’ disease
Transient gestational hyperthyroidism (associated with hyperemesis gravidarum)
Toxic multinodular goitre
Toxic adenoma
Subacute thyroiditis
Trophoblastic tumour
Iodide-induced hyperthyroidism
Struma ovarii
TSH receptor activation

Thyroid Disease during Pregnancy 31
delivery. Congestive heart failure and thyroid storm may also occur and the risk
of pre-eclampsia is signif icantly higher in women with poorly controlled hyper-
thyroidism and low birth weight may be up to nine times as common. Neonatal
hyperthyroidism, prematurity and intra-uterine growth retardation may be
observed. A retrospective review documented a 5.6% incidence of fetal death or
stillbirth in 249 pregnancies from hyperthyroid mothers and a further 5% fetal
and neonatal abnormalities. Women with thyroid hormone resistance who,
despite being euthyroid, had high levels of circulating T4 had a significantly
increased miscarriage rate compared to euthyroid unaffected couples [30].
However, a recent study of women with subclinical hyperthyroidism, compris-
ing 1.7% of women, showed no significant adverse pregnancy outcomes sug-
gesting that treatment of this condition in pregnancy is not warranted [31].
Nevertheless, there is no doubt that overt clinical and biochemical hyperthy-
roidism should be treated to lessen the rate of complications described above.
Gestational amelioration of Graves’ disease is often associated with a reduction
in titre of TSHR Ab and a change from stimulatory to blocking antibody activ-
ity [32]. A variety of TSHR Abs directed against the TSH receptor may occur in
pregnant patients with Graves’ disease. Zakarija et al. [33], e.g., reported the
presence of high titres of two species of stimulating antibody in a patient who
gave birth to 3 children with transient neonatal hyperthyroidism due to transpla-
cental passage of the antibodies. A small number of newborns from mothers
with Graves’ disease develop central hypothyroidism. This is characterised by
low FT4 concentrations in combination with suppressed TSH levels and a
blunted TSH response after TRH administration. This situation may arise
because of passively transferred thyroxine from the mother who is hyperthyroid
in the short term or as a result of longer term (1 month) of neonatal hyperthy-
roidism due to passively transferred TsAb. There is a suggestion from the
clinical description that maternal thyrotoxicosis before 32 weeks of gestation
may be an important time point for the development of central hypothyroidism
in the baby. The syndrome provides some indication of the effect of excess
maternal thyroid hormones on the development of the hypothalamic pituitary
thyroid axis as well as the effect of excess neonatal thyroid hormones on the
same system [34].
Management of Graves’Hyperthyroidism
Preconception
There is a good case for a preconception clinic for patients with Graves’
hyperthyroidism who wish to become pregnant. Firstly, education about the
effects of the disease on maternal health and fetal well-being can be given to

Lazarus 32
allay fears which are commonly present in these women. The patient’s thyroid
status should be checked frequently to minimise risk of miscarriage should she
be hyperthyroid at the time of conception. If treatment had been commenced
with methimazole or carbimazole a change to propylthiouracil (PTU) is
recommended to reduce the admittedly rare occurrence of aplasia cutis [35]
and the equally rare methimazole embryopathy [36] reported following the
administration of the former drugs. The patient may have been rendered euthy-
roid by partial thyroidectomy or radioiodine therapy. However, if these proce-
dures are performed the patient may require thyroxine therapy (with a
requirement for an increase in dose and monitoring during gestation); in addi-
tion, there is still a small risk of neonatal hyperthyroidism even if the mother is
euthyroid.
Previously Treated Patients with Graves’Disease
These patients may have received antithyroid drugs, surgery or radioiodine
therapy and be euthyroid on or off thyroxine therapy. The important concern
here is that neonatal hyperthyroidism may still occur. Guidelines [37] state that
if previous antithyroid drugs alone have been used there is no need to measure
TSH receptor antibodies as the maternal thyroid function gives a reliable esti-
mate of fetal thyroid status and the risk of neonatal hyperthyroidism is very low
(table 4). TSH receptor antibodies should be measured early in pregnancy in a
euthyroid pregnant women previously treated by either of the other modalities.
If the level is high (as def ined by the local laboratory) at this time the fetus
should be evaluated carefully during gestation normally by checking the fetal
heart rate and the antibodies measured again in the last trimester (table 4). If
there is a detectable titre of stimulating antibodies at 36 weeks the neonate
should be checked for hyperthyroidism at birth.
Table 4. Guidelines for measurements of thyroid-stimulating hormone-receptor antibodies in a preg-
nant woman with Graves’ disease (reproduced from Laurberg et al. [37], with permission from the Society
of the European Journal of Endocrinology)
Patient status Measurement
Euthyroid – previous ATD not necessary
Euthyroid T4 therapy check in early pregnancy: if low or absent no further testing
Previous radioiodine therapy/surgery if high – check fetus and check antibodies in last trimester
Receiving ATD during pregnancy measure in last trimester
ATD Antithyroid drugs; T4 thyroxine.

Thyroid Disease during Pregnancy 33
Graves’Hyperthyroidism Inadvertently Treated with
Radioiodine in Early Gestation
The practical procedures surrounding the administration of radioiodine ther-
apy for Graves’ disease vary widely. In many clinics routine pregnancy testing is
not performed before 131I administration. Despite denial of pregnancy several
reports of inappropriate radioiodine administration have highlighted the concern
about the fetal radiation risk [27]. The maternal thyroid uptake, the gestational age
and the ability of the fetal thyroid to concentrate iodine are all vital in determining
the radioiodine exposure in utero. The fetal thyroid concentrates iodide after
13–15 weeks of gestation with peak concentrations occurring at 20–24 weeks and
is relatively more avid for iodine than the maternal thyroid [38]. The fetal tissues
are also more radio-sensitive. Administration of up to 15 mCi (555 MBq) 131I for
hyperthyroidism up to 10 weeks of gestation does not compromise fetal thyroid
function and the low fetal whole body irradiation is not considered sufficient to
justify termination of pregnancy. Limited clinical data suggests that 131I given
after 10–12 weeks results in biochemical hypothyroidism in the neonate. In these
cases management should maintain high normal maternal circulating thyroxine
levels and ensure prompt treatment of the neonate with thyroxine. The availability
of neonatal screening programmes for congential hypothyroidism ensures that
mental retardation can be avoided by appropriate thyroxine treatment.
Patients Found to Have Hyperthyroidism during Pregnancy
Medical therapy is preferred by most clinicians as radioiodine is contra-
indicated and surgery requires pre-treatment with antithyroid drugs to render
the patient euthyroid (table 5).
Table 5. Management of Graves’ hyperthyroidism in pregnancy
Confirm diagnosis
Start propylthiouracil
Render patient euthyroid – continue with low dose ATD up to and during labour
Monitor thyroid function regularly throughout gestation (4–6 times weekly) – adjust ATD if
necessary
Check TSAb at 36 weeks of gestation
Discuss treatment with patient
Effect on patient
Effect on fetus
Breastfeeding
Inform obstetrician and paediatrician
Review postpartum – check for exacerbation
ATD Antithyroid drugs; TSAb Thyroid-stimulating antibodies.

Lazarus 34
Propylthiouracil (PTU) should be given in a dose of 100–150 mg three
times daily until the patient becomes euthyroid at which time the dose should be
reduced to the lowest amount to maintain the euthyroid state with serum T4 at
the upper end of normal and continued up to and through labour. PTU is pre-
ferred to MMI or carbimazole because there is (in contrast to MMI) no evidence
of associated aplasia cutis [39]. There has been a suggestion of a specific methi-
mazole embryopathy in children exposed to the drug during the first trimester of
pregnancy which, although rare, has not been reported with PTU [36]. As these
risks are very small the patient who receives MMI can be normally reassured. In
terms of rapidity of action and fetal hypothyroidism inducing potential there is
probably little reason to choose PTU over MMI. The so-called ‘block and
replace’ regime in which thyroxine is given with antithyroid drug should not be
used because the dose of antithyroid drug would inevitably be too high and cause
fetal goitre and hypothyroidism. Hashizume et al. [40] reported that T4 adminis-
tration to pregnant women with Graves’ hyperthyroidism during pregnancy and
after delivery, together with methimazole, was effective in reducing the inci-
dence of postpartum recurrence of hyperthyroidism (vide infra) but these results
have not been confirmed. Rarely an episode of infection or the development of
pre-eclampsia may precipitate thyroid storm requiring the use of thionamides,
iodides, beta-blockers, fluid replacement and possibly steroid therapy and
plasmapheresis. PTU has a shorter half-life than methimazole and is not present
in as high a concentration in breast milk. Hence women receiving PTU can
breastfeed without significant risk to the neonate. Common complications of
thionamide therapy include skin rash, arthralgia and nausea in about 2% of
patients. A vasculitic syndrome may be more common with PTU. Methimazole
(or carbimazole) may be used as an alternative in this situation with only a 33%
chance of cross-reaction. Agranulocytosis is rare and is an indication for imme-
diate withdrawal of the drug and possible treatment with granulocyte colony
stimulating factor although the results are not always satisfactory. There is no
benefit in routine monitoring of the white blood count as the fall in white blood
count may be very rapid, but patients should of course be instructed to report
immediately if they develop a sore throat with or without a fever.
There is no significant effect of antithyroid drugs in utero or during breast-
feeding on the long-term health of the neonate or child assuming the dose dur-
ing gestation has not caused iatrogenic fetal hypothyroidism [41]. Beta-adrenergic
blocking agents such as propranolol may be used for a few weeks to ameliorate
the peripheral sympathomimetic actions of excess thyroid hormone which is
usually sufficient for the management of hyperthyroidism; prolonged use may
result in retarded fetal growth, impaired response to anoxic stress together with
postnatal bradycardia and hypoglycaemia. These drugs will need to be used in
the uncommon instance of intolerance to both of the available thionamide

Thyroid Disease during Pregnancy 35
drugs. Lithium therapy for hyperthyroidism is contraindicated in pregnancy
because of its known teratogenicity.
Monitoring of the Fetus in a Mother with Graves’ Disease
As neonatal thyrotoxicosis is known to be associated with neurological
impairment in some cases there is a requirement to monitor the fetus rather than
wait till birth to diagnose thyroid dysfunction. The use of serial in utero ultra-
sonographic measurements has been shown to accurately measure fetal thyroid
size [42]. If the fetal thyroid does not reduce in size in response to antithyroid
drug administration then transplacental passage of TsAb causing fetal hyper-
thyroidism should be suspected. A recent comprehensive study by Luton et al.
[43] showed that the sensitivity and specif icity of fetal thyroid ultrasound at
32 weeks for the diagnosis of clinically relevant fetal thyroid dysfunction was
92 and 100%, respectively.
Graves Orbitopathy
Eye symptoms and signs of Graves’ hyperthyroidism including excessive
watering, pain and irritation as well as chemosis, periorbital oedema, proptosis
and ophthalmoplegia may occur before, during or after the onset of hyperthy-
roidism and are more common in cigarette smokers. Treatment during preg-
nancy initially should be symptomatic with topical eye drops and elevation of
the head of the bed. Careful monitoring is necessary to check for any signs of
optic neuropathy. Oral or intravenous prednisone therapy is indicated in severe
congestive ophthalmopathy but should be used sparingly in pregnancy. In line
with the Graves’ hyperthyroidism, the ophthalmopathy would be expected to
improve during gestation.
Surgery
Subtotal thyroidectomy is indicated if control of the hyperthyroidism is
poor on account of poor compliance or inability to take drugs. Patients with a
very large goitre may also require surgery because of pressure symptoms.
Surgery is preferred in the second trimester as there is a higher risk of associated
abortion at an earlier stage of gestation. In general surgery should be avoided if
it is considered that medical therapy has a reasonable chance of success.
Management of other causes of hyperthyroidism:
(a) Hyperemesis gravidarum is common and around 5% of cases require
hospital admission because of dehydration and ketosis. Thyroid function should
be checked in these patients; a correlation has been established between the
severity of the hyperemesis and thyroid function with an elevated FT4 and FT3

Lazarus 36
with suppressed TSH. In those patients who are hyperthyroid antithyroid drugs
may be given. The diagnosis of gestational thyrotoxicosis will be confirmed by
noting the absence of TSH receptor stimulating antibodies.
(b) Toxic multinodular goitre and toxic adenoma: Radioiodine which may
be a treatment of choice is absolutely contraindicated in pregnancy. The condi-
tions may be managed with antithyroid drugs during gestation; if necessary
surgery may be performed during the 2nd trimester but if possible it is better to
postpone this till the postpartum period.
(c) Subacute thyroiditis: The diagnosis is suggested by the presentation of
a painful thyroid in the presence of hyperthyroidism. As radionuclide evaluation
(which would demonstrate a low iodine uptake) is contraindicated diagnosis
may be made with a fine needle aspiration biopsy of the thyroid associated with
an elevation in systemic markers of inflammation. Treatment is firstly with
analgesics for pain and oral prednisolone therapy if inflammation is severe.
Frequent monitoring of thyroid function is required as a small number of
patients will develop hypothyroidism.
The other causes of hyperthyroidism listed are rare and referral to a spe-
cialist centre is advised.
Postpartum Graves’ Disease
Patients with Graves’ disease may develop Graves’ hyperthyroidism as a
post partum phenomenon due to the immune rebound of TSH receptor antibod-
ies. In Graves’disease patients, TSHR Abs have been shown to decrease during
late gestation with a significant rebound in the late postpartum [44]. In this sit-
uation the hyperthyroidism of Graves’ disease may be followed immediately by
transient hypothyroidism due to co-existing destructive postpartum thyroiditis
during the early postpartum period despite increasing TSAb activity. This may
be important when considering postpartum relapse of the disease. Screening for
TSAb during pregnancy may detect patients with Graves’ disease at risk of
postpartum relapse and is also helpful when measured postpartum in diagnos-
ing Graves’ disease as the cause of hyperthyroidism as opposed to the hyperthy-
roid phase of postpartum thyroiditis [45]. The cost benefit of this proposed
screening strategy is not available and it is probably not practical in most
countries.
Hypothyroidism
The incidence of hypothyroidism during pregnancy is around 2.5% [46].
The aetiology is usually autoimmune thyroiditis characterised by the presence
of anti-TPO antibodies. Significant titres of these antibodies are found in about
10% of women at about 14 weeks of gestation. Other causes of hypothyroidism
in pregnancy include postoperative thyroid failure and non compliance with

Thyroid Disease during Pregnancy 37
existing thyroxine therapy. In areas of iodine deficiency the circulating maternal
thyroxine concentrations are low although TSH is usually in the normal range.
In this situation the incidence of thyroid abnormalities is higher and in particu-
lar thyroid autoimmunity may be associated with diminished thyroid reserve
and an increase in spontaneous abortion.
The diagnosis of hypothyroidism is made by noting an elevated TSH
accompanied by a low serum FT4. Subclinical hypothyroidism is recognised to
be equally as important in its adverse effects, affecting mother and neonate as
the full expression of the disease [47]. Maternal hypothyroxinaemia (without
increased TSH) is also being increasingly accepted as deleterious to the neu-
ropsychological development of the child [48]. Care should be taken in the
interpretation of TSH concentrations in early gestation due to the thyrotrophic
effects of hCG.
Previous studies have documented the effects of hypothyroidism on mater-
nal and fetal well-being, drawing attention to increased incidence of abortion,
obstetric complications and fetal abnormalities in untreated women. Women
already receiving thyroxine for hypothyroidism require an increased dose dur-
ing gestation. This is critical to ensure adequate maternal thyroxine levels for
delivery to the fetus especially during the first trimester. The dose should nor-
mally be increased by 50–100 g/day as soon as pregnancy is diagnosed; sub-
sequent monitoring of TSH and FT4 is then necessary to ensure correct
replacement dosage [49].
Maternal Thyroid Disease in Pregnancy: Effect on
Child Development
Thyroid hormones are major factors for the normal development of the
brain. The mechanisms of actions of thyroid hormones in the developing brain
are mainly mediated through two ligand-activated thyroid hormone receptor
isoforms [50]. It is known that thyroid hormone deficiency may cause severe
neurological disorders resulting from the deficit of neuronal cell differentiation
and migration, axonal and dendritic outgrowth, myelin formation and synapto-
genesis [23]. This is the situation well documented in iodine-deficient areas
where the maternal circulating thyroxine concentrations are too low to pro-
vide adequate fetal levels particularly in the first trimester. Recent work has
raised concern that in an iodine-sufficient area maternal thyroid dysfunction
(hypothyroidism, subclinical hypothyroidism or hypothyroxinaemia) during
pregnancy results in neuro-intellectual impairment of the child. Two studies,
have shown that a low thyroid hormone concentration in early gestation can be
associated with signif icant decrements of IQ of the children when tested at

Lazarus 38
7 years and 10 months, respectively [51, 52]. Pop et al. [53] have also shown a
significant decrement in IQ in children aged 5 years whose mothers were
known to have circulating anti-TPO antibodies at 32 weeks gestation and were
biochemically euthyroid. Haddow et al. [51] found that the full IQ scores of
children whose mothers had a high TSH during gestation were 7 points lower
than controls (p 0.005) and that 19% of them had scores of less than 85 com-
pared to 5% of controls (p 0.007). More recently, the Dutch group [54] have
again confirmed that maternal hypothyroxinaemia during early gestation is an
independent determinant of neurodevelopmental delay. Further, they have sug-
gested that when FT4 concentrations increase during gestation in women who
have had low FT4 in early pregnancy infant development is not adversely
affected [54]. The neurodevelopmental impairment is similar to that seen in
iodine-deficient areas and implies that iodine status should be normalised in
regions of def iciency. However, much of the USA and parts of Europe are not
iodine-deficient which raises the question of routine screening of thyroid func-
tion during early pregnancy or even at preconception. Another reason for
screening could be to focus on the risk for postpartum thyroiditis [55]. The fol-
lowing numerical issues should be considered in relation to such a strategy: the
incidence of an elevated TSH in pregnancy is around 2.5%; the prevalence of
anti-TPO antibodies is 10% as ascertained at a routine antenatal booking clinic;
the incidence of thyroid dysfunction observed in anti-TPO-positive pregnancies
is up to 15%. While these numbers are impressive the question as to whether
there is any effective intervention must be addressed. Although one study has
reported an improved psychological outcome in children from thyroxine-treated
mothers (compared to those children from inadequately treated mothers) there
are no results of any formal prospective randomised trials examining, for exam-
ple the effect of T4 intervention therapy given to susceptible women on subse-
quent child development. These considerations emphasize that it is important to
ensure an adequate thyroid hormone supply to the developing fetus in all areas
of the world whether iodine-deficient or not [56]. Further studies in this area are
required to answer questions relating to thyroid function screening before and
during pregnancy.
Nodular Thyroid Disease
Thyroid nodules are claimed to be detected in up to 10% of pregnant
women. Fine needle aspiration biopsy is the first investigation of choice which
may yield a malignancy/suspicious result in 35% [57]. When malignancy is
diagnosed it is usually a differentiated tumour which may be surgically resected
in the second trimester or in some cases safely left until the postpartum period
before therapy is started. The impact of pregnancy on thyroid cancer seems to
be minimal in that there is no difference in rates of metastases or recurrence

Thyroid Disease during Pregnancy 39
compared to non-pregnant women with the same disease [58]. Whether women
already treated for thyroid malignancy should become pregnant is of concern
but current evidence suggests that differentiated thyroid cancer should not
inhibit an intended pregnancy. Previous 131I therapy does not result in demon-
strable adverse events in subsequent pregnancies although miscarriage appears
to be more frequent during the year preceding conception [59].
Neonatal Thyrotoxicosis
About 1–5% of children born to mothers with Graves’ disease will
develop neonatal thyrotoxicosis due to transplacental passage of maternal thy-
rotrophin receptor stimulating IgG antibodies [60]. It has been established that
the presence of TsAb at 36 weeks gestation in women with Graves’ disease has
a significant positive predictive value for the probability of neonatal hyperthy-
roidism. Fetal hyperthyroidism is associated with intrauterine growth retarda-
tion, craniosynostosis and fetal death. In neonates cardiac failure, arrhythmias,
hepatosplenomegaly and jaundice may be seen. In addition they may have
vomiting, poor weight gain and be hyperkinetic. Treatment includes the admin-
istration of iodine, PTU, dexamethasone and adequate sedation. Reassurance
may be given to the parents that the disease will remit permanently in 8–20
weeks due to the known half-life of IgG and remission by 10 months is nearly
always achieved [61]. A subset of infants with neonatal hyperthyroidism appear
to produce their own thyroid-stimulating immunoglobulins and therefore
will not respond as readily to antithyroid drug therapy and require ablative
treatment.
In the absence of maternal thyroid immune disorder, non autoimmune
hyperthyroidism due to an activating thyrotropin receptor germ line gene muta-
tion must be considered as a cause for neonatal hyperthyroidism. The condition
may be sporadic or be inherited in an autosomal, dominant pattern and is char-
acterised clinically by a variable severity of hyperthyroidism and goitre,
absence of thyroid associated ophthalmopathy and dermopathy and negative
thyroid antibodies [61]. Other clinical features including craniosynostosis,
advanced bone age, low head circumference and psychomotor retardation have
been described. A recent analysis of all reported cases of non autoimmune
hyperthyroidism [62] drew attention to the observation that the mean gestation
duration was significantly less than that seen in children with congenital
hypothyroidism due to inactivating mutations of the TSH receptor (35.8 vs.
39.4 weeks, p 0.003). The role of excess thyroid hormone in premature
delivery is not yet established but is clearly relevant and requires further inves-
tigation. It is critical to determine if there is an activating TSH receptor muta-
tion as the treatment in this case must be thyroid ablation to achieve long-term
remission.

Lazarus 40
Neonatal hyperthyroidism has occurred due to the McCune-Albright syn-
drome [60], a condition characterised by a somatic activating mutation in the
gene GNAS1 that encodes the -subunit of GTP-binding protein that stimulates
adenylate cyclase. In the murine D3 knock out mouse referred to previously
[23], observation has shown that the lack of D3 function resulted in a probable
overexposure of T3 during a critical period of thyroid axis development fol-
lowed later by central hypothyroidism.
In conclusion a considerable increase in our appreciation of the physiol-
ogy, immunology and clinical aspects of thyroid function in relation to gestation
has occurred during the past decade. Important research into thyroidal influ-
ence on fetal development as well as delivery of thyroid hormones to the fetus
will drive future clinical studies to improve recognition and management of thy-
roid disease before, during and after pregnancy.
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Thyroid Disease during Pregnancy 43
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Prof. J.H. Lazarus
Centre for Endocrine and Diabetes Sciences, University Hospital of Wales
Heath Park
Cardiff, CF14 4XN, Wales (UK)
Tel. 44 2920 716900, Fax 44 2920 712045, E-Mail Lazarus@cf.ac.uk

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 44–55
Thyroid Function in the Newborn
and Infant
Bessie E. Spiliotis
University of Patras School of Medicine, Patras, Greece
The thyroid gland is an endocrine organ of vital importance for the neonate
since normal thyroxine concentrations are essential for the normal neurodevel-
opment of the newborn and subsequently the infant and child. The recent
advances in our understanding of fetal thyroid hormone physiology have also
shown the importance of the placental transfer of maternal thyroid hormones
and the normal function of the fetal thyroid gland for normal brain development
of the fetus with subtle differences in the outcome of the term newborn as
opposed to the preterm newborn.
Fetal Thyroid Function and Maternal Thyroid Hormones
The onset of active fetal thyroid function (FTF) coincides with full matura-
tion of the pituitary portal vessels at 16–20 weeks of gestation [1]. Before the
period of FTF, the neocortex of the fetal brain undergoes important phases of
development which are largely dependent on the presence of thyroxine (T4) and
triiodothyronine (T3) [1, 2]. Low concentrations of T4 and T3 are present in
early embryonic and fetal tissue before the onset of FTF in concentrations that
are directly influenced (especially the T4 levels) by those in the maternal circu-
lation [3–14]. When maternal T4 and T3 concentrations are abnormally low in
the f irst trimester, fetal brain development is adversely affected and there is a
defect in the histogenesis and cerebral cortex cytoarchitecture, defective neu-
ronal migration at the beginning of fetal neocorticogenesis, and a defective cor-
tical expression of several genes in the fetal brain such as neuroendocrine-specific
protein A [15, 16]. At the time of neural tube closure thyroid hormone receptor
(TR) isoforms are already present in the fetal brain and these most likely medi-
ate the biological effects of the T3 that has been locally generated from T4

Thyroid Function in Newborns 45
transferred from the mother. Consequently, if the mother has T4 deficiency then
the fetus will be T3-deficient even if maternal T3 is normal. This is because
during early development serum-derived T3 essentially does not contribute to
cerebral T3. Studies have shown that normal concentrations of T3 alone in the
maternal or fetal circulation without normal T4 concentrations have no protec-
tive effect on the fetal brain because during fetal and postnatal development
cerebral structures depend entirely on the local generation of T3 from T4 by
type II 5⬘-iodothyronine deiodinase (D2), the activity of which is inversely
related to the availability of T4 [17]. This might explain why in most cases of
congenital hypothyroidism in a newborn with a mother who has normal thyroid
function there is no permanent severe central nervous system damage when T4
is administered in the first 3 months of neonatal life. In this case, the fetal brain
has not been severely damaged before birth and normal development can still
be achieved by prompt administration of T4 [18–22]. The most severe brain
damage occurs when both the mother and fetus have low T4 levels during
the entire gestational period as occurs in iodine-deficient environments.
Iodine deficiency during pregnancy can result in a global loss of 10–15
intellectual quotient points at a population level in the offspring and it consti-
tutes the world’s greatest single cause of preventable brain damage and mental
retardation [23–27].
Maternal-Fetal Unit and the Function of the Fetal Thyroid Gland
During gestation the normal function of the maternal-fetal unit is crucial
since it is the cornerstone for the physiological development of the fetus.
Ultrasound-guided amniocentesis and cordocentesis have given researchers a
greater insight into the mechanisms of maternal-fetal transfer of T4 and T3
which is crucial for normal brain physiology of the fetus. The human fetus is
surrounded by two distinct fluid cavities for most of the first trimester: the inner
(amniotic) cavity contains the fetus, and the outer (exocoelomic) cavity sepa-
rates the amniotic cavity from the placenta and contains the secondary yolk sac
(fig. 1a). The exocoelomic cavity is the site of important molecular exchanges
between the mother and the fetus [28–30]. The coelomic fluid results from an
ultrafiltrate of maternal serum with specific placental and secondary yolk sac
bioproducts [30]. It has been shown that T4 (and possibly T3) is present in
colelomic fluid as early as 5.6 weeks’ gestation [29, 31]. Maternal T4 is trans-
ferred into the exocoelomic cavity and subsequently into the fetal gut and cir-
culation via the secondary yolk sac. The second mode of transfer of maternal
nutrients starts at the end of the first trimester. The secondary yolk sac and 2/3
of the placental mass degenerate, and the amniotic cavity containing the fetus

Spiliotis 46
grows and obliterates the exocoelomic cavity (fig. 1b) considerably changing
the maternal-fetal exchange pathways. From the 11 to 12th weeks of gestation
and onward, maternal nutrients, including thyroid hormone, are transferred by
the placenta directly into the fetal circulation.
The placenta plays an important role in the development and function of
the thyroid gland in the fetus. The placenta produces various hormones that can
influence the fetal thyroid gland (e.g. chorionic gonadotropin, TRH). The most
important role of the placenta though is in regulating the passage of hormones
and drugs, from the mother to the embryo, which influence the fetal thyroid
gland. For many years its was unknown how the very small amounts of mater-
nal T4 which are allowed to pass the placental barrier (sometimes as low as 1%
of the maternal concentrations in the first trimester) can play such a major role
in the normal fetal physiology of the developing brain and fetal tissues. The
answer came from studies which showed that fetal concentrations of total T4
were misleading because the proportion of T4 that is not bound to proteins
Fig. 1. Maternal-fetal unit during the
first (a) and second (b) trimesters of pregnancy.
AC ⫽Amniotic cavity; CL ⫽chorion laeve;
ECC ⫽exocoleomic cavity; P ⫽placenta;
SYS ⫽secondary yolk sac; U ⫽uterus;
UC ⫽umbilical chord. Adapted from [29]
with permission.
UU
AC
UC
UC AC
ECC
ECC
SYS
U
U
CL
U
U
P
P
P
UU
a
b

Thyroid Function in Newborns 47
(FT4) is much higher than in adult sera and the concentrations of T4 that are
available to developing tissues reach values that are comparable to those know
to be biologically active in their mothers [28, 29] (f ig. 2). The T4-binding pro-
teins and the concentrations of maternal T4 or FT4 that are allowed to pass the
placental barrier determine the concentrations of FT4 in the fetal fluids and this
is determined ontogenically. Therefore, it has become clear why an eff icient
barrier to complete maternal thyroid hormone transfer is necessary as the same
concentrations that are available in the maternal sera might possibly be toxic to
the developing fetal tissues [22, 30]. However, if the fetus is hypothyroid the
placenta allows T4 from the mother to pass to the fetus in larger quantities [31].
In contrast to what happens with thyroid hormones the placenta allows the
free passage of TRH and iodine from the mother to the fetus. As mentioned pre-
viously, if there is iodine insufficiency in the mother the neonate may develop
severe psychomotor retardation [23–27]. Furthermore, the placenta allows the
passage of certain drugs (propylthiouracil and methimazole) and immunoglobu-
lins (like TSH-receptor-stimulating antibodies) from the mother to the fetus
which can influence the function of the thyroid gland of the fetus and the neonate.
Hypothalamic-Pituitary-Thyroid Axis
during Gestation
Thyrotropin-releasing hormone (TRH) in the fetal hypothalamus regulates
the thyroid-stimulating hormone (TSH) in the pituitary gland early on in the
fetus. Pituitary TSH can be detected for the first time around the 10–12th week
of gestation. Its concentrations in the serum of the fetus are approximately
3–8 mIU/l from week 12 and increase gradually during the final weeks of
gestation to 10–12 mIU/l. This is accompanied by a parallel increase in fetal
thyroid radioiodine uptake and by a progressive increase in the serum concen-
trations of both total T4 and FT4. It is intriguing that TSH bioactivity is greatly
increased with respect to that circulating in the mother in spite of the increasing
FT4 concentrations in the fetus (fig. 2).
This confirms the hypotheses that fetal serum TSH is not of maternal ori-
gin, that it is not under hypothalamic neuroendocrine control by the fetal hypo-
thalamus and that it is not under negative feedback control by the thyroid
hormones [26]. This raises the question though of the origin of fetal TSH. There
have been reports of synthesis of TSH by the rat and monkey brain [32]. Also
primary cultures of human astrocytes and early human fetal brain have shown
the presence of a TSH receptor in these areas of the brain [33]. This receptor
mediates extrathyroidal cAMP-independent biological effects of TSH, among
which is the stimulation of type II deiodinase in astroglial cells. It has been

Spiliotis 48
Fig. 2. Parameters of thyroid hormone
status from 12 weeks Postmenstrual age
until birth obtained in vivo by cordocentesis.
a, bFetal FT4 serum concentrations reach
maternal concentrations shortly after
midgestation whereas those of FT3 are low
throughout pregnancy. Also shows the FT4
levels found in sera from premature babies
(䊏) as compared with those in utero. cMost
fetal TSH levels are higher than those of the
mother. Adapted from [17] with permission.
12
9
6
3
0
12 20
TSH (mU/l)
28
Maternal
Fetal
36
Postmenstrual age (weeks)
10
8
6
2
0
12 20
Free T3 (pmol/I)
28 36
4
25
20
15
5
0
12 20
Free T4 (pmol/I)
28 36
10
Maternal
Fetal
Maternal
Preterm
Fetal
a
b
c
speculated that the possible extrathyroidal actions of TSH might be acting in
brain development as a growth factor [34].
Thyroxine-binding globulin (TBG) also increases during this period as a
result of the action of placental estrogens on the embryonic liver [35].

Thyroid Function in Newborns 49
During the second trimester of gestation there is a gradual increase in the
ratio of FT4/TSH in the embryonic serum [36]. The concentration of T3 in the
serum of the fetus is low during the entire period of pregnancy because type I
deiodinase has not matured yet [37].
The concentrations of TRH in the embryonic serum are higher than those
in the mother because there is additional production of TRH by the placenta and
because TRH is metabolized more slowly in the embryo [37]. It has been spec-
ulated that the reason for the significant decrease of the high TSH levels at birth
may be the neonate’s sudden severance from the placenta which produces high
amounts of TRH-like peptides that might be stimulating extrapituitary synthesis
of TSH or TSH-like proteins [26].
As mentioned earlier, the activity of the type I deiodinase is low during the
entire period of pregnancy and consequently the concentrations of T3 in the
fetus are low, i.e. 50–60 ng/dl when the neonate is born. The reason T3 is low
during fetal life is not known but it is thought that it is low in order to avoid
thermogenesis in the fetal tissues and in order to facilitate the anabolic func-
tions of the rapidly developing fetus [36].
In contrast, types II and III deiodinase, which are expressed in the brain
and the pituitary of the fetus, are activated mid-way through gestation.
Consequently, the levels of T3 in the fetal brain are 60–80% of those in adults
already from the 20–26th week of gestation despite T3 concentrations being
low in the serum of the fetus [30]. If the fetus is hypothyroid then the action of
type II deiodinase increases in the brain of the fetus while the action of type III
deiodinase decreases. The reason for this is so that larger quantities of T3 can be
produced in order to protect the brain as long as there are physiological levels of
T4 in the mother [38].
Action of the Thyroid Hormones
The action of the thyroid hormones in the adipose tissue, the liver, the
heart, the muscles and the bones are expressed during neonatal but not fetal life.
It is not known whether this delay in the action of the thyroid hormones in these
tissues is related to the maturation of the thyroid hormone signaling pathway at
a molecular level or related to the maturation of thyroid hormone metabolism.
The actions of the thyroid hormones, which are specific to each individual tis-
sue, depend on the prevalent isoform of the thyroid hormone receptor (TR)
which is expressed in each tissue and on cofactors at the site of action of the
thyroid hormones. The highest concentrations of TRs are found in developing
neurons and in various regions in the brain of the fetus and the neonate such as
cortex, cerebellum, and visual and auditory cortices. There are many indications

Spiliotis 50
that the TR␤1 isoform of the receptor is the one which promotes, via T3,
the vital development of the central nervous system in the fetus, the neonate and
the child in combination with the ␣1 receptor [39, 40]. It is of interest that the
deafness that exists in the TR␤1 knockout rat also exists in endemic cretinism
in some patients with resistance to thyroid hormones due to lack of the TR␤1
gene [41].
Thyroid Synthesis in the Full-Term Newborn
During the birth process many changes occur in the function of the thyroid
gland in the full-term neonate. The most dramatic change is the abrupt increase
in TSH which takes place in the f irst 30 min after parturition which can reach
levels of 60–70 mIU/l. This increase causes a major stimulation of the thyroid
gland with an increase in T4 in the serum by about 50% and a 3- to 4-fold
increase in T3 within 24h [36, 37]. Studies in experimental animals have shown
that the increase in TSH is a consequence of the relative hypothermia that exists
in the environment outside of the uterus. The increase in T3 occurs not only
because TSH levels increase but also because of an increase in the action of type
I deiodinase during birth. The high levels of reverse T3 (rT3) decrease relatively
quickly during the neonatal period. The increase in the action of type II deiodi-
nase causes an increase in T3 in the adipose tissue of the neonate which is nec-
essary for thermogenesis and the synthesis of proteins in the neonate [31, 37].
Within the thyroid gland during the neonatal period in the full-term infant
it has been shown that both the colloid content in the neonatal thyroid tissue and
the amount of iodine in extracted proteins display transient variations.
Thyroid Synthesis in the Pre-Term Newborn
The function of the thyroid gland in the pre-term neonate reflects the imma-
turity of the hypothalamic-pituitary-thyroid axis which corresponds to the week
of gestation of the pre-term neonate. There is a gradual increase in the concen-
tration of TSH, TBG, T3 and T4 during gestation [42, 43]. After parturition there
is an increase in T4 and TSH just as in full-term neonates, but the increase is
much smaller in pre-term neonates than what it is in the full-term neonates and
there is a dramatic decrease in the concentration of T4 during the following 1–2
weeks [44]. This decrease in T4 is more important in low birthweight and signif-
icantly premature neonates (⬍1.5 kg and ⬍30 weeks of gestation) where the
level of T4 may not be detectable [44, 45]. In most cases though total T4 is
influenced and not FT4 as much since TBG is low in pre-term neonates due to

Thyroid Function in Newborns 51
immaturity of the liver. Another reason for the fall in T4 in pre-term neonates is
the reduced storage of iodine which exists due to the prematurity [31]. Preterm
neonates have greater difficulty in maintaining a positive iodine balance than
full-term neonates because pre-term neonates lose large quantities of iodine in
the urine and because their iodine uptake system is immature [45–47]. Also
because the requirement for thyroid hormones is considerably enhanced within
the first few months of life it is normal that the turnover rate of thyroidal iodide
increases. Even in the presence of TG with normal hormone content, the renewal
rate of the intrathyroidal pool of T4 has to be very rapid to provide the premature
infant with a normal hormone supply. This could be an important factor for
increased risk of neonatal hypothyroxinemia in very premature infants [47].
Due to the immaturity of the thyroid gland preterm neonates have a
reduced ability of adjusting to excessive amounts of iodine which are found in
skin antiseptics which contain iodine and are frequently used in preterm neona-
tal units. That is why it is recommended that these should not be used.
Additionally, rT3 remains at higher levels and T3 remains at low levels for
a longer time in pre-term than in full-term neonates because type I deiodinase is
immature [31].
Function of the Thyroid Gland in the Neonate and Infant
After the large increase in the serum concentrations of the thyroid hor-
mones and TSH which occur during the first days of neonatal life there is a
gradual decrease in the levels of T4, T3 and TSH during the life of the neonate
and infant. The most important difference between this period and adult life is
that there is a larger production and utilization of T4 in the neonates and infants.
The neonates produce 5–6 ␮g/kg/day of T4 with a gradual decrease during the
first years of life to reach levels of 2–3 ␮g/kg/day of T4 at 3–9 years of age. This
is in contrast to adults who produce 1.5 ␮g/kg/day of T4 [42].
The weight of the neonatal thyroid gland is a good indicator of maternal
iodine intake during pregnancy. On an adequate maternal iodine intake, the
weight of the neonatal thyroid is less than 1.5 g [48]. Due to the increased
turnover of iodine and consequently of thyroglobulin in the early neonatal
period, decreased iodine intake will bring about an increased consumption of
reserve colloid, as a result of the increased activity of the follicular cells which
would at the beginning cause a decrease in thyroid weight. Then due to the
iodine deficiency, after prolonged TSH stimulation there might be hypertrophy
of the follicular epithelium and hyperplasia may occur leading to an increase in
thyroid weight. In areas of severe iodine deficiency, average thyroid weights in
term newborn infants are approximately 3 g [49].

Spiliotis 52
The size of the normal thyroid gland increases gradually by approximately
1 g per year until the age of 15 when it has reached adult size, i.e. 15–20g [31].
Recent studies have shown that neonates with pathological levels of TSH
in the first days of life which have physiological levels of TSH at follow-up
within the first or second month of life (transient hypothyroidism) have a 70%
chance of having mild thyroid gland dysfunction (subclinical hypothyroidism)
at 16 months of age and older (f ig. 3). It is worthy to note that there is a high
prevalence of antithyroid antibodies in the children who are false-positive at
screening [50, 51].
It has also recently been shown that when there is intrauterine growth retar-
dation, when neonates have a low birthweight and are short for gestational age
(SGA), there is a considerable decrease in free T4 and free T3, and a moderate
increase in TSH in childhood especially in the children that show blunted
‘catch-up’ growth [51–53]. Additionally, a significant reduction in the expres-
sion of thyroid receptor isoforms in the central nervous system of the SGA
neonates was found which jeopardizes psychomotor development [54]. The rea-
son for these changes seems to be that in SGA neonates, due to poor nutrition of
the embryo, there is an intrauterine reprogramming of certain organs (such as
the pancreas, liver and muscles) in order for the embryo to survive, and this
reprogramming appears to include the thyroid gland [52]. The reprogramming
of these organs in the SGA neonates appears to be permanent.
Fig. 3. A serum TSH concentration higher than normal (3.9 mIU/l or the 99.7th per-
centile of the concentrations obtained in control infants) was found at 16–44 months of age
in 28 of 56 infants who had high TSH at birth but normal FT4 concentrations. Adapted from
[51] with permission.
12
10
8
6
4
2
0
TSH (mU/l)
Controls Group I Group II
‘False-positive’

Thyroid Function in Newborns 53
In conclusion, thyroid function and subsequent normal neurodevelopment
in the neonate is greatly influenced by the conditions present in the fetal-maternal
unit during gestation which are dependent upon normal maternal iodine and
thyroxine status as well as a good nutritional capacity of the fetus.
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Bessie E. Spiliotis, MD
Division of Pediatric Endocrinology, Department of Pediatrics
University of Patras School of Medicine
GR–26504 Rion Patras, TK (Greece)
Tel. 30 2610 993 948, Fax 30 2610 910 869, E-Mail besspil@endo.gr

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 56–79
Pediatric Aspects of Thyroid Function
and Iodine
Meyer Knobela, Geraldo Medeiros-Netob
aThyroid Unit, Division of Endocrinology and Metabolism, Hospital das Clínicas, and
bDepartment of Internal Medicine, University of Sao Paulo Medical School,
Sao Paulo, Brazil
Iodine is a nonmetallic micronutrient present in the human body in minute
amounts (15–20 mg), almost exclusively in the thyroid gland. It is an essential
component of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3),
comprising 65 and 59% of their respective weights. Thyroid hormones, and
therefore iodine, regulate many key biochemical reactions, especially protein
synthesis and enzymatic activity. They also play a determining role in the
process of early growth and development of most organs, especially that of the
brain, which occurs in humans during the fetal and first 2–3 years of postnatal
life. Consequently, iodine deficiency, if severe enough to affect thyroid hormone
synthesis during this critical period, will result in hypothyroidism and brain
damage. The clinical consequence will be irreversible mental retardation [1].
Iodine is found in relative abundance in marine plants and animals, in the
thyroid gland of vertebrates, in deposits of organic origin, in certain natural
mineral water, in sedimentary phosphate rock, and in association with certain
mineral deposits. Most of the Earth’s iodine is found in its oceans and most of
the iodine ingested by humans comes from food of animal and plant origin.
This iodine, in turn, is derived from the soil. In general, the older an exposed
soil surface, the more likely the iodine has been leached away by erosion. Only
a relatively small fraction is derived from drinking water. A most important fac-
tor in the depletion of iodine has been glaciation, which removes old soil and
scrapes bare the virgin rocks, which have iodine concentrations far lower than
those of the covering soil. This situation is found in regions that remained
longest under Quaternary glaciers and lost their iodine when the ice thawed.
Mountainous regions, such as those found in the Himalayas, the Andes, the
Alps, Vietnam, China, Indonesia and Africa and also in flooded river valleys,

Pediatric Aspects of Thyroid Function and Iodine 57
such as the Ganges, are among the most severely iodine-deficient areas in the
world [2, 3].
Optimal Iodine Intake
The recommended daily iodine intake is variable depending the age of the
subject (table 1). The recommended intake of iodine in neonates reflects the
observed mean iodine intake of young infants exclusively fed human milk in
iodine-replete areas [4, 5]. However, it is well established that the iodine content
of breast milk is critically influenced by the dietary intake of the pregnant and
lactating mother [4, 5]. The iodine intake required in order to achieve a positive
iodine balance and to insure a progressively increasing intrathyroidal iodine
pool in the growing infant is at least 15 g/kg/day in full-term and 30 g/kg/day
in preterm infants; this corresponds approximately to 90 g/day [6].
These recommendations derive from consensus statements by several
groups, including the International Council for Control of Iodine Deficiency
Disorders, the World Health Organization, UNICEF, and the Food and Nutrition
Board of the US National Academy of Sciences. The amounts are based on the
following: the calculated daily thyroid hormone turnover in euthyroidism, the
iodine intake producing the lowest values for serum thyrotropin (TSH) and
for serum thyroglobulin (TG), the amount of thyroid hormone replacement
Table 1. Recommended iodine allowance (RDA) and urinary iodine concentration for different age
groups (adapted from [6–8])
Life stage Age Estimated Urinary iodine
iodine intake concentration
g/day g/l
Premature infants 0–6 months 90 ⬍100
Term infants 0–6 months 90 ⬍100
Children 6–12 months 90 ⬍100
Children 1–3 years 90 100–150
Children 4–8 years 90 100–150
Children 9–13 years 120 100–150
Adolescents 14–18 years 150–200 100–200
Adults 19 years and older 150–299 100–299
Pregnant women all ages 230–300 200–300
Lactating women all ages 260–300 200–300
Recent ICCIDD RDA for pregnant and all ages 250–350 200–300
lactating women

Knobel/Medeiros-Neto 58
necessary to restore euthyroidism to athyreotic subjects, the iodine intake asso-
ciated with the smallest thyroid volumes in populations, and the lowest inci-
dence of transient hypothyroidism in neonatal screening with blood spot TSH.
About 90% of iodine is eventually excreted in the urine. The median urinary
iodine concentration in casual (‘spot’) samples, expressed as micrograms per
liter (␮g/l), is currently the most practical biochemical laboratory marker of
community iodine nutrition. It is more useful and much simpler than measuring
24-hour samples or calculating urinary iodine/creatinine ratios. Recommendations
by the International Council for the Control of Iodine Deficiency Disorders,
WHO, and UNICEF [9] set 100 ␮g/l as the minimal urinary iodine concentra-
tion for iodine sufficiency. This figure corresponds roughly to a daily intake of
150 ␮g iodine. The upper limit for safe iodine intake is uncertain and varies
widely among individuals and populations. Occasional intake up to 1 mg iodine
per day may be safe for most people, and much higher amounts are usually tol-
erated for a brief period of time, without major problems.
Iodine Deficiency
When the aforementioned physiological requirements are not met in a
given population, a series of functional and developmental abnormalities occur,
including thyroid function abnormalities.
Iodine deficiency is now accepted as the most common cause of preventable
brain damage in the world. According to the World Health Organization
(WHO), iodine deficiency disorders (IDD) affect 740 million people through-
out the world, and nearly 50 million people suffer from some degree of
IDD-related brain damage. The spectrum of IDD includes endemic goiter and
cretinism, endemic mental retardation, decreased fertility rate, increased
perinatal death and infant mortality, and varying degrees of other growth and
developmental abnormalities (table 2). Nearly 2.2 billion people throughout the
world live in areas of iodine deficiency and risk its consequences. Major inter-
national efforts have produced dramatic improvements in the correction of
iodine deficiency in the 1990 decade mainly through the use of iodized salt and
iodized vegetable oil in iodine deficient countries [7].
The mechanism by which the thyroid gland adapts to an insufficient iodine
supply is to increase the trapping of iodide as well as the subsequent steps of the
intrathyroidal metabolism of iodine leading to preferential synthesis and secre-
tion of T3. They are triggered and maintained by increased secretion of TSH,
which is ultimately responsible for the development of goiter. The acceleration
of the main steps of iodine kinetics and the degree of hyperstimulation by TSH
are much more marked in the pediatric age groups, including neonates, and the

Pediatric Aspects of Thyroid Function and Iodine 59
development of goiter appears as an unfavorable side effect in the process of
adaptation to iodine deficiency during growth, because it leads to a vicious
cycle of iodine loss and defective thyroid hormones synthesis [11] (table 3).
Endemic goiter is one of the earliest and most visible sign of iodine defi-
ciency [12]. According to iodine def iciency level this response may be adequate
to preserve euthyroidism, but at the cost of an enlarged thyroid and the atten-
dant risks of neck compression and eventual hyperfunctioning autonomous
nodules with hyperthyroidism. An insufficient adaptation in adults produces
hypothyroidism with its usual clinical stigmata. The damage is greater when
iodine deficiency provokes hypothyroidism during fetal or early postnatal life,
because thyroid hormone is necessary for proper development of the central
nervous system, particularly its myelination. Individuals who were hypothyroid
at this critical period frequently have permanent mental retardation, which can-
not be corrected by later administration of thyroid hormone or iodine.
Most of the populations which live in areas of iodine deficiency are in
developing countries, but many in the large industrialized countries of Europe
Table 2. The spectrum of IDD across the life-span (adapted from [10])
Fetus abortions
deaf mutism
stillbirths
congenital anomalies
increased perinatal mortality
endemic cretinism
deaf mutism
Neonate neonatal goiter
neonatal hypothyroidism
endemic mental retardation
increased susceptibility of the thyroid
gland to nuclear radiation
Child and adolescent goiter
(subclinical) hypothyroidism
impaired mental function
retarded physical development
increased susceptibility of the thyroid
gland to nuclear radiation
Adult goiter, with its complications
hypothyroidism
impaired mental function
hyperthyroidism in the elderly
(after iodized salt)

Knobel/Medeiros-Neto 60
are also affected. Correcting this public health problem is the goal of a massive
global campaign that is showing remarkable progress so far. But despite its
importance to most other countries, iodine deficiency receives little attention in
the United States because its elimination years ago has been widely assumed [3].
Health Consequences of Iodine Deficiency by Developmental Stage
Prenatal Development
Fetal iodine deficiency is caused by iodine deficiency in the mother. The
result of iodine deficiency during pregnancy is impaired synthesis of thyroid
hormones by the mother and the fetus. An insufficient supply of thyroid hor-
mones to the developing brain may ensue in mental retardation [13–15].
An important issue on thyroid function and regulation in the fetus is the
concept that during the first half of gestation the thyroid hormone available to
the fetus is predominantly of maternal origin. T4 from the mother is the most
important source of T3 for the fetal brain and protects it from a possible hor-
mone def iciency until birth [16, 17]. Once the fetal thyroid secretion starts,
fetal supplies are of mixed fetal and maternal origin. Although fetal thyroidal
secretion is believed to constitute an increasing proportion of the hormone
available to the developing fetus, maternal transfer of T4 may still contribute
significantly to fetal needs (20–50% of normal values) up to term, mitigating
the consequences of inadequate fetal thyroid function [17, 18]. The iodine con-
tent of the fetal thyroid increases progressively from less than 2 ␮g at 17 weeks
of gestation up to 300 ␮g at term [6].
In conditions of mild iodine deficiency (iodine intake: 50–99 ␮g/day) [12],
the serum levels of free T4 steadily decrease during gestation while, in iodine
sufficiency, there is only a slight (15%) decrease by the end of gestation. As a
consequence, serum TSH levels increase progressively. This situation of
chronic thyroid hyper stimulation results in an increase in serum TG and in an
increase in thyroid volume by 20–30% during gestation, a figure twice higher
than in conditions of normal iodine supply [19].
Table 3. Summary of mechanisms involved in the adaptation to iodine
deficiency (adapted from [32])
Increased thyroid clearance of plasma inorganic iodine
Hyperplasia of the thyroid and morphologic abnormalities
Changes in iodine stores and thyroglobulin synthesis
Modifications of the iodoamino acid content of the gland
Enrichment of thyroid secretion in T3
Enhanced peripheral conversion of T4 to T3 in some tissues
Increased thyroid-stimulating hormone production

Pediatric Aspects of Thyroid Function and Iodine 61
In moderate iodine def iciency (iodine intake: 20–49 ␮g/day), the anom-
alies are of the same nature but more marked. The few studies conducted in
populations with severe iodine deficiency [13] showed that the prevalence of
goiter reaches peak values of up to 90% in females of child bearing age and that
during pregnancy, serum T4 is extremely low and serum TSH is extremely high.
Comparative studies carried out in New Guinea and the Democratic Republic
of Congo showed that, in spite of the fact that the two areas are submitted to a
similar degree of severe iodine deficiency (iodine intake ⬍20 ␮g iodine/day),
serum T4 in pregnant women is much higher in the Congo (8.0 ␮g/dl) than in
New Guinea (3.0–5.0␮g/dl). This discrepancy was understood only when it
was demonstrated that in the Congo, iodine def iciency is aggravated by sele-
nium deficiency and thiocyanate overload.
Accordingly, iodine deficiency results in relative hypothyroxinemia during
pregnancy, thus leading to enhanced thyroidal stimulation (through the TSH
feedback mechanisms) and goitrogenesis in both the mother and fetus. Goiter
formation is the most directly ‘visible’ consequence of iodine deprivation, and
pregnancy should therefore be viewed as an environmental factor to trigger the
glandular machinery and induce functional and anatomical abnormalities of the
thyroid in areas with a reduced iodine intake.
Newborns and Infants
Infant mortality is increased in areas of iodine def iciency, and several stud-
ies have demonstrated an increase in childhood survival when iodine deficiency
is corrected [20]. Infancy is a period of rapid brain growth and development.
Even in the absence of congenital hypothyroidism, iodine deficiency during
infancy may result in abnormal brain development and, consequently, impaired
intellectual development [21].
In mild iodine deficiency, the serum concentrations of TSH and TG are
still higher in neonates than in their mothers. The frequency distribution of
neonatal TSH on day 5, at the time of systematic screening for congenital
hypothyroidism, is shifted towards elevated values. The frequency of values
above 5␮U/ml (blood) is 4.5%, while the normal value is below 3% [22].
In moderate iodine deficiency, the anomalies are of the same nature, but
more drastic. The frequency of neonatal TSH above 20–25 ␮U/ml (blood), that
is above the cut-off point used for recalling the neonates because of suspicion of
congenital hypothyroidism in programs of systematic screening for congenital
hypothyroidism, is increased. This frequency is inversely related to the median
urinary iodine of populations of neonates used as an index of their iodine
intake. In addition, transient neonatal hypothyroidism can occur with a fre-
quency approximately 6 times higher in Europe than in the United States, where
the iodine intake is much elevated.

Knobel/Medeiros-Neto 62
In severe iodine def iciency, the biochemical picture of neonatal hypothy-
roidism is exaggerated. In Congo, as many as 11% of the neonates have both a
cord serum TSH above 100 ␮U/ml and a cord T4 below 3.0 ␮g/dl, i.e. a situa-
tion similar to the one found in thyroid agenesis.
The changes in neonatal TSH and thyroid function in the neonates in all
conditions of iodine deficiency are much more frequent and severe than in their
mothers. The hypersensitivity of neonates to iodine def iciency is explained by
their very small intrathyroidal iodine pool, which requires increased TSH stim-
ulation and a fast turnover rate in order to maintain a normal secretion of thy-
roid hormones.
The most important and frequent alterations of thyroid function due to
iodine deficiency in Europe occur in neonates and young infants. The fre-
quency of transient primary hypothyroidism is almost 8 times higher in Europe
than in North America [23]. This syndrome is characterized by postnatally
acquired severe primary hypothyroidism lasting for a few weeks and requiring
substitutive therapy [24]. The risk of transient hypothyroidism in neonates
increases with the degree of prematurity [25]. The specific role played by
iodine deficiency in the etiology of this type of hypothyroidism is demonstrated
by the disappearance of neonatal transient thyroid failure in Belgian pre-terms
following systematic supplementation with 30 ␮g potassium iodide/day. In
Toronto, where the iodine intake is elevated, the iodine content of the thyroid in
full-term infants is 292␮g. In Brussels, with a borderline iodine intake, the
iodine content of the thyroid is 81 ␮g and in Leipzig, which used to be severely
iodine-deficient, the content is only 43 ␮g. As the turnover rate of intrathyroidal
iodine is markedly accelerated in iodine-deficient neonates, thyroid failure is
more likely to occur. These neonatal data contrast with adult data which have
shown that the iodine stores of the thyroid are not affected by iodine deficiency
unless the degree of deficiency is severe [8].
Contrasting with the plentiful data on the consequences of iodine defi-
ciency on thyroid function during pregnancy, in the neonate and in adults, there
are few data on the impact of the deficiency on thyroid function in the young
infant.
In conditions of mild iodine deficiency, as indicated earlier, the frequency
distribution of neonatal TSH is shifted towards elevated values and the fre-
quency of transient hyperthyrotropinemia and transient primary hypothy-
roidism is much higher than in iodine-replete areas [24]. In particular, thyroid
function of preterm infants is characterized by a biochemical picture including
low total and free T4, elevated TSH and exaggerated TSH response to TRH.
This picture of primary subclinical hypothyroidism is in contrast with the pic-
ture of tertiary hypothyroidism evidenced in preterm infants in iodine-replete
areas, characterized by the fact that TSH remains normal in spite of low free T4.

Pediatric Aspects of Thyroid Function and Iodine 63
In conditions of severe iodine deficiency, the data in infants are still scant-
ier: in Congo, it was found that the frequency of biochemical signs of congeni-
tal hypothyroidism (9.0%) was as frequent in infants aged 5 days as in neonates
[26]. Follow-up studies showed that in some of these infants, the signs sponta-
neously corrected within a few weeks. The transient character of hypothy-
roidism in some of these infants may explain why the incidence of congenital
hypothyroidism (close to 10%) is almost ten times higher than the prevalence of
myxedematous endemic cretinism in the general population of the Ubangi area
of northern Congo (1%). Another factor could be the high mortality rate of
hypothyroid newborns and young infants [26]. It was proposed that transient
neonatal and infantile hypothyroidism in Congo resulted in endemic mental
retardation while permanent hypothyroidism occurring during this critical
period resulted in the long-term development of endemic cretinism [26].
Mechanisms of Brain Damage due to Iodine Deficiency during the
Perinatal Period
As mentioned, thyroid hormones are crucial for brain development both
during fetal and early postnatal life [14]. Type II 5⬘-iodothyronine deiodinase
(DIO2) activity, which generates T3 from T4, is found during this period in the
human fetal cerebral cortex [27]. The effects of T3 on the central nervous sys-
tem are mediated by the regulation of the expression of genes that synthesize
proteins implicated in cerebral neurogenesis, neuronal migration and differenti-
ation, axonal outgrowth, dendritic ontogeny and synaptogenesis. They are also
necessary for cerebellar neurogenesis (predominantly during early postnatal
life), gliogenesis (predominantly during late fetal life to 6 months postnatally)
and myelogenesis (during the second trimester of gestation to 2 years of postna-
tal life). From clinical studies on the effect of iodine deficiency of both mother
and fetus it becomes clear that T4 is required for brain development during ges-
tation [18, 28, 29]. Low T4 levels during neonatal life, especially if persistent,
could be a negative factor contributing to the neurodevelopmental problems of
very preterm infants. Indeed, retrospective studies have shown a relationship
between hypothyroxinemia and developmental delay and a increased risk of
disabling cerebral palsy [30, 31]. In agreement, the most dramatic consequence
of iodine deficiency on brain and physical development is endemic cretinism
[32]. This is a polymorphous clinical entity, which happen in remote, underde-
veloped areas of the Third World and may affect up to 15% of populations liv-
ing in conditions of severe iodine deficiency [33, 34] (fig. 1).
The disorder is found in India, Indonesia, China, Oceania (Papua New
Guinea), Africa (Congo), and South America (Ecuador, Peru, Bolivia). In all these
locations, with the exception of Congo, neurological features are predominant
[33, 35]. Endemic cretinism may be defined essentially by severe and irreversible

Knobel/Medeiros-Neto 64
changes in mental development in individuals born in an area of endemic goi-
ter; such individuals exhibit a combination of some of the following character-
istics not explained by other causes: (1) a predominantly neurological syndrome
consisting of defects of hearing and speech associated or not with characteristic
disorders of stance and gait of varying degree; (2) stunted growth; (3) mental
deficiency; (4) hypothyroidism, and (5) sexual immaturity. In its fully devel-
oped form, mental deficiency, deaf-mutism, and motor spastic diplegia are
associated with or without goiter. This condition is referred to as the neurologi-
cal form of endemic cretinism, in contrast to the myxedematous form [34, 36]
(fig. 2). The typical myxedematous cretin has mental retardation, severe
hypothyroidism and non palpable thyroid. This division of the syndrome into
two broad categories has been the subject of some confusion and disagreement
which undoubtedly originates from the repeated observation of the occurrence
of neurological signs in myxedematous cretins, indicating that the two physiog-
nomic forms of the syndrome varied from one geographical area to another
with mixed clinical characteristics. Although the myxedematous type is more
Fig. 1. As the total goiter rate (TGR) increases in a given population due to chronic
iodine deficiency there is sharp increase in the prevalence of endemic cretinism (% of all
newborns). As depicted in this figure there is no significant difference between geographical
areas (Asia, South America and Africa). Adapted from [92].
13
12
11
10
9
8
7
6
5
4
3
2
1
0
0 102030405060708090100
Total goiter rate (%)
Prevalence of cretinism (%)
Zaire
Equador
Ásia

Pediatric Aspects of Thyroid Function and Iodine 65
common in Congo, the condition may be found in the Himalayas, the Hetian
and Luopu districts of Xing-Jiang (China), Sicily (Italy), and South America
(Bolivia and Peru) (fig. 2).
Based on epidemiological studies and on experimental aspects of thyroid
homeostasis during the perinatal period in conditions of iodine def iciency it
was possible to reconcile the physiopathologic events to explain the clinical pic-
ture features of endemic cretinism [13–15].
In severe iodine deficiency, maternal hypothyroidism does occur during
pregnancy and the contribution of maternal thyroxine to the saturation of the T3
receptors of the brain of the growing fetus is decreased, resulting in the devel-
opment of the neurological features of endemic cretinism. The particular pat-
tern commonly found in Africa (i.e. myxedematous cretinism) might be explained
by the fact that in this area iodine deficiency is complicated by selenium
deficiency. Selenium deficiency results in the accumulation of peroxide in the
hyperstimulated thyroid glands, and excess peroxide induces thyroid cell
destruction, thus leading to parenchymal fibrosis and hypothyroidism [37]. On
Fig. 2. a The predominantly neurological syndrome of Endemic Cretinism consists in
mental deficiency, hearing defect (resulting in deaf-mutism), motor spastic diplegia, with
characteristic disorders of stance and gait as it was seen in this young boy from Equador.
bThe typical myxedematous cretin has mental and physical retardation, severe hypothy-
roidism and non palpable thyroid (the child from Zaire, Africa). Adapted from [32].
a b
Neurologic (South America) Mixedematous (Zaire, Africa)

Knobel/Medeiros-Neto 66
the other hand, deficiency in type I 5-desalogenase (DIO1) in pregnant mothers
induced by selenium deficiency causes decreased catabolism of T4 to T3 and
thus increased availability of maternal T4 for the fetus and its brain [26]. These
aspects explains why in situations characterized by isolated severe iodine defi-
ciency such as New Guinea, China, Indonesia and Thailand, the clinical picture
of endemic cretinism is characterized by a dominant neurological picture and
why, when selenium deficiency and SCN overload are added, as in Congo, the
neurological signs are mitigated and the picture is dominated by severe
hypothyroidism. The role of SCN in the etiology of endemic cretinism in Africa
has been proposed because of the observation that people in areas with severe
uniform iodine deficiency exhibit cretinism only when a certain critical level
threshold in the dietary supply of SCN (through cassava consumption, a staple
food in these areas) is reached. The action of SCN is entirely due to an aggrava-
tion of iodine deficiency resulting in fetal hypothyroidism [26].
Thus, the neurological form is the result of maternal iodine deficiency that
affects the fetus before its own thyroid is functional. In the myxedematous or
hypothyroid form in addition to iodine deficiency, selenium deficiency and the
presence of goitrogens (SCN) in the diet interfere with thyroid hormone produc-
tion [38]. Endemic cretinism, therefore, constitutes the extreme expression of a
spectrum of abnormalities in the physical and intellectual development in chil-
dren, as well as diminished functional capacity of the thyroid gland, observed in
inhabitants of areas with severe iodine deficiency and endemic goiter (fig. 3).
Children and Adolescents
Iodine deficiency in children and adolescents is often associated with goi-
ter. The incidence of goiter peaks in adolescence and is more common in girls.
School children in iodine deficient areas show poorer school performance,
lower IQs, and a higher incidence of learning disabilities than matched groups
from iodine-sufficient areas. A recent meta-analysis of 18 studies concluded
that iodine deficiency alone lowered mean IQ scores in children by 13.5 points
[39, 40].
The view that endemic goiter constitutes the most efficient mechanism of
adaptation to iodine deficiency is based, with a few exceptions [41] on informa-
tion available only in adults. But a study of the time course as a function of age
from 3 to 22 years of the main variables exploring thyroid function in two popu-
lations submitted to a similar degree of iodine deficiency, but with markedly dif-
ferent prevalences of goiter, showed that goiter constitutes, rather, an unfavorable
side effect to the mechanism of adaptation to iodine deficiency which is increased
trapping of iodide by the thyroid, as indicated by an elevated thyroidal uptake of
radioiodine [41]. It was also shown that the highest values of serum TSH were
observed in the youngest infants and children in spite of the fact that they had also

Pediatric Aspects of Thyroid Function and Iodine 67
the highest serum T4 values. These variations of the TSH/T4 ratio as a function of
age could reflect the increase with age of the iodine content of the thyroid and/or
changes in the sensitivity of the thyroid to TSH [41].
Euthyroid pubertal goiter is especially frequent in adolescents and occasion-
ally requires substitutive therapy by T4 or iodide. Its main cause is iodine defi-
ciency although thyroiditis has to be carefully considered [42]. Iodine metabolism
is accelerated during this period of life [8]. A very important issue is the demon-
stration that even in Europe today, clinically euthyroid schoolchildren born and
living in an iodine-deficient environment exhibit subtle or even overt neuropsy-
chointellectual def icits as compared with controls (not subjected to iodine defi-
ciency) living in the same ethnic, demographic, nutritional and socioeconomic
system. These deficits are of the same nature as those found in schoolchildren in
areas with severe iodine deficiency and endemic mental retardation, although
they are less marked [13]. As demonstrated in severe endemic goiter, such deficits
could result from transient thyroid failure occurring during fetal or early postnatal
life, i.e. during the critical period of brain development [43].
Fig. 3. The spectrum of clinical presentation of iodine deficiency in children and ado-
lescents. The three siblings lived all their existence in iodine deficiency area of Nepal. The
eldest brother has mental retardation and hearing was impaired. A small goiter was present
and hypothyroidism considered relatively mild. The second sibling has severe hypothy-
roidism stunted growth, a very large goiter, severe mental retardation, spastic diplegia and
was deaf-mute. The youngest brother had no goiter or hypothyroidism although stunted
growth was present with mild degree of mental retardation. Adapted from [93].
7 Years
TSH⫽316 ␮U/ml TSH⫽10.9 ␮U/ml
18 Years
19 Years

Knobel/Medeiros-Neto 68
Nutrient Interactions
Besides selenium shortage [44], deficiencies of vitamin A, zinc or iron
may also exacerbate the effects of iodine def iciency [7].
Deficiencies of selenium [45] and iron [46] can act in concert with iodine
deficiency to impair thyroid metabolism and modify the response to prophylac-
tic iodine [47]. Iron deficiency impairs thyroid hormone synthesis by reducing
activity of heme-dependent thyroid peroxidase. Iron deficiency anemia blunts
and iron supplementation improves the efficacy of iodine supplementation [48].
The clinical consequences of selenium def iciency include cardiomyopathy
(Keshan disease) [49], which is caused by a Coxsackie B virus infection under
conditions of selenium def iciency without concomitant iodine deficiency [50],
hypothyroid cretinism (in some parts of central Africa) and Kashin-Beck dis-
ease, an osteoarthropathy of the hands, fingers, elbows, knees, and ankles in
children and adolescents [51]. Recent studies in Tibet have suggested that this
disorder results from a combination of selenium and iodine deficiency [52].
One possibility is that necrosis of the growth plate and epiphyseal chondro-
cytes is dependent on locally produced T3 and sensitive to oxidative damage.
Thus, def iciency of iodothyronine deiodinase and GPx might result in local
thyroid hormone deficiency and cellular injury, a combination that causes
chondronecrosis.
Vitamin A supply affects thyroid function. The most vulnerable groups
are women of reproductive age and young children [53]. In rural Côte d’Ivoire,
32–50% of school-age children suffer from both vitamin A deficiency and goi-
ter [45]. In northern Morocco, 41% of children have vitamin A deficiency and
50% are goitrous [54]. In animals, vitamin A def iciency has multiple effects
on thyroid metabolism. Vitamin A deficiency decreases thyroidal iodine
uptake, impairs thyroglobulin synthesis, and increases thyroid size. In the
periphery, vitamin A deficiency increases free and total circulating thyroid
hormone, and binding of transthyretin to retinol-binding protein decreases
vitamin A turnover and enhances vitamin A delivery. Centrally, because
retinoic acid suppresses transcription of the pituitary TSH-␤gene through
activation of the retinoid X receptor, vitamin A status may modulate T4 feed-
back of TSH secretion. Vitamin A deficiency in rats increases pituitary TSH
beta mRNA and TSH secretion; both return to normal after treatment with
retinoic acid [55].
Although the literature has limited information, zinc status seems to affect
the metabolism of thyroid hormones [56] and zinc supplement also appears to
induce a cellular iron deficiency and, possibly, further reduce iron status [57].
In zinc-deficient rats, decreased DIO1 activity, lower T3 and free T4 serum
concentrations, and marked alterations of follicular cellular architecture,
including signs of apoptosis, were found [58].

Pediatric Aspects of Thyroid Function and Iodine 69
Goitrogens
Some foodstuffs (cassava, millet, babassu coconut, piñon, vegetables from
the genus Brassica and soybean) contain substances that interfere with iodine
utilization or thyroid hormone production, known as goitrogens [31, 59]. The
goitrogenic factor in cassava is related to the hydrocyanic acid liberated from
the cyanogenetic glucoside (linamarin) and endogenously changed to thio-
cyanate, which competitively inhibits trapping and promotes the efflux of
intrathyroidal iodine. Pearl millet is one of the most important food crops in the
semiarid tropics (large portions of Africa and Asia) [60]. Millet porridge is rich
in C-glucosylflavones and also contains thiocyanate. Both are additive in their
antithyroid effects. Babassu coconut is largely consumed in northern Brazil,
and studies have demonstrated the possible presence of flavonoids in the edible
part of the nut [32]. Thus, in areas where millet and babassu coconut are a major
component of the diet, their ingestion may contribute to the genesis of goiter.
Furthermore, flavonoids, besides being potent inhibitors of thyroid peroxidase,
also interact with thyroid hormone at the peripheral level. From turnips the
compound 1–5-vinyl-2-thiooxazolidone (VTO, goitrin) was isolated; it is similar
in action and potency to synthetic antithyroid drugs. The soybean isoflavones,
genistein and daidzein, have also been found to inhibit thyroid hormone synthe-
sis [61, 62]. Most of these goitrogens are not of clinical importance unless they
are consumed in large amounts or there is coexisting iodine deficiency. Recent
findings also indicate that tobacco smoking may be associated with an increased
risk of goiter in iodine-deficient areas [63].
Individuals at Risk of Iodine Deficiency
While the risk of iodine deficiency for populations living in iodine-defi-
cient areas without adequate iodine fortification programs is well recognized,
concerns have been raised that certain subpopulations may not consume ade-
quate iodine in countries considered iodine-sufficient. Vegetarian and nonvege-
tarian diets that exclude iodized salt, fish, and seaweed have been found to
contain very little iodine [64, 65]. Urinary iodine excretion studies suggest that
iodine intakes are declining in Switzerland, New Zealand, and the US, possibly
due to increased adherence to dietary recommendations to reduce salt intake.
Although iodine intake in the US remains sufficient, further monitoring of
iodine intake has been recommended [66, 67].
Iodine Excess
The thyroid gland has intrinsic regulatory mechanisms that maintain nor-
mal thyroid function even in the presence of iodine excess. When large amounts

Knobel/Medeiros-Neto 70
of iodine are given to subjects with normal thyroid function a transient decrease
in the synthesis of the thyroid hormones occurs for ⬃48h. This acute inhibitory
effect of iodine on thyroid hormone synthesis is called the acute Wolff-Chaikoff
effect and is due to increased intrathyroid iodine concentrations. The escape
from or adaptation to the acute Wolff-Chaikoff effect is a decrease in the thyroid
iodide trap, thereby decreasing the intrathyroid iodide concentration [68], due
to a decrease in the sodium iodide symporter (NIS) mRNA and protein expres-
sion [69]. For this reason, most people can tolerate high doses of iodine without
developing thyroid abnormalities. Excess iodine ingestion (up to 1.5–3.0 mg/
day) also decreases the release of T4 and T3 from the thyroid resulting in small
decreases in serum T4 and T3 concentrations with compensatory increases in
basal and TRH-stimulated TSH concentrations, all values remaining well
within the normal range. These iodine-treated subjects remained euthyroid
although they continued to ingest the excess iodide and serum thyroid hormone
and TSH values returned to basal levels when the iodide was discontinued.
These subtle changes in thyroid function were accompanied by increased
thyroid volume assessed by echography and a decrease in thyroid blood flow
determined by color Doppler flow imaging [70].
The smallest quantity of iodine, exceeding that consumed with the diet
in the United States, for instance, that does not affect thyroid function is
500 ␮g/day. The administration of 1 mg of iodine per week for 6 weeks fol-
lowed by the administration of 2 mg of iodine weekly for another 6 weeks did
not affect thyroid function. Other studies have suggested that the administra-
tion of 500 ␮g iodine daily induced a small but significant increment of basal
and TRH-stimulated serum TSH concentrations. Ingestion of 1,500 ␮g
of iodine per day for 15 days by euthyroid subjects invariably resulted in a sig-
nificant decrease in serum free T4 concentrations and FT4 Index with a
significant compensatory rise in basal and TRH-stimulated serum TSH con-
centrations [70]. There are adequate data to demonstrate that thyroid 131I
uptake or thyroid clearance of iodide decreases with increases in serum iodine
levels. Single doses ⬎10 mg suppress the uptake of radioactive iodine
to ⱕ1.5% within 24 h, and daily doses of ⱖ15 mg will maintain uptake below
2% [71].
Evaluation of iodine nutrition using the ThyroMobil model in 35,223
schoolchildren at 378 sites of 28 countries has shown that many previously
iodine-deficient parts of the world now have median urinary iodine concen-
trations well above 300 ␮g/l, indicating iodine excess which carries the risk
of adverse health consequences [72]. Table 4 shows the epidemiological criteria
for assessing iodine nutrition, based on median urinary iodine (UI) concentra-
tions in school-age children. These introduce a clear distinction between iodine
intake and its impact, i.e. the status of iodine nutrition. It was agreed that the

Pediatric Aspects of Thyroid Function and Iodine 71
optimal status of iodine nutrition corresponds to a UI concentration in school-
children situated between 100 and 200 ␮g/l [12].
Health Consequences of Excessive Iodine Intake
Excessive dietary iodine may increase the risk of thyroiditis, hyperthy-
roidism, hypothyroidism, and goiter [73]. In healthy adults, short-term iodine
intakes of 500–1,500 ␮g/day have mild inhibitory effects on thyroid function.
The consequences of prolonged exposure to high intakes of iodine, particularly
in children, are less clear. Endemic goiter in children has been described in
coastal Japan, where iodine intake from seaweed was ⬎10,000 ␮g/day. Lower
intakes, in the range of 400–1,300 ␮g/day, from iodine-rich drinking water,
were associated with increased serum thyrotropin and thyroid volume in a small
sample of Chinese children.
In children, excess dietary iodine has been associated with goiter and thy-
roid dysfunction. In a report of what the authors called ‘endemic coastal goiter’
in Hokkaido, Japan [74], the traditional local diet was high in iodine-rich sea-
weed. UI excretion in children consuming the local diet was ⬃23,000 ␮g/day.
The overall prevalence of visible goiter in children was 3–9%, but, in several
villages, about 25% of the children had visible goiter. Most of the goiters
responded to the administration of thyroid hormone, restriction of dietary
iodine intake, or both. TSH assays were not available, but it was suggested that
an increase in serum TSH was involved in the generation of goiter. No cases of
clinical hypothyroidism or hyperthyroidism were reported.
Goiter in children may also be precipitated by iodine intake well below
the high amount described in the studies from Hokkaido. Li et al. [75] exam-
ined thyroid status in 171 Chinese children from 2 villages where the iodine
Table 4. Adequate daily iodine intake and the consequences of excessive nutritional
iodine intake [World Health Organization, 5th Report on Word Nutrition, Geneva,
Switzerland, March 2004]
Urinary iodine Nutritional iodine intake Clinical effects
⬍20 ␮g/l totally deficient severe iodine deficiency
20–49 ␮g/l insufficient moderate iodine deficiency
50–99 ␮g/l insufficient mild iodine deficiency
100–299 ␮g/l ideal situation None
ⱖ300 ␮g/l excessive clinical increasing risks for autoimmune
thyroiditis and hyperthyroidism
(mostly in the elderly)

Knobel/Medeiros-Neto 72
concentrations in drinking water were 462 and 54 ␮g/l, and the children’s mean
UI concentrations were 1,235 and 428 ␮g/g creatinine, respectively. The mean
serum TSH concentration (7.8 ␮U/ml) was high in the first village and normal
(3.9 ␮U/ml) in the second village. In the f irst village, the goiter rate was ⬎60%
and mean thyroid volume (tvol) was 13.3 ml, whereas the goiter rate was
15–20% and mean tvol was 5.9 ml in the second village. However, only those
who developed goiter had positive antimicrosomal and TSH-binding antibodies.
There were no signs of neurological deficits in the children. In other report from
China, drinking water with iodine concentrations of ⬎300 ␮g/l resulted in UI
concentrations ⬎900 ␮g/l and a goiter rate of ⬎10% [76]. Although the mecha-
nism remains unclear, increased thyroid size associated with high iodine intake
may be due to autoimmune-mediated lymphoid infiltration of the thyroid [77,
78], inhibition of thyroid hormone release that increases serum TSH and thyroid
stimulation [79], or both. Taken together, the Chinese studies suggest that goiter
and thyroid dysfunction may occur in children at iodine intakes in the range of
400–1,300 ␮g/day. The mechanisms possibly involved in the role of iodine in
thyroid autoimmunity include the damage to the thyroid by the generation of free
radicals, a direct injury to the thyrocytes through the strong necrotic effect of
iodide and an enhancement of autoimmunogenic properties of TG [79].
It is worth to mention that perinatal exposure to excess iodine can lead to
transient hypothyroidism in the newborn. In Japan, large quantities of iodine-
rich seaweed such as kombu (Laminaria japonica) are consumed. The concen-
tration of iodine in serum, urine, and breast milk in addition to TSH, free T4,
and TG was measured in 34 infants who were positive at congenital hypothy-
roidism screening. Based on the concentration of iodine in the urine, 15 infants
were diagnosed with hyperthyrotropinemia caused by the excess ingestion of
iodine by their mothers during their pregnancy. According to serum iodine con-
centrations, these infants were classified into group A (over 170 ␮g/l) and
group B (under 170 ␮g/l) of serum iodine. During their pregnancies these moth-
ers consumed kombu, other seaweeds, and instant kombu soups containing a
high level of iodine. It was calculated that the mothers of group A infants
ingested approximately 2,300–3,200 ␮g of iodine, and the mothers of group B
infants approximately 820–1,400␮g of iodine per day during their pregnancies.
Twelve of 15 infants have required levo-thyroxine because hypothyroxinemia or
persistent hyperthyrotropinemia was present. In addition, consumption of
iodine by the postnatal child and susceptibility to the inhibitory effect of iodine
may contribute in part to the persistent hyperthyrotropinemia. It was proposed
that hyperthyrotropinemia related to excessive iodine ingestion by the mother
during pregnancy in some cases may not be transient [80] (table 5).
Pharmacological quantities of iodine are almost always due to the admi-
nistration of inorganic and organic medicinal compounds. Iodine-induced

Pediatric Aspects of Thyroid Function and Iodine 73
hypothyroidism (IIH) has been observed in 20% of children chronically treated
with amiodarone [81]; a drug extensively used as an antiarrhythmic agent which
contains 75 mg of iodine per 200 mg tablet, is known to affect thyroid homeosta-
sis by competitive inhibition of DIO1, which converts T4 to T3 and (reverse T3)
rT3. In contrast, the administration of a single dose of 50–70 mg of potassium
iodide KI to children to prevent radioactive contamination of the thyroid from
the Chernobyl reactor accident did not induce significant change in serum TSH
concentrations [82]. IIH may develop in children with cystic fibrosis, especially
when iodine was given along with sulfisoxazole [83]. Also, it has been observed
in children and adults with beta-thalassemia major requiring blood transfusions.
It is likely that hemosiderosis of the thyroid was the predisposing factor [84].
More Than Adequate Iodine Intake
Although not excessive, studies in more than adequate iodine intake (see
table 4) following iodine prophylaxis, also pointed out the possible development
of thyroid autoantibodies. Zois et al. [85] investigated the iodine status and the
impact of iodine prophylaxis on the prevalence of autoimmune thyroiditis
among schoolchildren in a formerly iodine-deficient community in northwest-
ern Greece. The findings were compared to those obtained from a similar survey
Table 5. Iodine-induced alterations of thyroid function in newborn infants after prena-
tal and perinatal exposure to povidone-iodine. Adapted from [94]
After birth
Thyroid function
Day 3 Day 5
Controls Neonates Controls Neonates p
exposed exposed
TSH, ␮U/ml 4.3 13.8* 2.0 8.0* ⬍0.001
Total T4, ␮g/dl 18.1 13.7* 2.0 13.8* ⬍0.001
Free T4, ng/dl 3.1 2.3* 2.7 2.4* ⬍0.001
T3, ng/dl 144.0 126.0 166.0 140.0 NS
Reverse T3, ng/dl 273.0 177.0* 214.0 138.0* ⬍0.001
Median values (*p ⬍0.001). Note that exposure to povidone-iodine (neonates exposed)
induces an elevated serum TSH and lower free T4 and total T4 concentrations. Furthermore,
20% of the infants had serum TSH values above 20 ␮U/ml (day 3) returning to normal (day
14) after two weeks.

Knobel/Medeiros-Neto 74
carried out 7 years previously in the same area. A total of 302 schoolchildren
(12–18 years of age) from a mountainous area of northwestern Greece were
examined for the presence of goiter, and blood and urine samples were collected
for assessment of thyroid function, antithyroid antibodies and urinary iodine
excretion. Median urinary iodine concentration in the children was ⬃200 ␮g/l.
Thyroid function was normal in all but 7children, who had subclinical hypothy-
roidism (2.5%). Antithyroid antibodies (antithyroid peroxidase and/or antithy-
roglobulin) were positive in 32 children, including those with subclinical
hypothyroidism (10.6%). Twenty-nine of these children (9.6%) also had the
characteristic hypoechoic pattern of thyroiditis on ultrasound studies and were
diagnosed to have autoimmune thyroiditis (AIT). It was concluded that iodine
prophylaxis has resulted in the elimination of iodine deficiency in this region of
Greece but this has been accompanied by an increase in the prevalence of AIT.
These authors followed up 29 children (12–18 years old) with AIT for 5 years to
track its course in the postiodination era [86]. At diagnosis, thyroid peroxidase
autoantibodies (TPOAb) were positive in 25 children (86%) and became positive
in all children during follow-up. Thyroglobulin autoantibodies (TGAb) were
positive in 17 children at diagnosis (59%) and became positive in 3 more chil-
dren (69%). Both antibody types increased by the end of the observation period.
Regarding thyroid function, 7 children (24%) at diagnosis had subclinical
hypothyroidism that persisted and 4 more children developed subclinical
hypothyroidism during the study period (38%). Only 5 of these children (45%)
had positive TGAb. There was an increase in thyrotropin (TSH) so that at the end
of the study all children had TSH greater than 2.5 ␮U/ml but none developed
overt hypothyroidism. Thyroid hypoechogenicity that increased over time was
seen in all children, especially in those with subclinical hypothyroidism. They
concluded that both antibody types increased in frequency and level, but TPOAb
were the predominant autoimmunity marker predictive of impending thyroid
failure in children with AIT, as was thyroid hypoechogenicity on ultrasound.
Although the short-term effects of iodine in inducing thyroid autoimmu-
nity by enhancing the immunogenicity of thyroglobulin are properly under-
stood, the long-term effects of dietary iodine in modulating the autoimmune
process are debated [87]. In this regard, a recent study suggested that thyroid
autoimmunity markers may evolve during the course of iodine prophylaxis
[88]. In particular, the authors reported a high prevalence of thyroid autoanti-
bodies among schoolgirls 5 years after the introduction of an iodine prophylaxis
program in Sri Lanka. The predominant antibodies were against thyroglobulin
(TGAb), whereas thyroid peroxidase autoantibodies (TPOAb) were less fre-
quent [88]. Interestingly, 3 years later, a shift in the pattern of autoantibodies
was observed with a significant reduction in the frequency of TGAb and the
predominance of TPOAb [89]. In a study from Epirus, an area under salt iodization

Pediatric Aspects of Thyroid Function and Iodine 75
for three decades, overall prevalence of juvenile AIT, as diagnosed by assess-
ment of thyroid antibodies was 3.3% and the goiter specif ic prevalence was
16.5% [90]. This scenario resembles what is currently occurring in India [91].
In a countrywide study to assess the thyroid status on Indian schoolchildren in
the post-salt iodization phase, the authors demonstrated that there was a resid-
ual goiter prevalence ranging from ⬃12 to ⬃31% (mostly grade 1, WHO def i-
nition) [9] in different age groups of boys and girls, striking relationship
between residual goiter prevalence and urinary thyocyanate excretion and sig-
nificantly higher thyroid autoimmunity markers and functional abnormalities
among goitrous children when compared to nongoitrous controls. Thus, after
the elimination of iodine deficiency, at least in the above mentioned areas, the
occurrence of clinically significant iodine-induced AIT appears to be a persis-
tent and progressive phenomenon.
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Meyer Knobel, MD, PhD
Thyroid Unit, Division of Endocrinology and Metabolism
Hospital das Clínicas, University of Sao Paulo Medical School
Av. Dr. Enéas Carvalho de Aguiar, 155, 8 A, bl 3, PAMb
Sao Paulo, SP 05403–900 (Brazil)
Tel./Fax ⫹55 11 3069 7970, E-Mail meyer.knobel@hcnet.usp.br

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 80–103
Thyroid Hormone Transport and Actions
Ulla Feldt-Rasmussen, Åse Krogh Rasmussen
Department of Medical Endocrinology, National University Hospital,
Rigshospitalet, Copenhagen University, Copenhagen, Denmark
Thyroid hormones (TH) are essential for normal development, differentia-
tion growth and metabolism of every cell in the body. The pro-hormone thyrox-
ine (T4) is synthesized by the thyroid follicles together with a small amount of
the biologically active hormone triiodothyronine (T3), which derives mainly
from tissue T4 deiodination. Approximately 0.03% of total T4 and 0.3% of total
T3 in serum are circulating in a free or unbound form while the major part of TH
is bound to circulating plasma proteins. These plasma proteins are responsible
for the maintenance of the large extrathyroidal pool of TH, but their function is
otherwise not quite clear, since wide differences in their concentrations do not
influence the thyroid functional status of the individual to any large degree [1, 2].
Thyroid Hormone Transport
Transport in the Blood
More than 99% of the circulating thyroid hormone is bound to plasma pro-
teins but can be liberated with great rapidity for entry into cells. The thyroid
hormone-binding proteins are comprised of thyroxine-binding globulin (TBG),
transthyretin (TTR or thyroxine-binding prealbumin), human serum albumin
(HSA) and lipoproteins. Their functions are most probably to ensure a constant
supply of TH to the cells and tissues by preventing urinary loss [3], protect the
organism against abrupt changes in thyroid hormone production and degrada-
tion, protect against iodine deficiency [2] and target the amount of TH delivery
by ensuring a site-specific, enzymatic alteration of TBG [4]. TBG has by far the
highest affinity for T4, the result of which being that TBG binds 75% of serum
T4, whereas TTR binds 20% and HSA 5% [2]. Some of the properties of the
binding proteins are displayed in table 1.

Thyroid Hormone Transport and Actions 81
Thyroxine-Binding Globulin
TBG carries the major part of both circulating T4 and T3 (as well as reverse
T3), and therefore quantitative or qualitative changes in TBG concentration have
a high impact on total serum T4 and T3. The protein is encoded by a single gene
on the X-chromosome and is produced and cleared by the liver. It has a single
iodothyronine-binding site with a slightly higher affinity for T4 compared to T3
[5]. When it is fully saturated it carries approximately 200 ␮g T4/l. The TBG
concentration in serum is between 11 and 21 mg/l (180–350 nmol/l), present
from 12th week of fetal life and 1.5 times higher in newborns and children until
2–3 years of age [6]. Estrogen has a marked effect on TBG by prolonging the
biological half-life from the normal 5 days, thus resulting in increased plasma
concentrations of TBG and total TH [7] while testosterone has the opposite
effect [8]. In children and adolescents this may have an implication in diseases
with a severe sex hormone overproduction related to the age, as well as oral con-
traceptives and pregnancy in adolescent girls.
Table 1. Some properties and metabolic parameters of the prinicpal thyroid hormone-
binding proteins in serum
TBG TTR HSA
Molecular weight, kDa 54* 55 66.5
Structure monomer tetramer monomer
Carbohydrate content, % 20 – –
Number of binding sites for T4 and T3 1 2 several
Association constant, Ka(M-1)
For T4 1 1010 2108** 1.5 106**
For T3 1 10911062105
Concentration in serum
(mean normal, mg/l) 16 250 40,000
Relative distribution of T4 and T3 in serum, %
T4 75 20 5
T3 75 520
In vivo survival
Half-life, days 5*** 2 15
Degradation rate, mg/day 15 650 17,000
HSA human serum albumin; TBG Thyroxine-binding globulin; TTR transthyretin.
* Apparent molecular weight on acrylamide gel electrophoresis 60 kDa.
** Value given is for the high affinity binding site only.
*** Longer under the influence of estrogen.
Reproduced with permission from Hayashi and Refetoff: Molecular Endocrinology: Basic
Concepts and Clinical Correlations. New York, Raven Press, 1995.

Feldt-Rasmussen/Rasmussen 82
Inherited TBG excess was first described in 1959 [9], and several familial
X-chromosome-linked TBG abnormalities have been described [10, 11]. A rare
TBG abnormality is seen in carbohydrate-deficient glycoprotein syndrome,
which is associated with severe mental and motor retardation [12]. Acquired
TBG abnormalities are mostly resulting in altered synthesis and/or degradation
and caused by, e.g., severe terminal illness, hypo- and hyperthyroidism, severe
liver disease and a variety of critical non-thyroidal illnesses [2, 13]. The latter
may be mediated by interleukin-6 or other cytokines suppressing acute-phase
reactants [14].
Transthyretin
TTR, previously called thyroxine-binding prealbumin binds only about
15–20% of the circulating TH and has a lower affinity for the hormones thus
dissociating from them more rapidly and thus responsible for much of the
immediate delivery of T4 and T3. Transthyretin is the major thyroid hormone-
binding protein in cerebrospinal fluid. It is synthesized in the liver and the
choroids plexus and secreted into the blood and cerebrospinal fluid, respec-
tively. Only 0.5% of the circulating TTR is occupied by T4 and it has a rapid
turnover of 2 days in plasma. Hence, acute reduction of the rate of synthesis
results in a rapid decrease of its serum concentration [2]. Acquired abnormali-
ties in TTR include major illness, nephrotic syndrome, liver disease, cystic
fibrosis, protein fasting and hyperthyroidism. However, changes in TTR con-
centrations have little effect on the serum concentrations of TH [15].
Albumin
HSA binds about 5% of the circulating T4 and T3. Its affinity for the hor-
mones is even lower, and since HSA associates with a wide variety of sub-
stances, including a number of different hormones and drugs, the association
between TH and HSA can hardly be regarded specific. Even marked fluctua-
tions in serum HSA concentrations have no effect on TH levels [16].
Lipoproteins
Lipoproteins transport a minor fraction of circulating T4 and to some
extent T3 [17]. The binding site for TH on apolipoprotein A1 is distinct from
that which binds to cellular protein receptors.
Consequences of Abnormal Binding Protein Concentrations
Abnormalities of the TH-binding proteins do not cause alterations in the
metabolic state of the individual nor do they result in thyroid disease. Thus,
abnormal concentrations of these binding proteins, due to changed synthesis,
degradation or stability, result in maintaining normal free TH concentrations.

Thyroid Hormone Transport and Actions 83
However, they do give rise to misinterpretation of most of the measurements of
serum levels of TH by available techniques. Depending on the severity of the
abnormality only total TH concentrations are affected, but also the measured
free TH levels by automated currently used methods give rise to incorrect
results [18]. In such cases, it may be necessary to provide a free TH estimate by
quantifying total hormone concentration with a subsequent estimate of the
available binding places by use of a TH uptake test or direct measurement of
TBG [2]. Even better is measurement of free TH concentrations by equilibrium
dialysis or ultrafiltration, but not many laboratories in the world perform these
measurements anymore.
Transport Across the Cell Membrane
The deiodinases involved in T4 to T3 conversion and T4 and T3 degradation
as well as the T3 receptors are located intracellularly. Therefore, both action and
metabolism of thyroid hormones are intracellular events requiring transport of
iodothyronines across the cell membrane. For a long time it was believed that TH
diffused passively over the cell membrane, but recent years of research has made
it increasingly clear that cellular transmembrane transport of TH is mediated by
transporters, that these transporters determine the availability of iodothyronines
to the intracellular sites for metabolism and action [19], and that the TH trans-
port is energy dependent [20] (fig. 1). Recently, specific transporters (organic
anion transporters and amino acid transporters) known to facilitate cellular thy-
roid hormone uptake have been identified [20–22]. Hennemann and Visser [22]
have defined requirements for (patho)physiological signif icance of thyroid
Fig. 1. Thyroid hormone transport and metabolism in a 3,3,5-triiodothyronine (T3)
target cell. Reproduced with kind permission from Jansen et al. [21].
T3
T4
rT3
T3
T2T4
Proteins
mRNA
Nucleus
D2
D1
D3
D2
D3
TRE
TR RXR

Feldt-Rasmussen/Rasmussen 84
hormone plasma membrane transport in the terms that it should be specific,
without significant diffusion, plasma membrane transport subject to regulation,
transport rate limiting on subsequent metabolism, and changes in transport
should be appropriate from the (patho)physiological point of view.
Organic Anion Transporters
These mediate uptake of iodothyronines and their sulphonated derivatives
and they are members of the Na/taurocholate cotransporting polypeptide (NTCP)
and the Na-independent organic anion transporting polypeptide (OATP) families
[23, 24]. NTCP is only expressed on hepatocytes and is the major transporter of
conjugated bile acids in the liver. The OATPs are a large family responsible for
transmembrane transport of a number of compounds including TH. The most
interesting OATP superfamily members in terms of TH transport are OATP1C1
and OATP14. The former has been demonstrated to be widely expressed both in
human brain and the Leydig cells of testis [25]. In the brain they seem to partici-
pate in maintaining the T3 concentration along with parallel changes in D2 expres-
sion. It has been demonstrated that the thyroid state modulates OATP1C1, and by
doing so counteracts the effects of alterations in circulating T4 levels on brain T4
uptake [26, 27]. In humans, OATP1C1 is also expressed in the testis where also D2
expression has been demonstrated [28]. This combination supports a role of TH in
development, growth and differentiation of Leydig cells. In particular T3 is very
important for testosterone biosynthesis and may therefore have an important role
in male puberty. Other OATPs have been demonstrated in a number of other tis-
sues and may exert a variety of effects, but this is not well clarif ied, and they are
possibly less tissue-specific considering the widespread expression [21]. Some
characteristics of the transporters are shown in table 2 [29–39].
Amino Acid Transporters
Iodothyronines are a particular class of amino acids built from two tyrosine
residues implying transport by specific amino acid transporters, in particular
the L and T type amino acid transporters, which therefore are involved in TH
uptake into several tissues [40–44]. Among those are members of the het-
erodimeric amino acid transporter (HAT) family. Their exact role is not clear,
but it has been demonstrated that overexpression of the heterodimer L-type
transporter in cells resulted in increased intracellular T3 availability and a con-
sequent augmentation of T3 action [45]. Evidence has also been presented to
suggest a role of members from the HAT family in supplying the placenta and
developing fetus with thyroid hormone [46].
The monocarboxylate transporter (MCT) family comprise to date 14 iden-
tified members in various tissues from different species [21]. MCTs are dis-
persed over autosomal chromosomes, except MCT8, which is X-linked [47]

Thyroid Hormone Transport and Actions 85
and a specific TH transporter [38]. Compared to other TH transporters the rate
of T3 and T4 transport is much higher and follows the criteria set down for
requirements of a transporter. The MCT8 gene is located in the region of the
X-chromosome associated with X-linked diseases [47], and it was therefore
hypothesized that a mutation in this gene would result in an X-linked form of
thyroid hormone resistance. Indeed, this hypothesis was verified first in a
6-year-old boy with highly elevated serum T3 and severe psychomotor retarda-
tion of unknown origin, where a deletion of the first exon of the MCT8 gene
was demonstrated [39]. Since then the same group have described 5 unrelated
Table 2. Characteristics of thyroid hormone transporters
Gene Protein Species Accession Chromo- Tissue Iodothyroine Ref.
code some distribution transport
SLC10A1 NTCP human NP_003040 14q24.1 liver T4, T3, rT3, T2 [28, 29]
SLC10A1 NTCP rat NP_058743 6q24
SLCO1A1 OATP1A1 rat NP_058807 4q44 liver, kidney, CP T4, rT3, T3, T2 [29]
SLCO1A2 OATP1A2 human NP_602307 12p12 brain, kidney, liver T3, T2, T4, rT3 [29–31]
SLCO1A4 OATP1A4 rat NP_571981 4 liver, brain, retina T4, T2, T3, rT3 [29, 32]
SLCO1A5 OATP1A5 rat NP_110465 4q44 kidney, retina, liver T3, T4 [30, 32]
SLCO1B1 OATP1B1 human NP_006437 12p liver T3, T4 [30, 33]
SLCO1B2 OATP1B2 rat NP_113838 4q44 liver T3, T4 [34]
SLCO1B3 OATP1B3 human NP_062818 12p12 liver T3, T4 [30]
SLCO1C1 OATP1C1 human NP_059131 12p12.3 brain, cochlea T4, rT3, T3 [25]
SLCO1C1 OATP1C1 rat NP_445893 4q44 brain T4, rT3, T3 [26]
SLCO4A1 OATP4A1 human NP_057438 20q13.33 multiple T3, T4, rT3 [31]
SLCO4A1 OATP4A1 rat NP_598292 3q43 multiple T3 (T4, rT3 NT) [31]
SLCO4C1 OATP4C1 human NP_851322 5q21.2 kidney, other T3, T4 [35]
SLCO4C1 OATP4C1 rat AAQ04697 9 T3, (T4 NT) [35]
SLCO6B1 OATP6B1 rat NP_596903 9q36 testis T4, T3 [36]
SLCO6C1 OATP6C1 rat NP_775460 9q36 testis T4, T3 [36]
SLC7A5 LAT1 human NP_003477 16q24.3 multiple (not liver), T2, rT3, T3, T4 [37]
SLC7A5 LAT1 rat NP_059049 19q12 tumors
SLC7A8 LAT2 human NP_036376 14q11.2 multiple, T2, rT3, T3, T4 [37]
SLC7A8 LAT2 rat NP_445894 15p13 tumors
brain, liver, kidney,
SLC16A2 MCT8 human NP_006508 Xq13.2 heart, thyroid, T3, T2, T4, rT3 [38, 39]
SLC16A2 MCT8 rat NP_671749 Xq31 eye, pituitary,
other
Reproduced with kind permission from Hennemann and Visser, http://www.thyroidmanager.org/chapter3B

Feldt-Rasmussen/Rasmussen 86
young boys aged 1.5–6 years with mutations or deletions in the MCT8 gene.
They all had a uniform type of severe psychomotor retardation of hitherto
unknown origin. The described phenotype comprised symptoms such as severe
proximal hypotonia with poor head control and lack of verticalization, absence
of targeted grasping, severe mental retardation with only rudimentary commu-
nicative skills and movement-induced increase in tone in the extremities [39].
Concerning thyroid function variables, T3 was invariably strongly elevated in
all the patients, T4 and free T4 were mildly increased while thyroid-stimulating
hormone (TSH) was in the normal range for age in 4 patients and increased in
one (f ig. 2). The various mutations have been described in more detail in a
recent review [21]. All the mothers of the 5 patients were proven to be carriers,
all of them with normal thyroid hormone levels and without psychomotor retar-
dation. Another group has described two other cases with different mutations
[48]. By studying the complex clinical picture of these patients it was assumed
that MCT8 had an important role in TH-dependent processes of brain develop-
ment. To provide a clue to the cellular function of MCT8 in brain, the expres-
sion of MCT8 mRNA in the murine central nervous system was studied by in
situ hybridization histochemistry [49]. In addition to the choroid plexus struc-
tures, the highest transcript levels were found in neo- and allocortical regions
(e.g. olfactory bulb, cerebral cortex, hippocampus, and amygdala), moderate
Fig. 2. Thyroid hormone serum levels in patients with mutations in MCT8. Hatched
areas indicate normal reference ranges for each analyte. Reproduced with kind permission
from Jansen et al. [21].
FT4 (pmol/l)
30
20
10
0
T4 (nmol/l)
150
100
50
0
rT3 (nmol/l)
0.4
0.3
0.1
0
0.2
T3 (nmol/l)
8
6
2
0
4
T3/rT3
250
200
50
0
150
100
TSH (mU/l)
10
8
2
0
6
4

Thyroid Hormone Transport and Actions 87
signal intensities in striatum and cerebellum, and low levels in a few neuroen-
docrine nuclei. Co-localization studies revealed that MCT8 was predominantly
expressed in neurons. Together with the spatiotemporal expression pattern of
MCT8 during the perinatal period, these results strongly indicated that MCT8
plays an important role for proper central nervous system development by
transporting TH into neurons as its main target cells [49]. Another hypothesis
raised by these clinical pictures was that MCT8 must play an essential role in
the supply of T3 to neurons in the central nervous system (fig. 3). T3 binds to
nuclear receptors in neurons, which are a primary action site for T3. The action
of T3 is terminated by deiodination by D3, which is expressed in the neurons.
However, for local production of T3 the neurons are dependent on neighboring
astrocytes expressing D2, which is necessary for the local deiodination (fig. 3).
Inactivation of MCT8 by mutation in the gene will result in an impaired supply
of T3 to the neuron, as well as a decrease in T3 clearance due to block of T3
access to D3 with a possible subsequent increase in serum T3, consequently
stimulating a further expression of D1 in the liver and kidney. The resulting
increase in conversion of T4 to T3 and breakdown of reverse T3 explains the
serum thyroid hormone concentrations in these patients.
The mutations in the MCT8 gene thus resulted in a severe hypothyroidism
in the brain with the consequent phenotype, but other tissues and organs did not
demonstrate signs of hypothyroidism e.g. bones and metabolism. It therefore
seems that other tissues than the brain, are not dependent on MCT8 for uptake
of TH. The elevated T3 did not exert any symptoms of hyperthyroidism in the
patients, indicating that other yet unknown regulating mechanisms must be in
place.
Fig. 3. Role of MCT8 in the neuronal uptake of T3. Reproduced with kind permission
from Jansen et al. [21].
T4
T3
T4 T2
T3 Protein
mRNA
Nucleus
Nucleus
Astrocyte Neuron
D2 D3
TRE
TR RXR
MCT8

Feldt-Rasmussen/Rasmussen 88
Deiodination of Iodothyronines
Deiodination is the foremost pathway of thyroid hormone metabolism both
in quantitative terms but also through activation of T4 by outer ring deiodina-
tion to T3, as well as inactivation of both T4 and T3 by inner ring deiodination
[reviewed in 50]. Three iodothyronine deiodinases (D1-D3) are identified as
seleno cysteino-containing membrane proteins with their active enzymatic sites
located in the cytoplasma. D1 and D2 convert T4 to T3, while D3 has only inner
ring deiodination activity and inactivates T4 and T3 to rT3 and T2, respectively
(fig. 1). D1 is expressed in liver, kidney and the thyroid, while D2 is expressed
in the brain, pituitary, thyroid gland and skeletal muscle. In contrast to the rat,
humans do not express D1 in the central nervous system. D3 is expressed in
brain and fetal tissues, placenta and pregnant uterus. Other characteristics of the
deiodinases are presented in table 3.
D1 has both outer and inner ring deiodination activities, but appears par-
ticularly important for the generation of plasma T3 and clearance of reverse T3
by outer ring deiodination. D1 is positively regulated at the pretranscriptional
level by T3, and is very potently inhibited by the antithyroid drug propylth-
iouracil. In humans, therefore, it might be expected that hyperthyroidism would
induce D1 with subsequent relative increase in T3 production. Hyperthyroidism
is indeed commonly associated with a higher increase in plasma T3 compared
to T4, and D1 activity has also been demonstrated to be approximately 3-fold
elevated in thyroid glands from Graves’ disease compared to euthyroid control
glands [51]. D2, on the other hand, has only outer ring deiodination activity,
preferring T4 over reverse T3 as substrate, and it is increased in hypo- and
decreased in hyperthyroidism. This regulation by the thyroid state can occur
both by pre- and posttranslational mechanisms. D2 is particularly important for
local T3 production in the brain as mentioned previously (fig. 3). D3 has only
inner ring deiodination activity and is therefore crucial for inactivation of TH,
with preference for T3 over T4 as the substrate. In fetal life, D3 probably serves
to protect against undue overexposure to active TH, which may be damaging to
the development in particular of the brain. D3 is higher in the brain in hyper-
thyroidism and lower in hypothyroidism, the reason for which is unclear.
A high degree of similarities has been demonstrated between the structures
of the deiodinases and the reactions they catalyze [50]. Yet, there are also
important differences in their catalytic properties (table 3; f ig. 4). D1 catalyzes
both outer and inner ring deiodination while D2 only outer ring and D3 inner
ring deiodination, respectively [52]. In addition to deiodination, iodothyronines
are metabolized by conjugation of the phenolic hydroxyl group with sulphate or
glucoronic acid (so-called phase II detoxification reactions) [53, 54]. The pur-
pose of this is to increase the water solubility of the substrates and thereby to

Thyroid Hormone Transport and Actions 89
facilitate their biliary and/or urinary clearance. The iodothyronine sulphate lev-
els are normally very low in plasma, bile and urine, because they are rapidly
degraded by D1, indicating that sulphate conjugation is the first step leading to
irreversible inactivation of TH [54]. Going back to the differences between the
three deiodinases, the effects of sulfation of the substrate vary as does the effect
of inhibitors (table 3). Most pronounced is the difference in the reaction to
propylthiouracil, which inhibits D1 very potently but does not inhibit D2 and
D3 [50]. Plasma T3 levels are decreased more by the D1 inhibitor propylth-
iouracil in hyperthyroid patients than in normal individuals, indicating that D1
makes a larger contribution to plasma T3 concentrations in hyperthyroidism
Table 3. Characteristics of the three iodothyronine deiodinases
D1 D2 D3
Deiodination ORDIRD ORD IRD
Preferred substrate rT3T4, T3 T4rT3 T3T4
Sulfation of substrates stimulation inhibition inhibition
Kinetic mechanism ping-pong sequential sequential
Inhibitors
Propylthiouracil 10 1,000 1,000
Iodoacetate 1 1,000 1,000
Gold thioglucose 0.02 1 1
IRD inner ring deiodination; ORD Outer ring deiodination; rT3 reverse tri-
iodothyronine; T4 thyroxine; T3 triiodothyronine.
Reproduced with kind permission from Kuiper et al. [50].
Fig. 4. Functional domains of the TH receptor. The TH receptor is depicted schemati-
cally. The zinc finger DNA-binding domain is denoted along with the carbo-terminal ligand-
binding domain. Other functional domains and interaction sites are indicated. Reproduced
with kind permission from Yen [96].
Domains A/B C D E
LIGANDDNA
Nuclear localization sequence
Corepressor interaction sites
Dimerization regions
Coactivator interaction sites

Feldt-Rasmussen/Rasmussen 90
compared to the euthyroid state [52]. So, although propylthiouracil is used to
treat hyperthyroidism mainly due to its inhibitory action on the enzyme, thyroid
peroxidase, propylthiouracil at high doses also inhibits D1 activity [55].
The production of TH is regulated by the hypothalamo-pituitary-thyroid
axis, while the biological activity of TH, i.e. the tissue availability of T3 is
mainly regulated by the three deiodinases [56]. The serum concentrations of
thyroid function variables are regulated very closely within the individual,
while there is a substantial interindividual variation in serum levels of both T4,
T3, TSH and thyroglobulin. This was first demonstrated by Feldt-Rasmussen
et al. [57] in 1979, and has later been verified by others [58, 59]. This pattern
indicates an important genetic component in the regulation of serum concentra-
tions of thyroid function variables, with an individual set-point for thyroid func-
tion. A classical twin study demonstrated results to support this by finding
approximately 67% heritability accounting for the variations in plasma concen-
trations of TSH, and free T3 and T4 [60], and in a population study of Mexican
Americans 26–64% of the interindividual variation was suggested to be due to
heredity [61]. Finally, Spencer has in a guideline publication with Baloch as
first author [18] described an individual TSH-free T4 log-linear set point ratio
as further support of this concept.
Along these lines polymorphisms have recently been identified in the D1
gene [62]. The T-allele of one of them (D1a) was dose dependently associated
with increasing plasma reverse T3 levels and decreasing T3/reverse T3 ratio,
while the G-allele of the other (D1b) showed the opposite. Since D1 physiologi-
cally plays a key role in production of serum T3 and in the clearance of reverse
T3, it might be assumed that the D1a-T variant has a negative effect on tissue
D1 activity, while the D1b-G variant could be responsible for a positive effect
[63]. Another study performed in a different population showed a dose effect
from D1a-T allele on serum T3 concentration and thus supported this hypothe-
sis [64]. In performing such studies it is important to pay attention to the age
distribution of the population since a decreased T3 production by D1 may be
masked by the production of T3 by skeletal muscle D2 in young subjects [64,
65]. Skeletal muscle size and strength increase during childhood and in young
adults, and again gradually declines throughout adult life. D1 activity increases
during childhood and adolescence and again decreases during ageing, but the
relative contribution of D2 to serum T3 production may be more important in
young compared to elderly subjects, resulting in a relatively smaller contribu-
tion to T3 production from D1 in young persons.
A polymorphism in the D2 gene did not demonstrate any relationship with
plasma concentrations of T3 or reverse T3 [62], which is possibly explained by
the fact that D2 plays the major role in local T3 production in D2-containing
tissues. It would therefore not be expected to f ind polymorphism relations to

Thyroid Hormone Transport and Actions 91
plasma concentrations, and an effect of the polymorphism on intracellular T3
cannot be excluded. One study described a correlation between the same poly-
morphism and insulin resistance in obese women [66]. Since there was no con-
comitant association with their body composition, it was hypothesized that the
results might be explained by a linkage to another polymorphism [62].
No significant association between concentrations of TH and a polymor-
phism in the D3 gene have been described and there have been no descriptions of
deficiencies of deiodinases neither in humans nor in animals [67]. The present
conclusion of studies over the recent years have clarified that genetic variation by
polymorphisms plays an important role in the serum concentrations of thyroid
function variables, and that deiodination of the iodothyronines are crucial players
in this unique set-point. In adults it is becoming increasingly clear also, that only
minor modifications from this set-point resulting in mild (or subclinical) hypo- or
hyperthyroidism, may induce alterations in thyroid hormone bioactivity with con-
sequences for clinical end-points such as bone mineral density, atherosclerosis
and heart rate, with increased morbidity and even increased mortality [68, 69].
How frequent such alterations are in children has not been investigated, and there-
fore it is unknown if, e.g., polymorphisms in the deiodinase genes may have an
impact on bone development in children and adolescents.
Because D1 is a selenoprotein, one might expect to find decreased D1
enzyme activity in selenium deficiency, and in rats this was indeed demon-
strated for hepatic and renal D1 [70, 71]. There are, however, differences in the
organ sensitivity to selenium deficiency, so studies may show difference in
results depending on the organs studied. Furthermore, it is difficult to study in
humans, because it is difficult to find pure, isolated selenium deficiency. Yet,
mildly elevated serum T4 levels have been described in selenium-deficient
humans [70–73]. Selenium supplementation in an area with both iodine and
selenium deficiency has resulted in an unexpected reduction of serum T4, and
in some an increase of serum TSH as indication of worsening of hypothy-
roidism [74, 75]. This reaction might be explained by selenium def iciency cau-
sing reduced D1-catalyzed inner ring deiodination of iodothyronines, thereby
protecting against hypothyroidism. These results are in contrast to a study by
Roti et al. [76], who examined the effect of selenium supplementation in an area
with mild iodine deficiency. The eight female subjects had a positive perchlo-
rate discharge test after a previous episode of subacute or postpartum thyroidi-
tis and thus might have been at risk of developing thyroid dysfunction, but they
all remained with normal TH concentrations after selenium supplementation.
Nonetheless, it seems that restoration of adequate iodine supply is essential
before selenium intake is increased, thereby avoiding selenium-dependent deio-
dinative degradation of TH, subsequent urinary loss of iodine and TSH stimula-
tion of an iodine depleted thyroid gland [77].

Feldt-Rasmussen/Rasmussen 92
The issue of selenium intoxication is still controversial, and intakes of sele-
nium up to 400 ␮g/day have not resulted in any adverse effects [78]. Signs of
reversible intoxication have been reported by ingesting more than 1,000 ␮g/day
over a long time [78]. Nevertheless, paramedication, over-the-counter administra-
tion, and uncontrolled use of selenium containing preparations with accompanying
strong advertisements on the Internet should be monitored and restricted in order
to avoid uncontrolled distribution of selenium and its accumulation into body pro-
teins. These commercial preparations are marketed and sold under names such as
Thyroid Helper, Daily Energy, Daily Protector, Thyroid Booster and many more.
During critical illness at any age, pronounced alterations in plasma thyroid
hormone concentrations occur. It is a whole body response to virtually any seri-
ous illness and covers synonyms such as nonthyroidal illness (NTI), low T3 syn-
drome and euthyroid sick syndrome [79]. The validity of thyroid hormone
measurements was initially described as questionable [80], and although it is gen-
erally accepted that a low free T3 perhaps together with low free T4 and TSH at
later stages is a hallmark of the disease, the interpretation of serum values of
thyroid function variables is still questionable [18]. In fact, an estimate of free TH
concentration by total hormone measurement and correction for binding sites on
the binding proteins by a TH uptake test is superior to the so-called ‘direct’ free
TH measurements by automated analyses, since the direction of changes of each
of the measurements will indicate whether the encountered abnormality is within
(i.e. thyroid dysfunction) or outside the thyroid gland (i.e. NTI) [18].
The typical changes of NTI have initially been described as low T3 (later
also T4) together with elevated reverse T3, and studies on the role of deiodi-
nases during critical illness focused on D1 and D2, since the reduction of circu-
lating T3 was thought to be due to decreased peripheral deiodination by D1, D2
or both [52, 81, 82]. It is, however, also possible that D3 is induced in the liver
and abundant tissues such as skeletal muscle, thereby decreasing the ratio
between T3 and reverse T3, a mechanism that might have been underestimated
in the previous studies [50]. Cytokines, in particular interleukin-6, may be
responsible for part of these changes in NTI, but cannot explain the full effect
[83, 84]. Pulsatility of hypothalamic-pituitary hormones including TRH-TSH is
almost abolished in this syndrome, and restoration of all the axes by injection of
hypothalamic hormones can restore the abnormalities almost completely [85,
86]. Whether this also involves pituitary D1 and D2 is not fully clarified [87].
Genomic and Nongenomic Actions of Thyroid Hormones
As mentioned above, the biological activity of thyroid hormones is largely
exerted by T3 and is determined by the intracellular T3 concentration, which is

Thyroid Hormone Transport and Actions 93
dependent on a number of factors: the circulating concentration of T3 and its
precursor T4, the activity of transporters mediating the cellular uptake of T4
and T3 and the relative activities of the iodinases catalyzing the outer-ring deio-
dination of T4 to T3 and the inner ring deiodination of T4 and T3 to inactive
metabolites.
Most thyroid hormone actions are initiated by an interaction of T3 with
specific nuclear receptors, which act largely as transcription factors exerting a
modifying effect on the expression of a variety of genes, the genomic actions.
However, extranuclear processes may also contribute to the overall biologic
actions of thyroid hormones [88–90]. These effects occur rapidly and are shown
to be unaffected by inhibitors of transcription and translation suggesting that
thyroid hormones may also mediate non-genomic actions [reviewed in 91].
The heart is a major target organ for thyroid hormone action, and the T3
effects are shown to be mediated by both nuclear and extranuclear mechanisms
leading to enhanced velocity of cardiac contraction and increased speed of dias-
tolic relaxation [reviewed in 92].
Receptor-Specific Nuclear Actions (Genomic Actions)
Thyroid hormone receptors belong to a large superfamily of nuclear hor-
mone receptors that include the steroid hormone, retinoic acid, vitamin D and
peroxysomal proliferator receptors (PPARs). The receptors have a central
DNA-binding domain and a carboxy-terminal ligand-binding domain (fig. 4).
The two major isoforms, the thyroid hormone receptor -1, -2 (TR) and -1,
-2, -3 (TR) have a high homology in these two domains, while the amino-
terminal regions are more variable. Two thyroid hormone receptor genes
located on chromosomes 17 and 3, respectively [89, 93–94] encoding for TR
and TR, respectively. TR-1, TR-2, TR-1 and TR-3 are expressed widely,
whereas TR-2 is predominantly restricted to the hypothalamic/pituitary axis in
the negative feedback regulation of TSH.
T3 binds to TR-and TR-resulting in nuclear gene expression. The
receptors are ligand-regulatable transcription factors that recognize and interact
with specific DNA sequences (thyroid hormone response elements) in the pro-
moter region of target genes leading to consequent effects on transcription [95,
96] (f ig. 5a). The transcriptional activity of target genes is either increased or
decreased. Examples of target genes that are positively regulated by TH are:
fatty acid synthetase, growth hormone, lysosome silencer, malic enzyme, type I
5-deiodinase and negative regulated: epidermal growth factor receptor, pro-
lactin, TSH, thyrotropin-releasing hormones, type II 5-diodinase [96] The
genomic effects have response times of hours to days. After TR binding to TH

Fig. 5. a The genomic pathway of TH action. T3 is converted from T4 by deiodinase or
transported directly into the cell whereupon it binds to nuclear TRs. In positively regulated
target genes, corepressors are subsequently released and coactivators recruited, resulting in
histone acetylation and RNA polymerase II-mediated transcription. bSchematic representa-
tion of the proposed model of the nongenomic pathway of thyroid hormone action. T4 and T3
binds to integrin V3 and activates the MAPK pathway. It is possible that nuclear hormone
receptors are serine phosphorylated and with down-stream transcriptional regulation result in
angiogenesis. Other TH-regulated pathways have been depicted but little is known about
their mechanisms. ERestrogen receptor ; PLC Phospholipase C; PKC protein
kinase C; STAT1signal transducer and activator of transcription 1. Reproduced with
kind permission from Yen [109].
Antiporters
Transporters
TRRXR
T3Nucleus
Cytoplasm
Target gene
mRNA
Protein
Deiodinase
TH transporter
T3T3
T4
/ cofactors
histone
acetylation
Transcription
Translation
T3
Nucleus
Cytoplasm
mRNA
Protein
Transcription
Translation
PLC
PKC
MAPK
(ERK1/ERK2)
Signal transduction
Serine phosphorylation
TR, ER, STAT1, p53
T3, T4T3, T4
?Kinases
?Enzymes
Actin polymerization
Mitochondria
Integrin
V3
T3
a
b
Feldt-Rasmussen/Rasmussen 94

Thyroid Hormone Transport and Actions 95
response elements the transcriptional activity is altered by an interaction
directly or indirectly with a complex array of transcriptional cofactors including
corepressors, coactivators, integrators. Even unliganded TRs interact with core-
pressors and repress expression rather than being an inactive passive receptor.
This also explains that TR knockout mice are not suffering from as pronounced
a hypothyroidism as might be expected [97].
Mutations have been demonstrated in the TR-gene with resultant famil-
ial resistance to thyroid hormones. These patients are identified by their
persistent elevation of circulating free T3 and T4 without a suppressed TSH
concentration. The thyroid hormone resistance syndrome will be dealt with in
more detail in a subsequent chapter.
Nongenomic Actions (Extranuclear Actions)
A number of T3 effects occur rapidly and are unaffected by inhibitors of
transcription and protein synthesis. The site of these actions has been localized
to the plasma membrane, cytoplasm and cellular organelles. The nongenomic
actions often have a short latency. Cell culture studies suggest that thyroid hor-
mones rapidly, and nongenomically regulate the Ca2ATPase enzyme, the Na
channel via protein kinase C (PKC), the Kchannel via phosphatidyl-inositol 3
(PI3)-kinase, the Na/Hantiporter via PKC and mitogen-activated protein
kinase (MAPK) [98]. The nongenomic actions thus presumably include the reg-
ulation of ion channels, oxidative phosphorylation and mitochondrial gene tran-
scription and involve the generation of intracellular secondary messengers
signaling pathways including induction of calcium, cyclic AMP or protein
kinase signaling cascades [91, 98–100]. Recently, integrin V3, has been
identified as a plasma membrane TH-binding site [101]. Furthermore, it has
been shown that both T4 and T3 activate MAPK activity leading to phosphory-
lation of TR[90]. Additionally Davis and colleagues [102, 103] showed a
proangiogenic action of the thyroid hormone analogues GC-1 and 3,5-
diiodothyropropionic acid (DITPA) initiated at the cell surface interacting with
integrin. The proposed model (represented schematically in fig. 5b) thus
includes that TH activates the MAPK cascade and promotes angiogenesis via
TH binding to membrane-bound integrin V3.
TH Analogs, Metabolites, and Antagonists
Several tissue- and TR isoform-specif ic compounds have been developed
as potential treatments for hypercholesterolemia, obesity, and heart failure
[reviewed in 96]. In the development of these compounds it is attempted to use

Feldt-Rasmussen/Rasmussen 96
information on tissue-specific uptake of the compound. One of the initial com-
pounds was investigated in mice, who subsequently had lower serum choles-
terol levels without cardiotoxicity. Recently, several other TH analogs have been
described that have compared to TR. Since thyroid hormone receptors in the
liver, isoform-selective affinity for TRis approximately 90% TR, and in the
heart mostly TR, these isoform-selective compounds may serve as novel
agents to lower serum cholesterol with minimal cardiotoxicity. Recently,
KB141 was shown to be a potential treatment for obesity by decreasing body
weight via stimulation of metabolic rate and oxygen consumption.
Some TH analogs and derivatives can also bind specif ically to proteins
other than thyroid hormone receptors, and are involved in nongenomic cell sig-
naling pathways. Recently, Scanlan et al. [104] identified 3-iodothyronamine,
which is a naturally occurring byproduct of TH, with interesting physiological
actions as it produced a rapid drop in body temperature and heart rate when
injected intraperitoneally in mice. These physiological actions are thus opposite
of those observed for T3, and may provide a counter-regulation to the transcrip-
tional effects of TH by nuclear thyroid hormone receptors.
The TH-related compound demonstrated with low metabolic activity and
low affinity for nuclear thyroid hormone receptors, DITPA was able to increase
cardiac contractility and peripheral circulation without significant effects on
heart rate as well as improve hemodynamic performance in animal models of
congestive heart failure after myocardial infarction [105]. Preliminary studies
have been performed in patients with heart failure demonstrating a signifi-
cant improvement in systolic cardiac index and systemic vascular resistance
[106]. Future studies are needed with this and similar compounds to clarify
if such drugs may represent a novel class of drugs for the treatment of heart
failure.
Mitochondrial Actions of Thyroid Hormone
Both genomic and nongenomic actions of thyroid hormones may mediate
mitochondrial effects regulating metabolism, cellular proliferation, differentia-
tion and apoptosis [107]. It has long been known that TH has profound effects
on mitochondrial activity and cellular energy state [108].
Summary and Conclusions
The functions of binding to plasma proteins are most likely a protection from
fluctuation in TH production and degradation, a projection against environmental

Thyroid Hormone Transport and Actions 97
deficient supply of e.g. iodine, and possibly also a protection of urinary loss of the
smaller molecules of unbound TH compared to the bound forms [2]. The normal
human organism has a high capacity for compensating to a maintained normal
thyroid function by almost any reduction in the plasma binding proteins.
Several transporters that mediate the cellular entry of TH have been identi-
fied, but most of them are not specif ic for thyroid hormones. Up to now only
two truly TH-specific transporters have been found: OATP1C1 with high
preference for T4 and MCT8 with preference for T3 as the ligand [21]. Since
delivery of TH to the cells is a crucial mechanism for subsequent TH action,
abnormalities in these transporters probably result in disease, e.g. a described
mutation in the MCT8 caused tissue-specif ic hypothyroidism in the brain with
milder affection of other organs [39].
In both qualitative and quantitative terms, deiodination is by far the most
important pathway of thyroid hormone metabolism. Deiodination by the deiod-
inases D1-D3 are extremely important for TH delivery to its intracellular action
mechanisms. The deiodinase activities are actively regulated in a variety of
fashions, and active differentially in various tissues. Clinically, the importance
of the deiodinases in the regulation of thyroid hormone bioactivity becomes
apparent when their activity is affected by pathophysiological conditions, such
as thyroidal and non-thyroidal illness and malnutrition. The selenium contain-
ing deiodinases are important players both in the physiological regulations of
thyroid function, e.g. with relations to fetal development in general and brain
development in particular, and in responses to antithyroid drug therapy such as
propylthiouracil. In conditions of limited and inadequate supply of both iodine
and selenium, complex rearrangements of TH metabolism enable adaptation to
this unfavorable situation by increasing retention of selenium in the brain, the
endocrine tissues, and especially in the thyroid gland.
During nonthyroidal critical illness at all ages a series of typical changes of
serum concentrations of thyroid-related function tests are found, which are pro-
bably ascribed to both downregulation of D1 and possibly D2, but recently also
induction of D3 has been suggested to play an important role, which has proba-
bly been underestimated in previous studies. Possibly, both cytokines and the
hypothalamo-pituitary axes also play important roles in this complex condition.
Independent of the mechanisms and consequences of thyroid function test
abnormalities in transport binding protein levels, thyroid hormone resistance or
NTI, it is important for all clinicians to be aware of the pitfalls in the use of rou-
tine methods for measurement of circulating variables of thyroid function such
as TSH, and total and free T3 and T4.
The increased knowledge of the molecular mechanisms of thyroid hormone
receptor structure and isoforms together with TH actions mediated by nuclear
and extranuclear pathways has a high potential for opening for possibilities to

Feldt-Rasmussen/Rasmussen 98
design new therapeutic agents, e.g. for treatment of cardiac failure, hypercholes-
terolemia, or for treatment of obesity without the central effect that most other
anti-obesity drugs display. This could be a very important pharmaceutical
progress in the solution of the increasing obesity epidemic in the Western world.
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Ulla Feldt-Rasmussen, MD, Dr MSci
Department of Medical Endocrinology PE 2132
National University Hospital
Blegdamsvej 9, DK–2100 Copenhagen (Denmark)
Tel. 45 35452399, Fax 45 35452240, E-Mail ufeldt@rh.dk

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 104–117
The Thyroid and Autoimmunity in
Children and Adolescents
Anthony P. Weetman
School of Medicine and Biomedical Science, University of Sheffield, Sheff ield, UK
Thyroid autoimmunity is the commonest disease process to affect thyroid
function. The prevalence of thyroid autoimmunity increases throughout life,
with a possible decline in frequency in the very old as a ‘healthy survivor’
effect. The mere presence of thyroid autoimmunity, as demonstrated by the
presence of thyroid autoantibodies or focal thyroiditis, for example, does not
equal thyroid disease, since the majority of people with focal thyroiditis do not
become hypothyroid [1]. On the other hand, as far as we know the formation of
thyroid-stimulating antibodies (TSAb) leads to Graves’ disease in the great
majority of subjects, even if in rare cases their levels may oscillate and be asso-
ciated with a fluctuating clinical course. After a brief review of the basic
immunological mechanisms which underlie autoimmune thyroid diseases, this
chapter will focus on the comparatively few studies which have looked specifi-
cally at the pathogenic mechanisms in these disorders in children and adoles-
cents, and then look at the autoimmune disease associations which have
considerable clinical relevance to the management of such patients.
Mechanisms of Thyroid Autoimmunity
Predisposition
It is well established that a complex interplay of diverse environmental and
genetic susceptibility factors interact in predisposing an individual to autoim-
mune thyroid disease (fig. 1). Moreover, the contribution that each factor makes
varies from patient to patient, and as yet there are no clear genotype-phenotype
correlations. We have shown that polymorphisms in the thyroid stimulating hor-
mone receptor (TSH-R) are associated with Graves’ disease but not autoimmune

Thyroid Autoimmunity 105
hypothyroidism [2]. The other known genetic loci associated with thyroid autoim-
munity, namely HLA, CTLA-4 and PTPN22, are shared between these 2 thyroid
conditions, as well as many other autoimmune diseases [reviewed in 3]. Several
environmental factors have been delineated but some of these remain controver-
sial and of unknown action, such as smoking and stress [4, 5]. Evidence for
the involvement of infections is lacking (thyroid autoimmunity rarely follows
subacute thyroiditis, for instance), but there does appear to be an association
between congenital rubella infection and subsequent thyroid autoimmunity [6].
Failure of Self-Tolerance
Genetic and environmental factors predispose to autoimmune disease
through their effects on immunological tolerance (table 1). It is well established
that most autoreactive T cells are deleted in the thymus, and this involves the
intrathymic expression of self-antigens during development. This process is
most clearly demonstrated in autoimmune polyglandular syndrome type 1, in
which there is a defect in the autoimmune regulator (AIRE) gene, which pre-
vents transcription of self antigens in medullary thymic epithelial cells and, as
a result, there is a failure to negatively select organ-specif ic thymocytes [7].
However, the main autoimmune endocrinopathies in this syndrome do not
include thyroid disease, although there is a slightly higher frequency of this dis-
order than expected in patients with the syndrome. Therefore, the expression of
Fig. 1. Interaction of factors predisposing to autoimmune thyroid disease.
HLA
CTLA-4
PTPN 22
TSH-R
Others: ? CD40
? vitamin D
Iodine
Stress
Irradiation
Smoking
Drugs
Others: ? infection
? toxins
Clinical autoimmune
thyroid disease
Female sex
Age
Pregnancy
Others: ? birthweight
? fetal microchimerism
? response to stress
Genetic factors
Endogenous factors
Environmental factors

Weetman 106
thyroid autoantigens in the thymus may be regulated by other transcription fac-
tors, or other mechanisms may be important in regulating tolerance.
One likely additional mechanism involves T regulatory cells. Once again, a
disorder caused by a single gene defect in man in revealing in illustrating the
importance of this type of tolerance mechanism. In the IPEX (immune dysreg-
ulation, polyendocrinopathy, enteropathy, X-linked) syndrome, there is a defect
in the FOXP3 gene which encodes a transcription factor essential for the func-
tion of CD4, CD25T cells with immunoregulatory properties, and such
patients have a fatal disorder with severe autoimmune disease including that
against the thyroid [8]. In fact, the existence of T regulatory cells was first
defined by elegant experiments on experimental autoimmune thyroiditis
induced in rats by neonatal thymectomy and sublethal irradiation [9]. Disease
could be prevented by transfer of cells from healthy donors, which subsequently
led to identification of this important CD4, CD25subset.
Another clinical illustration of this pathway appears to be the common
autosomal dominant condition, autoimmune polyglandular syndrome type 2,
which of course includes thyroid autoimmunity as 1 of the 3 cardinal endo-
crinopathies, alongside Addison’s disease and type 1 diabetes mellitus. Although
there are no quantitative differences, CD4, CD25T cells from patients
with this syndrome have markedly reduced suppressive capacity compared to
controls or patients with isolated endocrinopathies [10]. Disturbances in these
or other populations of immunoregulatory T cells may be responsible to ‘recon-
stitution’ Graves’ disease, in which thyroid disease appears as lymphocyte
counts rise in patients with previously low counts, such as occurs after HAART
treatment in HIV disease [11].
A final important pathway for T cell tolerance is likely to be induced by the
expression of HLA class II molecules on thyroid epithelial cells in response to
-interferon released by any local inflammation. In the absence of costimula-
tion mediated through CD80 or CD82 (which thyroid cells do not express),
Table 1. Mechanisms to ensure immunological self tolerance and prevent autoimmune
disease
Deletion or anergy of autoreactive T and B cells during fetal life
Peripheral tolerance, including deletion or anergy of T cells by antigen presentation in the
absence of a co stimulatory signal
Sequestration of autoantigen, including tissue expression of Fas ligand (immunological
privilege) causing apoptosis in Fas-expressing autoreactive T cells
Clonal ignorance; absence of activated CD4cells required for CD8T or B cells
Active suppression of autoreactive T cells; particularly by CD4, CD25T regulatory cells
Mutual inhibition of Th1 and Th2 cytokine pathways

Thyroid Autoimmunity 107
antigen presented by class II thyroid cells is able to induce anergy and tolerance
in naïve T cells, rather than their activation [12]. Unfortunately, in an already
initiated autoimmune response, in which autoreactive, memory T cells have
been exposed to costimulation delivered by professional antigen-presenting
cells, HLA class IIthyroid cells are able to induce further T cell activation,
leading to exacerbation of the autoimmune response. Overall the relative
importance of these and other tolerogenic pathways in thyroid autoimmunity is
unclear, but unlikely to be similar in all patients.
Mechanisms of Disease
Although thyroglobulin (TG) and thyroid peroxidase (TPO) autoantibodies
are useful diagnostic markers, their role in causing tissue injury, at least primar-
ily, is minimal. They may, however, be important in causing secondary damage,
through antibody dependent cellular cytotoxicity (ADCC) or complement fixa-
tion (TPO antibodies) [13]. TSAb are obviously central to the pathogenesis of
Graves’ disease and there have been several recent studies which have shown
the potency of monoclonal TSAb in causing thyroid cell activation [14]. Indeed,
there is now a real issue over the exact relationship between the hyperthy-
roidism and the thyroid lymphocytic infiltrate which is so frequently accepted
as an inevitable accompaniment of Graves’ disease [15]. Perhaps Graves’ dis-
ease is a ‘pure’ B cell-mediated disorder that is very frequently associated with
T cell-dependent thyroiditis, and whether one leads to the other becomes a crit-
ical question. The main mechanism of thyroid destruction in autoimmune thy-
roid disease is probably T cell-mediated cytotoxicity, but a number of pathways
of tissue injury are involved (fig. 2) [15].
Autoimmunity in Juveniles
Probably the most frequent clinical presentation of thyroid autoimmunity
in children and adolescents is with a small asymptomatic goitre typically
appearing around 11 to 12 years of age and comprising a mild lymphocytic thy-
roiditis. Patients are usually euthyroid. This entity was characterised by Hazard
[17] as showing little if any Ashkenazy cell metaplasia, marked colloid phago-
cytosis in affected follicles and areas of epithelial hyperplasia. The levels of
antibodies against TG and TPO are typically much lower than in the adult and
there is a tendency to spontaneous remission [18]. There is still a female to male
preponderance in children, but perhaps 3-fold less than in adults.
The overall clinical course is variable and may fluctuate, including periods
of thyrotoxicosis [19]. Even patients with severe hypothyroidism may be come
euthyroid. In 15 patients with overt hypothyroidism from Japan, reversibility

Weetman 108
was associated with iodine restriction in the diet and disappearance of anti-
bodies capable of blocking the TSH-R [20]. In another study of 21 children with
atrophic thyroiditis and 48 children with a lymphocytic goitre, all treated with
thyroxine, five of the goitrous patients recovered normal thyroid function [21].
These clinical observations indicate that autoimmune thyroiditis in chil-
dren and adolescents is typically less severe than in adults, with lower levels of
autoantibodies and a more fluctuating course which includes spontaneous
recovery. There do not appear to be good, very long-term follow-up studies
which show what happens to these individuals over subsequent decades.
Predisposing Factors
Children not only encounter a somewhat different range of environmental
factors to adults, but also have overall a lower chance of encountering aetiolog-
ical agents simply because of their shorter period of exposure. In turn, this has
led to the suggestion that genetic factors are likely to play a larger role in child-
hood thyroid autoimmunity than in adults, while environmental factors would
have an increasing role in adults as they age. Despite possible ascertainment
artefacts, initial studies have certainly shown that children and adolescents with
autoimmune thyroiditis have strikingly strong family histories of thyroid and
other autoimmune disease, including those in the non-organ-specific category.
For instance, in 35 such juvenile patients, there was a family history of thyroid
Fig. 2. Pathogenic mechanisms in autoimmune hypothyroidism. From Weetman [16],
with permission.
-IFN, TNF
IL-1
Lymphocytic infiltrate
producing cytokines with
sublethal effects on TFC
Complement activation causing
sublethal effects
(metabolic defects, upregulation
of TFC cytokines)
CD8 cytotoxic lymphocyte
killing by granule
(perforin and granzyme)
exocytosis and Fas ligand binding
to Fas on TFC
Loss of tight junctions allowing
TPO antibody to bind TPO and
activate complement
Fas and Fas ligand
upregulation TFC
leading to ‘suicide’ or
‘fratricide’

Thyroid Autoimmunity 109
disease in 27% (compared to 17% in adult Hashimoto patients) and there was a
28% frequency of positive antinuclear factor antibodies, compared to 9% in
adults with thyroiditis [22]. In another study of 20 child probands with chronic
lymphocytic thyroiditis and 18 with Graves’ disease, there was a considerable
risk of developing thyroid autoimmunity in their siblings, which was demon-
strated by the 50% prevalence of thyroid antibodies in the siblings of probands
with either type of thyroid disease [23]. When one or both parents also had anti-
bodies, there was a significantly greater risk of thyroid autoimmunity in their
offspring. An even stronger familial clustering of thyroid autoimmunity is
apparent when detection of TPO antibodies is combined with f ine needle aspi-
ration biopsy [24].
There have been relatively few studies looking specifically at the genetic
associations of autoimmune thyroid disease in children. Those studies which
have been conducted suffer from the limitations of small sample size to an even
greater degree than those in adults, in turn related to the relative infrequency of
such conditions in children, and presumably ethical constraints as well. The
entire thyroid and other autoimmune literature contains many examples of
genetic associations which have not been replicated, as a result of inadequate
power and population stratif ication [25]. As well as relatively simple associa-
tion studies using a candidate gene approach, there have been attempts to iden-
tify novel genes which contribute using genome-wide screening, but again
these have not been replicated, and indeed the problem of sample size is magni-
fied in such approaches [26].
HLA alleles confer the best established and strongest susceptibility to
autoimmune thyroid disease. In Caucasians, the HLA-DR3 specificity is most
consistently associated with both Graves’ disease and Hashimoto’s thyroiditis
and there are conflicting reports concerning a possible role of HLA-DR4 or
DR5 in the latter [29]. In a study of 18 patients with juvenile autoimmune thy-
roiditis, 63% were HLA-DR4, but obviously this is too small a sample to draw
firm conclusions, and a direct comparison with adult cases would have been
desirable [28]. In another study of 91 juvenile patients, there was evidence of a
higher risk conferred by the presence of HLA-DR3, DQ2, as well as positive
TPO antibodies, in the fathers of the children [29].
Most recently, the association of the HLA-A1, B8, DR3 (DRB1*0301)
haplotype with autoimmune thyroid disease was confirmed in 90 Italian chil-
dren (mean age 11 years) [30]. Intriguingly there was a signif icant interaction
between DRB1*0301 and infection with Helicobacter pylori in the children
with autoimmune thyroid disease but not controls. It seems premature to specu-
late on a causal relationship between thyroid disease and H. pylori based on
such data, rather than there simply being a shared predisposition (perhaps
linked to HLA), but further studies are clearly warranted.

Weetman 110
Many genetic studies in children have focussed on type 1 diabetes mellitus,
for obvious reasons, and coincidental autoimmune thyroid disease has been co-
analysed in this context. How representative such patients are is unclear, as they
constitute an example of autoimmune polyglandular syndrome type 2. This is
considered further below, but in the context of genetic associations, the pres-
ence of TPO antibodies in juveniles with type 1 diabetes is associated with the
HLA-DQA1*0301, DQB1*0302 haplotype in Caucasians [31]. These results
have been conf irmed subsequently but the association does not extend to the
presence of parietal cell antibodies [32].
It is well recognised that different racial groups have different susceptibility
factors for the same autoimmune disease, and in Korean children with type 1
diabetes, DRB1*0401 was associated with presence of autoimmune thyroid dis-
ease [33]. In non-diabetic children DQA1*0301 was associated with thyroid dis-
ease, but again small numbers (n 21) limit the conclusions that can be drawn.
As in adults, CTLA-4 polymorphisms are also associated with type 1 dia-
betes and other autoimmune disorders, but within a group of Japanese diabetic
children there was an association between polymorphism in exon 1 (G/G geno-
type) and the co-existence of thyroid autoimmunity, as well as with younger age
of onset of diabetes [34]. It has been claimed that childhood and adult Graves’
disease may be more genetically different. In Japanese children, there was a
similar association with CTLA-4 polymorphism to adults, but the HLA associa-
tion was with DRB1*0405 and DQB1*0401 [35]. However only 43 children
were analysed and there was no direct comparison with adult patients. A larger
study of 65 Chinese children with Graves’ disease found that HLA-
DQB1*0303 was increased and DQB1*0201 was decreased, and these results
also are somewhat different to those of local adult patients, but again there was
no direct comparison [36]. Reports of an association between polymorphisms
in the MICA (major histocompatibility complex class I chain related gene A)
gene and Graves’ disease in juveniles may reflect linkage disequilibrium with
other, more important HLA genes [37]. Finally, in Caucasian children
DRB1*0301 was associated with Graves’ disease, as in adults, but the strength
of association appeared to be even greater in children [38].
One very long established genetic association remains unexplained,
namely the increased frequency of autoimmune thyroid disease in Turner’s syn-
drome [39]. In a typical series of 84 girls with this condition, evaluated at mean
age 10 and followed for a mean of 8 years, hypothyroidism was detected in 24%
and hyperthyroidism in 2.5% [40]. In 42% there were thyroid autoantibodies
and thyroid dysfunction first became apparent at 8 years of age. Although these
clinical observations are secure, it is still unclear why the association exists, but
together with the increased frequency of both autoimmune hypothyroidism
and Graves’ disease in prepubertal children, this seems to argue in favour of

Thyroid Autoimmunity 111
a genetic susceptibility effect conferred by the X-chromosome. In the case
of Turner’s syndrome, this might involve loss of some important autoimmune
regulatory function.
In relation to environmental factors, diffuse autoimmune thyroiditis and
high levels of thyroid autoantibodies are rare in children in moderately iodine-
deficient areas, although TG and TPO antibodies occur at low levels quite fre-
quently [41]. Overall however the prevalence of thyroid antibodies in children
in relation to iodine intake is not well established, although pilot data show
equal prevalence of TPO antibodies in iodine replete and moderately iodine-
deficient patients [42]. Overall, therefore, the effect of dietary iodine on thyroid
autoimmunity appears, at best, modest.
Children do seem more susceptible than adults to develop thyroid autoim-
munity after fallout radiation or as a side effect of irradiation given for treat-
ment of head and neck lesions. Hashimoto’s thyroiditis occurred in 30% of 90
patients who had received head and neck irradiation as children or adolescents;
the mean length of follow-up was 26 years [43]. A careful follow-up of children
exposed to fallout after the Chernobyl nuclear reactor accident found a signifi-
cantly higher frequency of thyroid antibodies in children aged 7–14 years com-
pared to unexposed controls (81 vs. 17%) and ultrasonographic abnormalities
compatible with lymphocytic thyroiditis were also increased [44]. The dose of
131I that the children had been exposed to correlated with thyroid antibody lev-
els, up to a thyroid gland dose of 4 Gy.
Perhaps the most striking indication for a likely role of environmental fac-
tors has been demonstration of a five-fold higher frequency of juvenile Graves’
disease in Hong Kong compared to Denmark [45]. Although it is conceivable
that this could have a partial genetic basis, this explanation seems far less likely
as there does not seem to be such a difference in adults and the pace of change is
rapid. In this series, there was a female preponderance of Graves’ disease but this
increased at adolescence, suggesting the involvement of a sex chromosome-
encoded factor and, later, sex steroids then operate as susceptibility factors.
Finally, a survey of physicians’ experience of childhood Graves’ ophthal-
mopathy has conf irmed that this is uncommon but appears to be found more
frequently in countries in which there is a high prevalence of teenagers who
smoke [46]. This fits with the fact that smoking is a well known risk factor in
adults, for reasons which are still unclear [4]. There is also indirect evidence
from this survey of a possible adverse effect of passive smoking in children
younger than 10 years of age.
Pathogenesis
Apart from the tendency to spontaneous remission, which is in part related
to fluctuation in the level of TSH-R blocking antibodies [2], and the lower levels

Weetman 112
of thyroid autoantibodies, there are no particularly distinct pathogenetic fea-
tures of autoimmune thyroiditis which have been delineated. However, these
clinical observations do suggest that the autoimmune response is not fully
developed and is susceptible to modulation. Further work to define how this
modulation occurs (and why it fails to prevent some children developing per-
manent hypothyroidism) would be very useful.
Such studies as there are have not compared children and adults with thy-
roid disease directly making conclusions about any differences tenuous. Clear
phenotypic differences exist between circulating lymphocyte subsets in chil-
dren with Graves’ disease and in healthy age-matched controls, including
an increase in CD19(B cells), CD4, CD45R0(T memory cells) and a
decrease in CD8T cells, but how such changes relate to intrathyroidal
autoimmune events has not been established [47]. The same group has more
recently shown a positive correlation between the level of TSAb and circulating
T cell expression of CTLA-4 (CD152) in children with Graves’ disease [48]. It
is difficult to envisage how these two parameters may relate, and more work is
required on the intrathyroidal T cell populations which are more clearly
involved in the autoimmune response.
Other Autoimmune Disorders
Probably the bulk of immunologically related studies in children and ado-
lescents with autoimmune thyroid disease have addressed the frequency of
association with other autoimmune disorders, especially type 1 diabetes melli-
tus. Although there are few lessons to be gleaned from such reports in a narrow
immunological sense, given the fact that all such disorders share similar genetic
susceptibility factors, there are clear implications for screening, which in turn
frequently leads to questions over the utility of TG and TPO antibody testing.
The effectiveness of screening strategies for measuring non-thyroid autoanti-
bodies in autoimmune thyroid disease has been reviewed recently [49]. Major
difficulties in such association studies concern adequate population size and
inclusion of suitably matched contemporary controls. In attempting to establish
baseline frequencies for thyroid antibodies in the healthy population it is clear
that age is crucial, since in females, but not males, the prevalence of thyroid
antibodies increases at puberty and there is unexplained geographical hetero-
geneity which is not related to goitre prevalence or iodine intake [50].
Type 1 Diabetes Mellitus and Thyroid Autoimmunity
It is clear that thyroid autoimmunity is more frequent than expected in type 1
diabetes. However, the frequency of autoantibodies in diabetic patients which

Thyroid Autoimmunity 113
are directed against glutamic acid decarboxylase (65-kDa isoform) and IA-2
does not differ between those with or without other autoimmune disorders,
including thyroid disease [51]. In a series of 216 diabetic children (mean age 13
years), 10% had TPO antibodies, 8.7% had TG antibodies and 5.9% had both
autoantibodies [52]. Around half of those with thyroid antibodies had an ele-
vated TSH and/or echographic features of thyroiditis on ultrasound, or devel-
oped these within a mean of 3.5 years of follow-up, and there was an increased
risk in those with the highest antibody levels. A similar set of f indings have
come from a 3-year follow-up of 105 diabetic children with a mean age of 12.7
years at the beginning of the study; the prevalence of thyroid dysfunction rose
from 5 to 8%, while the prevalence of TPO antibodies remained constant at
13% and TG antibody positively declined from 14 to 7% [53]. An even higher
figure for thyroid autoantibody positivity (25%) was reported in 109 children
with a mean age of 13, and the frequency in their first-degree relatives was 27%
compared to half the prevalence in controls [54]. Another series found that
18.4% of 197 diabetic children had thyroid antibodies, compared to 7.8% of
first-degree relatives and 3.2% of controls [55].
Both series also make clear that these patients are at a signif icantly
increased risk of coeliac disease as well, and support the case for consideration
of screening for both coeliac disease and thyroid disease in children with type 1
diabetes mellitus. Parietal cell antibodies are also found in around 20% of dia-
betic patients, but occur in a somewhat older patient population; those with con-
current thyroid autoantibodies are at 50% greater risk of developing parietal
cell antibodies [56].
Other Diseases
Many other diseases are associated with autoimmune thyroid disease in
adults but rather few studies have examined these specif ically in children [57].
Pernicious anaemia is rare in the young, but in 129 children, mean age 9.7
years, with autoimmune thyroid disease, parietal cell antibodies were present in
30%, and almost half of these had elevated gastric levels [58]. In 80 Kuwaiti
children aged less than 12 years with alopecia areata, 17.5% had some evidence
biochemical evidence or positive thyroid autoantibodies [59]. Thyroid autoim-
munity is also more common than expected in juvenile rheumatoid arthritis,
and 25% of the relatives of such patients have autoimmune thyroid disease [60].
Conclusion
Autoimmune thyroid disease is uncommon in children and adolescents,
but there is a significant prevalence of self-limiting autoimmune thyroiditis

Weetman 114
with positive thyroid autoantibodies and biochemical thyroid dysfunction.
There is some evidence that the genetic predisposition to thyroid autoimmunity
differs between adults and children, and there are specif ic, clinically important
associations with other autoimmune disease in children. The area still requires
further association studies, in particular examining larger cohorts and directly
comparing results to series of adult patients from the same area, to elucidate
fully the differences, which might enhance our understanding of how the
autoimmune response can be modulated for therapeutic benefit.
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Anthony P. Weetman
Professor of Medicine
School of Medicine and Biomedical Science, University of Sheffield
Beech Hill Road
Sheffield, S10 2RX (UK)
Tel. 44 114 271 2570, Fax 44 114 271 3960, E-Mail a.p.weetman@sheffield.ac.uk

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 118–127
Congenital Hypothyroidism
Beate Kargesa, Wieland Kiessb
aUniversity Hospital for Children and Adolescents, University of Ulm, Ulm, and
bUniversity Hospital for Children and Adolescents, University of Leipzig, Leipzig,
Germany
Epidemiology of Congenital Hypothyroidism
The incidence of congenital hypothyroidism (CH) as detected by common
neonatal screening programs, is approximately 1:3,000–1:4,000 in live births
[1]. Very recently, in the Netherlands a higher incidence of 1:1,800 was observed
using a screening based on thyroxine (T4), thyrotropin (TSH) and thyroxine-
binding globulin (TBG) measurement [2]. With this strategy, the incidence of
various types of CH was estimated 1:2,200 for permanent CH with 1:2,500 of
thyroidal origin, 1:21,000 of central origin, and 1:12,000 for transient hypo-
thyroidism. For unknown reasons, the female/male ratio in CH is consistently
2:1. Newborn infants with Down syndrome have an increased risk for CH of
approximately 1:140.
Genetic and Other Causes of Congenital Hypothyroidism
CH represents a heterogeneous group of thyroidal and non-thyroidal disorders
(fig. 1), leading to decreased or absent thyroid hormone action and clinical
sequelae. In 70–80% of the cases thyroid dysgenesis is found due to agenesis
(30%), ectopic gland (48%) or hypoplastic, eutopic gland (5%) [3]. A normal
(11%) or enlarged thyroid gland (6%) is observed in children with disorders of thy-
roid hormone synthesis. Up to 15% of cases with CH occur on a hereditary basis
(table 1), while the remaining majority of cases are considered sporadic forms.
Severe central hypothyroidism due to isolated TSH deficiency frequently
results from TSH-␤subunit (TSHB) mutations [4, 5]. Similarly, TSH deficiency
may be found as a component of combined pituitary hormone deficiencies

Congenital Hypothyroidism 119
(CPHD). In some of these patients, mutations in homeobox genes including
POU1F1, PROP1, LHX3, LHX4, HESX1 and PHF6 have been identified [6–8],
with PROP1 mutations accounting for the majority of cases with familial CPHD.
Isolated thyroid dysgenesis may be caused by inactivating (‘loss-of-function’)
mutations of the TSH receptor (TSHR) (fig. 2). CH in association with various
complex syndromes is found in patients carrying mutations of thyroid tran-
scription factors PAX8, TITF1, TITF2 or the stimulatory G protein ␣-subunit
Pituitary
development
Thyrotropin/
TSH receptor#
␤
␣
Thyroid
development
Hormone
synthesis*
T4/T3 action
Fig. 1. Anatomic and functional
levels at which CH may occur, including
exogenous and maternal causes of transient
CH. *Antithyroid medication, iodine defi-
ciency; #blocking TSHR antibodies.

Karges/Kiess 120
Table 1. Genetic causes of congenital hypothyroidism
Gene Protein Heredity Thyroid Associated
function volume malformation
Central (pituitary) hypothyroidism
TSHB TSH subunit AR ↓– n –
TRHR TRH receptor AR ↓– n –
POU1F1 AR/AD ↓– n GH, PRL deficiency
PROP1 AR ↓– n CPHD, pituitary mass
LHX3 AR ↓– n CPHD, pituitary mass,
pituitary rigid cervical spine
LHX4 transcription AD ↓– n CPHD, hindbrain-,
factors sella turcica defect
HESX1 AR/AD ↓– n CPHD,
septooptic dysplasia
PHF6 X-linked ↓– n CPHD, epilepsy,
septo-optic dysplasia
Thyroid aplasia or hypoplasia
TSHR thyrotropin AR ↓, ↑, or n –
receptor
PA X 8 AD ↓renal agenesis
TITF1 AD ↓– n choreoathetosis,
pulmonary disease
TITF2 AR ↓cleft palate,
choanal atresia
GNAS1 signalling protein AD n osteodystrophy
Abnormal thyroid hormone synthesis
TPO peroxidase AR ↑–
THOX2 oxidase AR ↑– n –
TG storage protein AR ↑– n –
Pendrin anion transporter AR ↑– n sensineural hearing loss
NIS Na⫹/I⫺symporter AR ↑– n –
DEHAL1 iodine recycling AR ↑– n –
Defects of thyroid hormone action
MCT8 transmembrane T3 X-linked ↑– n severe neurological
transporter abnormalities
THRB nuclear thyroid AD/AR ↑– n hyperactivity, learning
hormone receptor disorder
AD ⫽Autosomal-dominant; AR ⫽autosomal-recessive; GH ⫽growth hormone;
n⫽normal; PRL ⫽prolactin.
thyroid
transcription
factors

Congenital Hypothyroidism 121
gene (GNAS1) [9]. Although thyroid dysgenesis is the most common cause of
CH, mutations in thyroid transcription factors or TSHR gene are found in less
than 10%.
Inborn errors of T4 synthesis are frequently caused by inactivating muta-
tions of the thyroid peroxidase (TPO). A positive perchlorate discharge indicat-
ing total iodine organification defect is suggestive of a defect of TPO or, more
rarely, thyroid oxidase 2 (THOX2) function [10]. Low serum levels of thy-
roglobulin associated with enlarged thyroid gland and elevated TSH are typical
for thyroglobulin (TG) defects, while sensorineural deafness is a frequent find-
ing in Pendred’s syndrome. CH caused by mutations of the sodium iodine sym-
porter (NIS) is characterized by low radionuclide uptake in the thyroid [9].
Mutations in the iodotyrosine dehalogenase gene, DEHAL1, leading to a
iodine recycling defect have recently been identified in patients with goitrous
CH and presence of mono- and di-iodotyrosines in urine [11]. Iodothyronine
transporter defects associated with severe neurological abnormalities have been
described due to mutations of the monocarboxylate transporter gene (MCT8)
[12]. Hypothyroidism is usually mild with normal or elevated TSH. Familial
thyroid hormone resistance, caused by various thyroid hormone receptor
(THRB) defects, is paradoxically associated with elevated serum thyroid hor-
mone levels and mild-to-moderate hypothyroidism.
C
N
**
C41S
I167N
Q324X
L467P
G498S
W546X
C600R
R609X
F405fsX419
T655fsX656
IVS51G⬎A
IVS6+3G⬎C
R109Q
P162A
R310C
C390W
D410N
R450H
V473I
F525L
A553T
A593V
*
TSH-R inactivation
PartialComplete
Fig. 2. Schematic illustration of the thyrotropin receptor (TSH-R), a heptahelical G
protein-coupled receptor. The localization of inactivating TSH-R mutations is shown by sym-
bols. Mutations have been categorized as partial or complete loss-of-function variants
according to clinical and/or functional in vitro data.

Karges/Kiess 122
Less commonly, hypothyroidism is transient and may be attributable to
transplacental passage of maternal antithyroid medication, blocking TSHR anti-
bodies, iodine deficiency or excess, or heterozygous THOX2 gene mutations.
Debate on Newborn Screening Programs
To detect CH, primary TSH screening is used in most European countries,
Japan and Australia. However, using this approach, some forms of CH including
delayed TSH elevation in infants with TBG deficiency or low birth weight, central
hypothyroidism and hypothyroxinemia are missed. In North America, a T4-based
program with additional measurement of TSH in samples with lowest T4 concen-
tration is commonly used [1]. Primary T4 screening with backup TSH measure-
ments has the potential to detect primary hypothyroidism, TBG deficiency and
central hypothyroidism. The recall rate for primary hypothyroidism in both
approaches is 0.05%, and the rate of false positive results is higher using the pri-
mary T4 strategy.
Although both screening strategies detect CH of thyroidal origin, they
may miss patients with central CH because T4 may be only moderately
decreased and TSH is not elevated. In such patients, however, early diagnosis
is crucial not only for early and appropriate thyroxine replacement (f ig. 3), but
Sibling 1, age 34 months Sibling 2, age 10.5 months
3
50
60
70
80
90
6 1218240
97
50
Age (months)
Height (cm)
Child 2
Child 1
Start of L-T4
b
ac
Fig. 3. Clinical consequences of delayed versus early thyroxine treatment in two sisters
with congenital hypothyroidism caused by inactivating TSH-␤mutation (C105Vfs114X). In
child 1, thyroxine was initiated at 5 months of age. At 34 months of age, she is characterized
by severe psychomotor retardation, diff iculties to stand and walk (a), and growth retardation
(b). In contrast, thyroxine treatment was started immediately after birth in child 2, followed
by normal development (b, c).

Congenital Hypothyroidism 123
also to detect or rule out CPHD for which adequate and timely treatment is
fundamental.
In the Netherlands, a T4-TSH-TBG-based screening strategy has been
implemented which has been shown to detect CH of variable origin and sever-
ity [2] with a sensitivity of 95.8% and specif icity of 99.9% [13], associated
with the highest incidence rates worldwide. A high rate of false-positive results
mainly due to severe illness or TBG def iciency, and occasional false negative
cases in very mild forms of CH with normal T4 levels or in premature neonates
are pitfalls of this strategy that have to be addressed in the future.
Preterm infants with CH may have a delayed TSH increase owing to the
immaturity of the hypothalamic-pituitary-thyroid axis, and may thus be missed
by laboratory screening procedures. Therefore, a routine second screening
between 2 and 6 weeks of age has been suggested in preterm neonates [14]
leading to a reported additional 10% of cases.
Clinical Outcomes of Congenital Hypothyroidism
Longitudinal growth, final height and pubertal development are typically
normal in male and female individuals with CH in whom L-T4 therapy is
maintained as recommended [15, 16]. Pubertal timing and f inal height are
independent of etiology, severity of CH and the start of L-T4 treatment, but
girls with a higher initial dose L-T4 (⬎8␮g/kg/d) had an earlier onset of
puberty [15].
In contrast to physical signs, the neurodevelopmental outcome of patients
with CH largely depends on the early initiation and maintenance of adequate
postnatal L-T4 therapy, especially in cases of severe hypothyroidism (T4
⬍5␮g/dl). Despite neonatal screening, 10% of early treated infants with severe
hypothyroidism are likely to require special education [17]. Subtle differences
in intelligence, school performance and neuropsychological tests in comparison
to control individuals, classmates and siblings have been detected in adults with
CH despite early L-T4 treatment [18, 19]. While in some studies the severity of
CH was correlated with poor developmental outcome, recent observations indi-
cate that delayed and inadequate hormone substitution is a main predictor of
clinical outcome [18, 20].
Children with CH may have selective def icits on visual, language, motor,
attention and memory abilities [21]. Auditory brainstem evoked potentials were
abnormal in 25% of early-treated patients with CH [22]. Recent studies have
comprehensively analyzed the temporal patterns of thyroid hormone action in
the developing brain [21]. Hypothyroidism in early pregnancy is related to
impaired visual attention and processing as well as gross motor abilities.

Karges/Kiess 124
Exposure to maternal hypothyroxinemia in later pregnancy is linked to an
additional risk of subnormal visual skills, including impaired contrast sensitivity,
slower response speeds and fine motor deficits [23]. In case that hypothyroidism
occurs after birth, language and memory are brain functions predominantly
affected.
It has to be considered that syndromatic forms of CH due to functional
defects of thyroidal transcription factors or the iodothyronine transporter (table 1)
may adversely affect CNS development independent of circulating thyroid
hormone levels. The long-term perspective for normal mental and neurologic
development is poor for infants with CH not detected by newborn screening.
Physical symptoms and growth may normalise when L-T4 treatment is started
later but within the f irst months of life but infants with severe perinatal
hypothyroidism frequently have low-to-normal IQ [1].
Less favorable neurodevelopmental outcome is related to late treatment
start, inadequate L-T4 dosage, poor social-economic environment, compliance
problems and severity of CH. A better neurodevelopmental outcome was
obtained with higher initial L-T4 dose of 11.6 ␮g/kg/day [24, 25] and faster
time to normalize thyroid function (⬍2 weeks) [26]. Since thyroid hormone
replacement is now more vigorous in achieving early correction than in previ-
ous decades, neonates with CH today may have eventually better intellectual
and neurological long-term outcomes.
Diagnostic Work-Up of Congenital Hypothyroidism
A positive newborn screening result calls for immediate diagnostic work-
up. Information on maternal medication or morbidity should be obtained to
assess the infant’s prenatal thyroid status. Clinical examination should be per-
formed to document signs and symptoms of CH and possible associated mal-
formations. There is an increased risk for other congenital anomalies (8.4%),
including cardiovascular, musculoskeletal and CNS malformations [3].
Confirmatory serum measurements of TSH and T4 are required, along
with thyroid hormone binding proteins and serum free T4. In cases of maternal
autoimmune thyroid disorder, assessment of TSHR blocking antibodies
may indicate a transient form of CH. Thyroglobulin levels tend to be high
in dyshormonogenesis and low in thyroid agenesis. Thyroid ultrasono-
graphy and/or thyroid scan are considered optional for management of CH [1]
but are necessary to clarify the underlying source of CH, to distinguish
between thyroid aplasia, ectopy or inborn errors of T4 synthesis. Testing thy-
roid function in first degree relatives may be informative because of the vari-
able penetrance of inherited CH. Measurement of iodine or iodotyrosines in

Congenital Hypothyroidism 125
urine are helpful if iodine exposure, iodine deficiency or recycling defects are
considered.
It is clinically important to distinguish permanent or transient forms of
CH. If imaging studies reveal ectopic or absent thyroid tissue, hypothyroidism
is probably permanent. If initial TSH is below 50 mU/l and there is no increase
after the neonatal period, at 3 years of age discontinuation of L-T4 may be
considered [1]. If TSH increases after 1 month discontinuation, permanent
hypothyroidism is probable, and L-T4 treatment must be resumed. Regular
follow-up visits are essential to ensure optimal growth and development includ-
ing auditory and visual abilities and neuropsychological skills.
In recent years genetic studies have revealed a variety of molecular defects
underlying CH. In the clinical management of patients with CH, however,
genetic testing is currently not yet recommended on a routine basis.
Treatment Recommendations
As the result of newborn TSH screening is available within 10–14 days,
treatment of CH is commonly initiated within the first 2 weeks of life. An initial
dosage of 10–15 ␮g/kg/d L-T4 per os is recommended [1]. T4 and TSH should
be normalized within 2 and 4 weeks of L-T4 therapy, respectively. Serum total
T4 or free T4 should be maintained in the upper half of the reference range
(10–16 ␮g/dl [130–204 nmol/l] or 1.2–2.3 ng/dl [18–30 pmol/l]) during the f irst
3 years of life with a low normal serum TSH concentration [1].
To ensure optimal dosage and compliance, frequent evaluations of thyroid
hormone serum levels are necessary. These tests should be obtained 2 and 4
weeks after L-T4 start, every 1–2 months during the first year of life, every 3–4
months between 1–3 years of age and 2–4 weeks after any change in dosage [1].
During L-T4 therapy, 4 or more episodes of elevated TSH (⬎5 mU/l) after the
age of 6 months were associated with inferior school performance [27]. These
episodes may be caused by poor parental empowerment or impaired T4
bioavailability. The latter may be caused by inhibited intestinal uptake of T4
through soy or fiber and medications with iron or calcium, malabsorption or
increased degradation by anticonvulsants.
Because poor compliance has major consequences, initial and ongoing
counseling of parents is of utmost importance. Education of parents by trained
professionals should address the etiology of hypothyroidism, the benefit of
early diagnosis in preventing mental retardation, the appropriate L-T4 applica-
tion, and the importance to follow treatment regimens and regular visits. Thus,
the pediatrician plays a central role to provide a medical home for every child
with CH to coordinate care and lifelong disease management.

Karges/Kiess 126
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PD Beate Karges, MD
Division of Pediatric Endocrinology and Diabetes
University Hospital for Children and Adolescents, University of Ulm
Eythstrasse 24
DE–89075 Ulm (Germany)
Tel. ⫹49 731 500 27738, Fax ⫹49 731 500 26714, E-Mail beate.karges@uniklinik-ulm.de

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 128–141
Newborn Screening, Hypothyroidism in
Infants, Children and Adolescents
Atilla Büyükgebiz
Department of Pediatric Endocrinology and Adolescence, Acibadem Health Group,
Acibadem Hospital, Istanbul, Turkey
Newborn Screening
Newborn screening (NS) for congenital hypothyroidism (CH) is one of the
major achievements of preventive medicine [1, 2]. Although since 1972 the
problem of CH has been resolved in developed countries by the implementation
of NS for CH, the problem exists for developing countries that still have no NS
programs for CH [2, 3]. Since diagnosis based on clinical f indings is delayed in
most instances because of few symptoms and signs, hypothyroidism in the new-
born period is almost always overlooked and delayed diagnosis leads to the most
severe outcome of CH, mental retardation. In a study from Denmark, it was
emphasized that only 10% of the affected infants were diagnosed within the first
month of life, 35% within 3 months. 70% were diagnosed within the f irst year,
while in the remainder the diagnosis was delayed to the 3rd and 4th years of life
[4]. In a retrospective analysis of 1,000 cases of CH from Turkey, the mean age
at diagnosis was 49 months and only 3.1% of cases were diagnosed within the
first month, whereas 55.4% were diagnosed after 2 years of age [5].
The first CH screening was performed by Dussault and Laberge [6, 7], in
Quebec, Canada in 1972. They detected 7 hypothyroid infants among 47,000
newborns during 3 years. The high frequency of false-positives delayed the
diagnosis and increased the cost and they arranged the cutoffs used for recall.
The babies recalled underwent thyroid hormones and TSH blood studies. In the
meantime, radioactively labeled antibodies for determining T4 in dried blood
spots began regionally in the USA and Europe. They went parallel with screen-
ing programs of PKU. In the initial report by Dussault et al. [8], the method was
recommended as a confirmatory test knowing that it would miss cases with
hypothlamic-pituitary hypothyroidism which they reported to be 10% of the

Newborn Screening, Hypothyroidism in Infants, Children and Adolescents 129
cases. In 1976, it was reported in the Lancet that cord blood TSH measurements
were shown to have greater sensitivity and specificity to cord blood T4 and
blood spot T4 (collected on 3- to 4-day-old newborns) and false-positives were
high in T4 method with high costs [9]. Walf ish [9], suggested routine T4
screening supplemented by TSH estimation be used in mass screening.
Blood spot T4 or TSH or both could be used in NS for CH. The latter,
which is more sensitive, is not cost effective so the f irst two are used in differ-
ent programs around the world. North America usually prefers primary T4 test-
ing supplemented with TSH and Europe prefers primary TSH in the detection
of CH [10–14]. TSH screening was shown to be more specific in the diagnosis
of CH, T4 screening was more sensitive in detecting newborns especially with
rare hypothalamic-pituitary hypothyroidism but less specific with a high fre-
quency of false-positives mainly in low-birth-weight and premature babies.
Thyroxine-binding globulin (TBG)-deficient babies who are euthyroid could be
detected by T4 screening who are not targets for NS.
1982, a Neonatal Thyroid Screening Conference held in Tokyo recom-
mended NS programs oriented to detect infants with elevated serum concentra-
tions of TSH [15]. They suggested that this could be accomplished by measuring
TSH in f ilter paper blood spot or by measuring T4 supplemented by TSH on the
same blood spot of infants who have T4 values in the lower 3rd to 10th percentile.
Methods
The aim is to detect all cases with the disease, as early as possible, with an
acceptable cost-benef it ratio and to avoid false-positive results. Today more
sensitive and automated methods (chemiluminescence, fluoroimmunoassay,
etc.) for determining both T4 and TSH in dried blood spots have been intro-
duced [16–21]. They have increased sensitivity and specificity. Besides the
development of more accurate test programs, some children may still be missed
in any screening program. The reasons could be failure of sample collection,
unsatisfactory samples, misinterpretation of samples and unsatisfactory recalls.
The ideal time to obtain the blood spot is 3–5 days after birth to minimize
the false-positive high TSH due to the physiological neonatal TSH surge that
elevates TSH levels and causes dynamic T4 and T3 changes in the f irst 1 or 2
days after birth. Early discharge of mothers postpartum has increased the ratio
of false-positive TSH elevations. The difficulty in screening for CH using cord
blood samples is in the handling and transport of the samples, making it an
impractical method for mass screening [22].
Whichever method is used, babies whose initial TSH is 50 U/l are most
likely to have permanent CH, whereas a TSH between 20 and 49 U/l is fre-
quently a false-positive or represents transient hypothyroidism. Transient CH is
particularly common in premature infants in borderline iodine deficient areas.

Büyükgebiz 130
In the primary TSH method, when 15 U/l (immunofluorometric method) or
20 U/l (radioimmunological method) is used as cutoff, the recall rate is quite
low to be 0.05%. Iodine def iciency could increase false-positives and increase
recall rate. The sensitivity of TSH method for CH is suggested to be 97.5% and
specificity 99% [23, 24].
Neonatal screening with the primary TSH method detects:
(a) overt and compensated primary hypothyroidism.
Neonatal screening with the primary TSH method misses:
(a) secondary-tertiary hypothyroidism;
(b) TBG deficiency;
(c) premature babies with very LBW with a delayed TSH surge.
In primary T4 screening, performed in some states of the USA, cutoff to
the 10th percentile resulted in 1.5% missed cases, whereas cutoff to the 5th per-
centile T4 values resulted in 3.5% cases. Only 0.2% of cases were missing
using the 20th percentile as a cutoff, but off course with increased cost in terms
of repeat testing [25]. Optimal screening requires initial T4 determination to be
followed by TSH determinations on low T4 samples.
Neonatal screening with the primary T4 method detects:
(a) overt primary hypothyroidism;
(b) secondary-tertiary hypothyroidism (1 in 50,000–100,000 live births);
(c) hypothyroxinemia in a sick and preterm newborn;
(d) TBG deficiency;
(e) hyperthyroxinemia.
Neonatal screening with the primary T4 method misses:
(a) compensatory hypothyroidism with subnormal T4 and elevated TSH levels;
(b) transient hyperthyrotropinemia where iodine deficiency is present.
Reliability of the laboratories is as crucial as the reliability of detection
methods (with emphasis on sensitivity, specificity and positive predictive
value). According to the recommendations of the working group of NS of ESPE
(European Society for Pediatric Endocrinology), screening should be con-
ducted in centralized laboratories covering 100,000 newborns per year [26].
These laboratories should participate in international control programs. In
North America it is estimated that 6–12% of the neonates with CH are missed
due to biological factors and screening errors [27, 28].
Neonatal Screening Results
Hypothyroxinemia (Low T4 and Normal TSH)
It occurs most commonly in premature infants, in whom it is found in 50%
of babies of less than 30 weeks’gestation [26]. Screening programs that employ

Newborn Screening, Hypothyroidism in Infants, Children and Adolescents 131
primary TSH analysis will miss these infants because of normal TSH levels.
Often the free T4 is less affected than the total T4. The reasons for the hypothy-
roxinemia of prematurity are complex. In addition to hypothalamo-pituitary
immaturity, low TBG levels and decreased conversion of T4 to T3 exists in pre-
matures. Numerous studies have shown that there is a correlation between the
degree of lowering of T4 and negative outcomes; both mortality and develop-
mental problems. Systematic supplementation of all low-birth-weight babies is
not recommended at this time [23, 29, 30].
Other causes of low T4 in the face of normal TSH are euthyroid sick syn-
drome, TBG deficiency, laboratory errors and central hypothyroidism [3].
Immature liver function, undernutrition and illness are the reasons for low T4
and normal TSH levels in euthyroid sick syndrome. Euthyroid sick syndrome
may be seen in the sick term newborns as well [23]. TBG deficiency is an
X-linked condition discovered only by screening programs using the primary
T4 approach. It does not require treatment since the plasma levels of free
thyroid hormone levels are normal and subjects are euthyroid. Its incidence is
estimated to be 1 in 2,800 [31]. TBG deficiency should be estimated especially
in male infants with low T4 and normal TSH and could be confirmed by
measuring TBG levels in the serum. Loss of protein from nephrotic syndrome
may also lead to low total T4. Errors in measurement may be caused by errors
in sample gathering, impregnation with water due to improper sample handling
or less amounts of blood spots or extremes hematocrit values which adversely
affect the measurements.
In a term neonate with a low free T4 but normal TSH level, true central
hypothyroidism, which is quite rare, should be ruled out. Mutations in the gene
coding for the beta subunit of TSH or the TRH receptor could be the causes
[32, 33]. Central hypothyroidism could coincide with other anterior pituitary
hormone deficiencies: hypoglycemia, microphallus, prolonged jaundice and/or
cryptorchidism [34–36].
Isolated Hyperthyrotropinemia (Normal T4 and Elevated TSH)
Elevated TSH, despite a normal or low normal T4 indicates inadequate
hormone production. It is most common in premature babies. Although
some babies have compensated hypothyroidism, the etiology is not clear in
the others. In early discharged babies (in the first day or two), because of
the cold-induced TSH surge, TSH values are found to be elevated. It could be
a transient finding due to goitrogens, iodine def iciency or medications.
Genetic defects of hormone biosynthesis and also dysgenesis especially
ectopia could be the causes. TSH rises with normal T4 levels could persist for
years [37].

Büyükgebiz 132
Low T4 and Elevated TSH
The most common cause is primary CH. There might be transient cases as
shown in table 1.
Although transient hypothyroidism may occur frequently, all the suspected
infants should be treated as CH for the first 3 years of life by taking into
account the risks of mental retardation. A re-evaluation after 3 years is needed
in such patients [1, 38–40].
Hypothyroidism in Infancy, Childhood and Adolescence
Hypothyroidism during childhood and adolescence can result from a vari-
ety of congenital or acquired defects (table 2).
Table 1. Causes of transient hypo-
thyroidism Maternal antithyroid medication
Exposure of topical iodine
Maternal iodine deficiency or excess
Maternal TSH receptor blocking antibodies
Medications (dopamine, steroid)
Prematurity (30 weeks)
Table 2. Causes of childhood hypothyroidism
(a) Congenital hypothyroidism
(b) Acquired hypothyroidism
– Autoimmunity (Hashimoto thyroiditis)
– Drug-induced hypothyroidism
Antithyroid
Anti-TBC
Iodine compounds
Lithium, cobalt, sulfonamides
– Thyroidectomy
– Endemic goiter
Iodine deficiency
Environmental goitrogens
– Irradiation of thyroid
Therapeutic radioiodine
External irradiation of nonthyroid tumors
– Infiltrative disorders
Amyloidosis
Histiocytosis
Cystinosis

Newborn Screening, Hypothyroidism in Infants, Children and Adolescents 133
Some children present with an asymptomatic goiter, whereas others may
present with mild tenderness or a sensation of fullness in the anterior neck [41].
The course of hypothyroidism is often so insidious that neither the child nor the
parents are aware of the physical changes that have occurred. These children
often have marked growth retardation before the disease is recognized, and the
expected effect on linear growth emphasizes the importance of serial growth
measurements in all children. Children who develop hypothyroidism before age
2 years may suffer some irreversible central nervous system damage and
developmental delay, the onset of hypothyroidism developed after infancy does
not cause mental retardation [42] (table 3).
Deceleration of linear growth is an important sign that is helpful in the early
recognition of this disease. Affected children are relatively overweight for their
height, although they are rarely obese. If hypothyroidism is severe and long-
standing, immature facies and immature body proportion (increased upper/lower
body ratio) may be noted with delay in dental and skeletal maturation. The chil-
dren have cold intolerance, dry skin and dry hair texture. In patients with severe
long-standing hypothyroidism, muscular pseudohypertrophy gives a Herculean
appearance called Kocher-Debre-Semelaign syndrome [23].
The child with severe primary hypothyroidism may develop enlargement
of the cella tursica. After radiologic examination, the detected mass represents
hypertrophy and hyperplasia of thyrotrophs in response to lack of negative feed-
back by thyroid hormones [43]. In laboratory evaluation they have high levels
of TSH with low levels of T4.
Puberty tends to be delayed in hypothyroid children, although sexual pre-
cocity has been described too [44]. The cause of precocious puberty in primary
Table 3. Symptoms of childhood hypothyroidism
Growth and developmental delay
Short stature
Infantilism in anthropometric ratios
Bone age delay
Motor developmental delay
Skin and hair
Pale, coarse, dry and cold skin
Hypertricosis in forehead and neck
Rare, dry, thick hair
Myopathy and muscular pseudohypertrophy
Delayed puberty
Rarely precocious puberty
Sluggish motor performance, sleepiness, cold intolerance

Büyükgebiz 134
hypothyroidism is presumed to be from chronic TRH stimulation of the pitu-
itary which could cause galactorrhea in girls with elevated prolactin levels [45,
46]. More recent studies have shown that TSH can bind and activate both LH
and FSH receptors and elevated TSH levels in stimulation of both LH and FSH
receptors could contribute to the development of precocious puberty [47, 48].
Diagnostic Evaluation
Measurement of TSH and thyroid hormones, antithyroid antibodies
namely thyroperoxidase (TPOAb) and thyroglobulin (TGAb) should be
obtained. The presence of the antibodies permits the diagnosis of autoimmune
thyroiditis. A hypothalamic cause vs. pituitary origin of the hypothyroidism
with low serum free T4 and TSH levels can be distinguished by TRH testing. In
children with hypothalamic hypothyroidism the peak serum TSH response to
TRH is often delayed beyond 30 min, and the TSH response may be prolonged
with serum TSH values that remain elevated for 2–3 h. In hypopituitarism, there
is little or no TSH response to TRH. Thyroid hormone resistance is character-
ized by elevated levels of T4 and T3 and an inappropriately normal or elevated
TSH concentration.
Treatment
The aim of treatment of hypothyroidism in childhood is to attain normal
growth, neurological and pubertal development. The drug of choice is Na L-
thyroxine (T4). It should be given once daily, half an hour before breakfast.
Iron, calcium and colestiramin interfere with the drug absorption.
If hypothyroidism exists for long periods, Na L-T4 treatment should be
given with gradual increments, beginning with small doses to prevent hyperac-
tivity, unsleepiness and school performance deterioration (table 4).
The mean dosage of Na L-T4 could be calculated as 100 g/m2. The dosage
should be arranged by the regular follow-ups with T4 and TSH measurements.
Hashimoto Thyroiditis
Chronic lymphocytic thyroiditis (Hashimoto) is an autoimmune disease
closely related to Graves disease [49]. It was first described by Hashimoto [50]
Table 4. Na L-T4 dosages with respect
to age in hypothyroidism 1–3 years 4–6 g/kg
3–10 years 3–5 g/kg
10–16 years 2–4 g/kg

Newborn Screening, Hypothyroidism in Infants, Children and Adolescents 135
in 1912. Although lymphocyte and cytokine-mediated thyroid destruction pre-
dominates in Hashimoto thyroiditis (HT), antibody-mediated thyroid stimula-
tion occurs in Graves disease and overlap may occur in some patients. HT arises
from a combination of genetic traits that heighten susceptibility in conjunction
with some environmental trigger.
HT occurs in 1% of children and adolescents and is the most common
cause of acquired hypothyroidism in the pediatric population [51]. The disease
has a predilection for females 4 to 7 times and a family history is present in
30–40% of patients. The prevalence increases with age with the common age of
adolescence [52]. HT accounts for many of the enlarged thyroids formerly des-
ignated as adolescent or simple goiter [53]. Goiter is present in two thirds of
children, resulting from lymphocytic infiltration and from the stimulatory
effect of TSH. The remaining one third of children have no goiter [54]. The
patients could be euthyroid, hypothyroid or hyperthyroid. Opthalmopathy may
occur in HT in the absence of Graves disease [55]. The course is variable. The
goiter may become smaller or may disappear spontaneously or it may persist
unchanged for years while the patients remain euthyroid. Some euthyroid chil-
dren acquire hypothyroidism gradually within months or years, and some ado-
lescent patients achieve spontaneous remission. Thyroid function tests are often
normal in HT, although the level of TSH may be slightly or moderately elevated
in some individuals. Thyroid scintigraphy can be entirely normal, but in most
instances the radioiodine uptake is decreased. Early in the course of the disease,
increase uptake could be noted. Thyroid ultrasonography shows scattered
hypoechogenicity in most patients [56].
Genetic susceptibility is present in HT. Associations have been observed
between HT and HLA-DR3, DR4 or DR5 [57, 58]. Familial clusters of HT are
common. The incidence in siblings or parents of affected children may be as
high as 25% [57]. TPOAbs are demonstrable in the sera of 90% of children with
HT. TGAbs occur in a smaller percentage of affected children but much more
common in adults. Thyrotropin receptor-blocking antibodies are frequently pre-
sent especially in hypothyroid HT patients and believed to be the cause of
hypothyroidism [51].
HT, a typical organ-specific autoimmune disease, is characterized histolog-
ically by lymphocytic infiltration of the thyroid. There is infiltration of lympho-
cytes and plasma cells between follicles and atrophy and fibrosis of the follicles
are present. HT is seen more frequently with type 1 DM, celiac disease, Addison,
autoimmune atrophic gastritis, chronic candidiasis and hypoparathyroidism, and
juvenile chronic arthritis [59–61]. HT is also associated with certain chromoso-
mal aberrations, in particular Turner, Down and Klinefelter syndromes [51, 53].
Progressive dementia and Hashimoto-related encephalopathy has been reported
in some HT patients [62, 63].

Büyükgebiz 136
Because the disease may be self-limited in some instances, there should be
periodic checks in treatment. Untreated patients should also be checked period-
ically. A TSH level greater than 10 U/ml warrants treatment with Na L-T4.
The initial dose should be arranged according to the age of the patient
(25 g/day to 100–150 g/day). The goiter may decrease in size as may persist
for years. Antibody titers fluctuate in both treated and untreated patients and
persist for years.
Iodine Deficiency
Iodine is essential for thyroid hormone synthesis and is present in soil,
water and air. Iodine deficiency disorders (IDD), which was referred to as
endemic goiter up to thirty years ago refers to iodine def iciency that can be pre-
vented by ensuring an adequate intake of iodine in population [64].
Goiter is the most frequent and visible manifestation of IDD and is an
important health problem. It effects intellectual growth in neonates and children
and almost 20 million people living in developing countries have some degree
of brain damage due to the effects of iodine def iciency (ID). ID in the mother
results in deficiency of the neonate. The most striking feature of ID is endemic
cretinism. In severe iodine deficiency, endemic goiter and cretinism; increased
perinatal death, decreased fertility rate and increased infant mortality occur.
Combined iodine and selenium deficiency causes a severe form of cretinism in
some areas. Two types of endemic cretinism have been defined [65–67]. In neu-
rological cretinism, the number of neuronal cells are decreased, brain weight is
reduced. Myxedematous cretinism has a less severe degree of mental retarda-
tion than neurological cretinism. Iodine def iciency in children is characteristi-
cally associated with goiter. Goiter rate increases with age and reaches a
maximum at adolescence [68–70].
Iodine is present in the human body in minute amounts (10–20 g). The
recommended dietary allowance is 60–100 g/daily for 1–10 years of age and
100 g/daily for adolescents and adults. Urinary iodine (UI) excretion provides
a measure of the nutritional status of iodine in a population. Dietary iodine
intake is positively correlated with its urinary excretion in iodine-repleted
areas. 24-hour iodine excreted in the urine shows the iodine nutritional status,
but it is impractical and can be unreliable. If nutrition is adequate UI/creatinine
is considered a more reliable measure of iodine excretion than random spot UI
concentration measurement since there are variations in iodine intake [71, 72].
There are several methods used to detect iodine in urine with different sensitiv-
ities; spectrophotometric method, HPLC, mass spectrometry and laser spec-
trometry [73–75]. UI excretion 50–99g/l is defined as mild iodine deficiency,

Newborn Screening, Hypothyroidism in Infants, Children and Adolescents 137
20–49 g/l is defined as moderate iodine deficiency and UI excretion 20 g/l
is severe iodine deficiency (table 5) [76, 77].
Prevention of Iodine Deficiency
(a) Iodized Salt. The daily recommended level of salt is 3–5 g. The level of
iodization of salt has to be sufficient to cover the requirement together with losses
from the point of production to the point of consumption. The packing of salt is
important, it loses some of its activity with boiling. Iodized salt was used for the
first time in 1920s in Switzerland and USA and in 1950s in Europe. But despite
the elimination programs ID still exists in different parts of the world [78–81].
Problems with the iodization of salt are [80]:
– Not reaching all target communities
– Plethora of small scale salt producers makes salt iodization programmes
difficult to implement in some countries
– Some salt producers are unwilling to pay for potassium iodate, which is
recommended agent for iodization or use less amounts
– Frequently unacceptable variation in the quality of iodized salt
– Some iodization programmes are not being adequately monitored
– Lack of laboratory facilities in many countries for monitoring salt and uri-
nary iodine levels
– Transient increase in the incidence of hyperthyroidism in some countries
after salt iodization
(b) Iodized Oil. Iodized oil (lipiodol) was first used in Papua New Guinea.
The effectiveness of the single dose iodized oil injection (4 ml) corrects iodine
deficiency for a period of 4.5 years [82]. Refrigeration is not required and the
cost is low with respect to iodized salt. It could be taken orally too [78]. Iodized
oil should be used in severe IDD areas until an effected program is introduced.
Table 5. Prevalence of IDD in school-aged children (WHO)
Region UI 100 g, % UI 100 g, millions
Africa 47.6 48,342
The Americas 14.1 9,995
East Mediterranean 55.4 40,224
Europe 59.9 42,206
SE Asia 39.9 95,628
West Pacif ic 19.7 36,082
Total 36.9 272,438

Büyükgebiz 138
(c) Iodized Bread, Iodized Milk, Iodized Water, Iodine Tablets. Used in
different countries as iodine sources [83, 84].
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Prof. Dr. Atilla Büyükgebiz
Department of Pediatic Endocrinology and Adolescence
Acibadem Health Group, Acibadem Hospital
Tekin Street No. 8
TR–34718 Kadikoy-Istanbul (Turkey)
Tel. 90 216 54 44 059, Fax 90 327 71 17, E-Mail atilla.buyukgebiz@asg.com.tr

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 142–153
Resistance to Thyroid Hormone in
Childhood
O. Bakker
Division of Endocrinology and Metabolism, Academic Medical Center,
Amsterdam, The Netherlands
Occasionally, a patient is seen in the clinic with apparent hypo- and/or
hyperthyroid symptoms but with conflicting results of thyroid function tests:
they have a nonsuppressed or even slightly increased TSH inappropriate for the
invariably increased free T4 in serum. This combination of hormone levels can
have several causes but there are two major ones namely a TSH-producing pitu-
itary adenoma and resistance to thyroid hormone (RTH). The latter will be the
subject of this chapter. The basic problem in RTH is a decreased sensitivity of
tissues to thyroid hormone. The decreased sensitivity is also present in the pitu-
itary, where it leads to a blunting of the feedback of thyroid hormone on the
pituitary. This in turn results in the above mentioned increased secretion of TSH
and thereby of T4. As will be explained below, the insensitivity is caused by
mutations in the thyroid hormone receptor beta isoform that reduce thyroid hor-
mone binding affinity. This does not just lead to a presentation resembling
hypothyroidism as would be expected – many patients present with symptoms
reminiscent of hyperthyroidism, especially with tachycardia.
Normally the net effects of thyroid hormone are brought about by the positive
or negative changes it causes in the expression of T3-responsive genes in target tis-
sues. For instance the rise in LDL-cholesterol found in hypothyroid patients can be
attributed to a decrease in LDL-receptor protein expression. The gene for this pro-
tein is sensitive to thyroid hormone. The presence of thyroid hormone is signaled
by nuclear thyroid hormone receptors (TR) of which at least five isoforms exist
(fig. 1). These are members of the so-called nuclear receptor family of which the
steroid, vitamin D and retinoic acid receptors are also a member. These receptors
influence gene expression by binding to specific DNA elements as dimers. TR can
bind as a homodimer (two identical monomers) or as a heterodimer (two different

Resistance to Thyroid Hormone in Childhood 143
monomers) to these specific DNA elements which are called thyroid-response ele-
ments (TRE), located in the promoter region of T3-responsive genes. There are at
least four active (T3 inducible) TR namely TR1, TR1, TR2 and TR3 which
bind T3 and one inactive one, TR2 which does not bind T3. They are derived from
two different genes located on chromosomes 17 and 3, respectively. The TR genes
are expressed at different levels in different tissues (fig. 1). Furthermore, a number
of different TRE can bind the receptors, sometimes in specific combinations, so a
plethora of regulatory possibilities is present. This explains how TR (after binding
T3) can both activate or repress a gene. The latter happens for instance in the case
of the feedback to the pituitary where the ligand-bound TR binds to a special TRE
of the TSHand -subunit genes and thereby shuts the gene down.
Thyroid hormone receptors are rather unique among their family in that
they can influence gene expression with or without ligand. This is because the
TR can bind to a TRE without hormone. When it does, it recruits a so-called co-
repressor protein which silences the gene. Upon binding of the hormone the
receptor homodimer releases the co-repressor and then falls apart. The ligand-
bound TR monomer then heterodimerizes with the retinoic X receptor (RXR)
and binds again to the same TRE but due to a conformational change is now
able to recruit a coactivator and so can increase gene transcription (fig. 2).
After the three dimensional structure of the thyroid hormone receptor had
been solved [1] it became apparent that thyroid hormone is tightly packed
inside the receptor molecule and that the last few amino acids of the receptor
protein (helix 12) act like a lid which closes the box into which the hormone
fits. From these studies, it has also become clear that the closure of the lid is
necessary for the formation of the binding site of the coactivator.
Fig. 1. Schematic representation of the five thyroid hormone receptor (TR) isoforms.
The receptor isoforms are shown schematically with the tissues where their expression is
most prominent. The black box represents the DNA-binding domain. TR1, TR2 and TR3
differ in their N-terminal domain whereas TR1 and TR2 differ in their C-terminal domain.
In both cases, an mRNA is transcribed from one gene which due to alternative splicing or
alternative promoter usage yields the or isoforms.
TR3
Schematic representation Tissue expression
Liver, kidney, lung
Pituitary
Liver, kidney
Skeletal muscle, brown fat, heart
Brain, hypothalamus
TR2
TR2
TR1
TR1

Bakker 144
Clinical
The first patients described with RTH had a very specific phenotype con-
sisting of short stature, delayed bone maturation, deaf-mutism and very obvious
winged scapulae [2]. Further research has shown, however, that a wide variety
of symptoms exists in this patient group (table 1) [3]. Up until now about 700
cases have been described [4] and the prevalence of the syndrome is estimated
at about 1 in 40,000 [5].
The clinical presentation is heterogeneous. Some patients have no or minor
symptoms, others have more marked symptoms which can be of a hypo- or hyper-
thyroid nature. It is even possible that the two co-exist within 1 patient.
Depending on the clinical presentation RTH has in the past been divided into two
classes. Patients who are able to maintain peripheral euthyroidism by increasing
the T4 production thus compensating for the decreased tissue sensitivity or who
present with hypothyroid symptoms, were classified as generalized resistance
(GRTH). Those patients who presented with hyperthyroid symptoms were classi-
fied as having pituitary resistance (PRTH). Unfortunately, the distinction is not as
definite as it may appear and has no firm pathophysiological basis. Hyperthyroid
symptoms have also been found in patients defined as having GRTH; furthermore
Fig. 2. Model for gene activation by the TR. When the TR is unliganded it binds to the
TRE of the gene as a homodimer (two identical TR monomers) and it represses gene expres-
sion by binding to a corepressor. When hormone binds to TR, the corepressor is released and
the homodimer falls apart. The TR receptor monomer then acquires another heterodimeriza-
tion partner RXR (the retinoic X receptor) and then binds again to the TRE as a heterodimer
(two different monomers) and attracts a coactivator which will signal to the transcription
machinery. As a result the gene is actively transcribed.
Unliganded – repressed
TRE
TR TR
Liganded – active
Coactivator
Corepressor
Corepressor
T3 TR
RXR
RXR
T3

Resistance to Thyroid Hormone in Childhood 145
no significant differences between GRTH and PRTH exist when parameters like
age, sex, goiter frequency, and FT3, FT4 and TSH levels are compared.
About two-thirds of the cases patients present with a goiter (table 1). When
the goiter is combined with resting tachycardia, palpitations and high T4 serum
concentrations, the wrong diagnosis of Graves’ hyperthyroidism has often been
made in adults [6]. This is now less of a risk since the advent of sensitive TSH
assays. One thing to keep in mind is that it has been shown that the bioactivity of
serum TSH in RTH patients is higher than normal even though the immunoreac-
tive TSH is normal, stimulating thyroid growth and T4 and T3 secretion [7].
In children, attention-deficit hyperactivity disorder (ADHD) has been
found more often (75%) in RTH patients than in their unaffected relatives
(15%). Furthermore, in RTH children problems occur in the areas of reading
skills and articulation [8]. One third of RTH patients have an IQ 85 which
could manifest as a learning disability, and it has been shown in one family that
RTH cosegregates with a lower IQ. The relation to ADHD should not be overin-
terpreted since two studies have shown that in two different cohorts of children
with ADHD no biochemical evidence was found for any RTH patient among them
[9, 10]. Other features that have been reported include reduced intrauterine
Table 1. Features of RTH
Biochemical Normal RTH Non-RTH
Raised free T4, pmol/l 12.8–24.4 412.1 17.90.5
Raised free T3, pmol/l 3.8–8.4 11.41.5 6.50.4
Normal or slightly elevated TSH, mU/l 0.5–4.5 3.150.3 2.50.2
Clinical Frequency
Goitre 65–95%
Tachycardia 50–80%
Emotional disturbances 73%
Recurrent ear, nose and throat infections 47%
ADHD 45%
Hyperactivity/learning disorder 19–42%
Low IQ (85) 35–50%
Delayed bone age 29–47
Hearing loss 21%
Short stature 18–26%
Normal indicates the normal range observed in the general population. RTH Values as
found in RTH patients; non-RTH values as found in nonaffected relatives of RTH patients.
Adapted from Brucker-Davis et al. [8] and Weiss and Refetoff [47].

Bakker 146
growth, low body mass index (30% of cases), childhood short stature and
delayed bone age [8]. Final adult height is often not affected. No effects of RTH
have been found on pubertal development, fertility and life expectancy.
Furthermore, recurrent pulmonary and upper respiratory tract infections have
been reported, as well as hearing defects which may be the result of recurrent
ear infections during childhood [8]. Atrial fibrillation is often found in older
patients.
Diagnosis
An increased level of free T3 and T4 in combination with nonsuppressed
TSH in serum is indicative of RTH, but is also observed in TSH-secreting pitu-
itary adenomas. There are, however, a number of other conditions which can
give rise to spuriously elevated T3 and T4 levels with normal TSH. It is there-
fore important to first rule out any of these other possibilities before embarking
on the path to RTH. Of course a careful check of the history will exclude causes
like drugs (amiodarone, iodine-containing X-ray contrast agents) and nonthy-
roidal illness which often are associated with a high serum FT4 but low FT3.
Familial dysalbuminic hyperthyroxinemia gives rise to markedly elevated total
T4 but normal FT4 levels in serum. Endogenous anti-T3 and anti-T4 antibodies
or heterophilic anti-TSH antibodies in the serum cause spurious results; a sim-
ple test to rule out the presence of such antibodies is diluting the serum and
checking that the level of the analyte measured decreases linearly with the dilu-
tion steps.
Having ascertained the validity of the obtained hormone test results, a dis-
tinction must be made between a TSH-secreting pituitary adenoma and RTH.
This can be difficult when imaging of the pituitary does not show a tumor. In
both cases TSH is refractory to thyroid hormone feedback. A TRH test can be
helpful. In the case of RTH there will be a response of TSH to the TRH which
will be less so when an autonomous pituitary tumor is present. Furthermore, the
subunit to TSH ratio is normal in RTH whereas it will be elevated in TSH-
secreting tumors [11, 12]. When the differential diagnosis clearly points to
RTH, the patients genomic DNA can be sequenced, in particular exons 7–10, to
confirm the diagnosis.
In cases where the diagnosis is not clear or when no mutation is found in
the receptor gene, tests aimed at measuring the effect of T3 in peripheral tissues
can be used. These tests were developed by Refetoff et al. [13], although not
many publications exist using the protocol in children. The scheme [13, for
details] consists of administering increasing doses of T3 in an in-patient setting
(0.5dose, 1dose, 2dose, each given for 3-day periods). The daily doses

Resistance to Thyroid Hormone in Childhood 147
of L-T3 in children are: 25 g for ages 1–3 years (body weight 8–15 kg); 50g
for ages 4–9 years (body weight 16–25 kg), and 75 g for ages 10–14 years
(body weight 26–45kg). The initial dose is halved and the last dose is doubled.
At the end of each 3-day period various T3-dependent peripheral tissue function
tests are done [13, for details]. Using this protocol significant changes in these
parameters can be found, especially when comparing RTH patients with nonaf-
fected subjects (when possible family members) and a diagnosis of RTH can be
made.
Management
Most patients have corrected themselves by increasing their serum thyroid
hormones in the presence of normal TSH [12, 14]. No treatment is necessary in
these cases. When the patient presents with hyperthyroid symptoms, especially
tachycardia, beta-blockers can be used. The thyroid hormone analogue 3,5,3-
triiodothyroacetic acid (TRIAC) has also been used successfully to treat some
symptoms of RTH in children such as increased TSH and goiter [15–18]. This is
due to the fact that TRIAC has a higher affinity for the TRthen for the TR,
and is metabolized more rapidly then T3. Because of this it has a limited effect
on organs like the heart with a predominance of TR. Similar treatment suc-
cesses with D-T4 [19, 20] have no clear explanation.
In cases where previous erroneous diagnosis has occurred resulting in
postsurgical or postradiation hypothyroidism, treatment with thyroid hormone
can be started. As an outcome for successful therapy serum TSH can be used;
required T4 doses can be as high as 1000 g/day [12]. In the case of ADHD
in RTH children it was found that T3 treatment improved symptoms [21].
Recently, ADHD symptoms in a child-bearing mutation F455I were success-
fully treated with TRIAC [22]. In another report, TRIAC was used to treat a
fetus harboring a TRmutation in utero to reduce fetal goiter [23]. Although
treatment was successful up to a point, some controversy has arisen due to
the fact that repeated chordocentesis was necessary (with all risks attached to
it) and that we do not know enough about placental TRIAC transport and
metabolism [12].
All in all it is clear that much more clinical groundwork is needed.
Molecular Issues
The first patients described with RTH in 1967 had, as mentioned above, a
very particular phenotype. The inheritance in these cases was autosomal-recessive.

Fig. 3. Position of the mutations in the ligand-binding domain of the TR. The muta-
tions that have been found in the TRcluster in three areas of the ligand binding domain
straddling the sites for corepressor binding and dimerization. The amino acid positions
between which the mutations are found are indicated above the boxes.
234–282
III III
310–353 429–461
Corepressor binding Dimerisation
Ligand binding domain
Ligand binding domain
DNA-
binding domain
Bakker 148
After a tight linkage was reported between the TRlocus [24] and RTH about
700 other cases have been described. One of the first patients had a homozy-
gous deletion of the TR1 allele, which as it turned out was the exception to the
rule since all other cases had point mutations or small deletions in the TR1
gene. As a result of these changes in the TR1 gene amino acids change or the
synthesis of the receptor protein is stopped prematurely. Interestingly, all muta-
tions found to date cluster in three areas of the receptor with some amino acid
positions very prone to mutation (fig. 3) [25 and references therein]. The inher-
itance of the point mutations is autosomal-dominant and patients are heterozy-
gous for the mutation. In 15% of cases RTH is sporadic and a mutation has
arisen de novo.
How do the mutant receptors give rise to the resistance phenomenon?
From the first case described, it is clear that losing the complete gene is only a
problem when both alleles are lost. The dominant nature of the inheritance of all
other mutants described indicates that the mutated receptors do interfere with
the action of their normal counterparts. From in vitro experiments it has
become clear that this is indeed the case and that the mutated receptors act in a
dominant negative manner, i.e. they decrease the effect of the hormone even
though the normal receptor is present [26, 27]. For the mutant receptor to act in
a dominant-negative manner, DNA binding and heterodimer formation are
essential [28]. When mutations which abolish either of the two are tested they
will not work as dominant-negatives.
On the basis of this, the interference with the normal way in which the TR
works can be envisaged to take place at several different levels. As shown in
figure 3 all mutations cluster in three particular areas. When these areas are plot-
ted onto the 3D structure of the TR, it becomes apparent that they are sur-
rounding the binding site for thyroid hormone (fig. 4). Therefore the first
possibility is loss of hormone binding. In this case the hormone cannot bind to

Resistance to Thyroid Hormone in Childhood 149
the receptor which will then not be able to release the corepressor and the result
of this is that the gene is not activated. Other receptor mutants have been found
that do bind T3 but which release the corepressor slower than normal [29, 30].
This will also lead to a decrease in gene activation. Another possibility is that the
mutant receptor molecules form heterodimers with RXR and go back to the TRE
but then fail to attract the coactivator in which case the gene remains silent.
Disruption of the TRgene in mouse models shows a phenotype reminis-
cent of the first RTH patients identified to harbor a homozygous deletion [31].
These animals also have serious hearing defects. When the deletion is heterozy-
gous, normal thyroid test results are found. The expression of mutant TRin
mice results in an animal model of RTH with lower body weight, hyperactivity
and learning problems, similar to the problems found in humans [32–35].
Another interesting point is that of the variation in peripheral symptoms
encountered which brings us back to the GRTH/PRTH distinction. The same
Fig. 4. Three-dimensional structure of the TRligand-binding domain. The 3D struc-
ture of the TRligand-binding domain is depicted as a ribbon following the peptide back-
bone (derived from NCBI-MMDB database, structure number 1BSX). The top of the
structure is the side of the DNA-binding domain. The dark ribbons indicate the three areas
where mutations preferentially occur. It can be clearly seen that these areas concentrate
themselves around the T3-binding site.

Bakker 150
mutation has led to the diagnosis PRTH in one family whereas it led to GRTH
in another. There are even reports that PRTH and GRTH can exist within one
family harboring the same TRmutation. It has therefore been argued that the
distinction between the two is an artifact based on the poor definition of the
symptoms. PRTH and GRTH can be viewed as two sides of a spectrum of a
single gene disease. However, it recently emerged that a novel mutation found
an newborn with severe RTH due to a frame-shift mutation gave rise to symp-
toms which point to predominantly pituitary RTH [36]. Wu et al. [36] also
showed that the mutation leads to an impaired interaction with the co-repressor
SMRT.
A possible reason for the variability in the symptoms with which patients
present could be that not all individuals express the same levels of TR (both
mutant and normal) in their tissues [37]. When the ratio between mutant and
normal TR changes so will the final effect of the mutant receptor. Furthermore,
not all mutations have the same effect on T3 binding [38]. Recently, it was
found that there is a relation between the T3-binding impairment and the out-
come of thyroid function tests [39]. Another factor could be the different tissue
distribution of the TR (fig. 1). In liver, the TRis the predominant isoform
which, however, is expressed in a zonal fashion, indicating that not every liver
cell will be sensitive to a mutated TR[40]. The heart on the other hand is a
predominantly TRtissue. Since the TRis normal in RTH patients but their
FT3 levels are high, it can be expected that they will react to the extra amount
of T3 in a hyperthyroid manner as far as the heart is concerned. Recently, it
appeared that the TR1 is expressed in the ventricles in only a subset of cardiac
cells which form the peripheral ventricular conduction system [41]. A mutated
TRwill therefore probably only affect this subset of cells. Furthermore, not
every individual will express the same amount of TR or corepressors/coactiva-
tors in a particular tissue leading to differences between individuals. An inter-
esting observation in this context is that some mutations are more deleterious
when present in the TR2 then in the TR1. Since the TR2 expression is
restricted to the pituitary it may be expected to give rise to a ‘PRTH’phenotype.
A number of cases have been reported where no mutation has been found
in the TRgene even though the biochemical evidence was there [42]. It has
been argued that the origin of the resistance in these cases is a faulty cofactor
[42–44]. This is supported by the recent finding that RXRknock-out mice dis-
play PRTH-like symptoms [45], and that SRC-1 knock-out mice manifest RTH
symptoms [46].
With the rapid increase of our knowledge of receptor structure and the way
agonists and antagonists interact with the receptors it can be envisaged that it
would be possible to design receptor agonists which will correct the receptor
defect. It has been shown for instance that a shift of 0.3 Å of helix 6 of the TR due

Resistance to Thyroid Hormone in Childhood 151
to the mutation of alanine 317 to threonine is the cause of the decrease in T3 bind-
ing. If an agonist were found which can ‘live’ with this small shift and thus acti-
vate the receptor, patients harboring this particular mutation could be treated.
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O. Bakker, PhD
Division of Endocrinology and Metabolism, Academic Medical Center
Meibergdreef 9
NL–1105 AZ Amsterdam (The Netherlands)
Tel. 31 205666071, Fax 31 206917682, E-Mail o.bakker@amc.uva.nl

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 154–168
Pendred Syndrome
Sameer Kassem, Benjamin Glaser
Endocrinology and Metabolism Service, Department of Internal Medicine,
Hadassah-Hebrew University Medical School, Jerusalem, Israel
History
The syndrome of familial profound congenital hearing loss associated with
large, multinodular goiter was f irst described by Vauhan Pendred [1] in 1896
(OMIM 274600). From its initial description until 1996, a large number of
articles were written describing novel cases and suggesting possible pathophy-
siologic mechanisms for the syndrome. However, all of these were based on
speculation, since the precise cause of the syndrome remained unknown for 100
years. Then, in 1996, using linkage analysis, 2 groups independently identified
the genetic locus responsible for the syndrome [2, 3]. The discovery of the pre-
cise gene mutated in Pendred syndrome, only 1 year later, opened a new phase
in the history of the syndrome [4].
Pendred syndrome is caused by loss-of-function mutations in the novel
protein called pendrin, which is encoded by the gene SLC26A4 (PDS).
Pendrin functions as an anion transporter and is expressed in the thyroid, the
inner ear, the kidney and the placenta. The precise mechanism by which muta-
tions in this single protein cause both defective thyroid function and profound
hearing loss has been the topic of extensive research ever since the discovery
of the gene.
Clinical Syndrome
The hallmark of Pendred syndrome is the combination of sensorineural
deafness and goiter in the presence of a positive perchlorate discharge test. The
clinical manifestations of this syndrome can be highly variable between
affected families and even within the same family [5].

Pendred Syndrome 155
The true incidence of the syndrome is not known, and depends in part on
whether it is def ined on a purely clinical basis, or on a genetic basis. The inci-
dence of congenital deafness has been reported to be between 1:1,000 and
1:2,000, and 1–8% of patients with congenital hearing loss are thought to have
Pendred syndrome [6, 7]. This suggests that the incidence of Pendred syndrome
may range from 1:12,500 to 1:200,000. However, this estimate is based on data
collected long before the genetic etiology of Pendred syndrome was known.
New studies are needed to determine what percentage of patients with congeni-
tal hearing loss have mutations in the PDS gene, and what percentage of these
have complete syndrome (see below).
Most patients with Pendred syndrome are born with severe to profound
bilateral sensorineural hearing loss, although some appear to have normal hear-
ing initially and lose their hearing suddenly or gradually later in childhood or
adolescence.
In contrast, the thyroid disease associated with Pendred syndrome rarely
presents in infancy, usually appearing in late childhood or early adolescence as
diffuse or multinodular goiter. Typically, the patients are clinically euthyroid,
although mild, compensated hypothyroidism, characterized by elevated TSH
with normal thyroxin and tri-iodothyronine levels, is often present. However,
clinical presentation is variable and Massa et al. recently described a case of
documented Pendred syndrome in whom the presenting thyroid pathology was
a painless, benign solitary thyroid nodule that resolved after hormone replace-
ment [8]. The size of the goiter is also variable, and may be small, detectable
only on close physical examination, or may reach massive proportions, causing
significant cosmetic problems or even tracheal compression (f ig. 1) [9].
Although the goiter tends to recur after surgery, partial thyroidectomy may be
required. The histological appearance of the thyroid tissue is characterized by
hyperplastic, diffuse goiter that develops into a multinodular pattern later in life
[10] (fig. 2). Frank hypothyroidism can occur after thyroidectomy, presumably
due to acute loss of thyroid mass, and full hormone replacement is advised
regardless of the extent of the surgical resection. The incidence and severity of
the goiter may be related in part to iodine intake, and high levels of dietary
iodine intake, such as typically seen in Japan, may protect against the goiter
[11, 12].
Patients with Pendred syndrome typically have elevated or high-normal
TSH levels in the setting of normal or low-normal levels of T4, with high T3/T4
ratios (fig. 3) [3]. Thyroglobulin levels are frequently elevated and may be
extremely high. However, the laboratory f indings are of minor clinical signifi-
cance since there is considerable overlap between patients and unaffected indi-
viduals. Furthermore, elevated TG levels are not specific and can be found in
MNG from any cause [9]. Although association has been made between the

Fig. 2. The histological appearance of thyroid tissue from a patient with Pendred syn-
drome and multinodular goiter. HE staining showing thyroid nodules surrounded by fibrous
capsules of different shapes and sizes as well as marked hyperplasia of the follicular epithe-
lial cells. The wide variability in size and shape of the colloid follicles is also demonstrated.
Kassem/Glaser 156
Fig. 1. CT of neck of Pendred syndrome patient with large multinodular goiter. In this
case, the goiter is symmetrical and does not cause any significant displacement or constriction
of the trachea. In some cases, critical tracheal compression may occur and thyroidectomy
may be required to prevent upper airway obstruction.

Pendred Syndrome 157
alterations in the expression of the gene responsible for Pendred syndrome and
thyroid cancers [13], it is not known if the incidence of cancer is increased in
this disease. Among 35 patients from a genetic isolate in Northern Israel, 1 was
diagnosed with papillary thyroid carcinoma [unpubl. observations].
Until genetic analysis for mutations in the gene responsible for Pendred
syndrome became available, the diagnosis relied on the constellation of clinical
and laboratory findings, in addition to a positive perchlorate discharge test.
Perchlorate is a competitive inhibitor of sodium-iodide symporter (NIS), the
thyroid cell surface protein responsible for transporting iodide from the plasma
into the thyrocyte. It has no effect on the iodination process itself; rather, it dis-
places iodide by competitive uptake at the NIS. When the NIS is blocked by
perchlorate, free iodide in the cytosol diffuses out of the cell. Under normal cir-
cumstances virtually all iodide transported into the cell is immediately organi-
fied, leaving very little free in the cytosol. However, in the presence of any
abnormality in the organification process, free iodide accumulates, and will dif-
fuse out if the NIS is blocked by perchlorate.
The test is performed by administering 1 g potassium perchlorate 2 h after
a tracer dose of 131I. Thyroidal radioactive iodine uptake is measured immedi-
ately before perchlorate administration and at 15min intervals thereafter. In
normal individuals, after radioactive iodide uptake into the thyroid gland is
blocked by the administration of potassium perchlorate, there is little loss of the
accumulated thyroidal radioactivity since virtually all of it is fully organified.
Fig. 3. Thyroid function tests in patients with Pendred syndrome but with no prior
surgery (P, black squares) and unaffected family members (C, black diamonds). The refer-
ence rage is shown by light gray shading. The slightly elevated TSH and TG seen in some of
the controls may be related to the fact that some are heterozygous for the PDS mutation and
that these families live in an area of relatively low iodine intake and high incidence of multin-
odular goiter. Significant differences were determined using the Mann-Whitney nonparamet-
ric test (*p 0.001).
NS
4
3
1
2
0
T3
(nmol/I)
CP
0.08
0.06
0.02
0.04
0
T3/T4
ratio
CP
*
25
20
5
10
0
TSH
(mIU/I)
CP
15
*
160
120
80
40
0
T4
(nmol/I)
CP
*
*
10,000
1,000
10
1
TG
(g/l)
CP
100
*

Kassem/Glaser 158
However, in individuals with Pendred syndrome, significant stores of unorgani-
fied iodide are present in the gland, and after potassium perchlorate administra-
tion, 10–80% of accumulated radioactivity may be discharged.
This test is of limited specificity and sensitivity for the diagnosis of Pendred
syndrome. Specificity is particularly poor, since a positive result can be obtained
in patients with any thyroid disease associated with an iodide organification
defect, including rare genetic diseases such as that caused by thyroid peroxidase
mutations (OMIM 274500), as well as very common diseases such as
Hashimoto’s thyroiditis and Graves’ disease [14]. Treatment with lithium or
antithyroid drugs will also cause abnormal organification and a positive test
[15]. Sensitivity is also limited, since a negative perchlorate discharge test has
been reported in a patient with genetically proven Pendred syndrome [16].
In as many as 50% of patients with congenital deafness and goiter, clinically
suspected to have Pendred syndrome, no PDS gene mutations can be found. In
some, this may be due to technical limitations of the methods used to detect muta-
tions, whereas in others, mutations in different genes may result in similar clinical
picture (genetic heterogeneity). Alternatively, the association of sensorineural
deafness and goiter may be a random phenomenon, since goiter is a common
finding, particularly in some regions of the world (phenocopies). Recently, con-
genital goiterous hypothyroidism and deafness was described in a patient who
was heterozygous for a recessive pendrin mutation, and compound heterozygous
for 2 different mutations in the thyroid peroxidase gene (TPO, OMIM 274500).
For this patient, the presence of congenital overt hypothyroidism and goiter sug-
gested clinically that the syndrome was not caused by PDS mutations alone, since
as described above, typical Pendred syndrome patients are clinically euthyroid
and the goiter is not present in the neonatal period. In another case, the coexis-
tence of sensorineural deafness and goiter were thought to be related to an
autoimmune phenomenon [17]. Thus, genetic heterogeneity and phenocopies of
Pendred syndrome may be common, and genetic analysis is required for def ini-
tive diagnosis. This may have important implications in terms of genetic counsel-
ing and family planning when the precise genetic diagnosis is not known.
Molecular Genetics
The gene associated with Pendred syndrome (SLC26A4, PDS) was mapped
to chromosome 7q13 in 1997 and cloned 1 year later using newly available data
and technology provided by the human genome project [2–4]. The gene spans
57 kb of genomic DNA and contains 21 exons. The 4,930 basepair-long mRNA
codes for a 780 amino acid protein, pendrin, which is predicted to contain 11 or
12 transmembrane domains [4, 18]. Immunohistochemical studies demonstrated

Pendred Syndrome 159
that the mature protein is expressed on the apical membrane of the follicular thy-
roid epithelial cells, in cells lining the endolymphatic duct, endolymphatic sac
and organ of Corti in the inner ear, in the intercalated cells of the kidney and in
trophoblast cells [4, 19, 20]. In the thyroid, pendrin expression is regulated by
TTF-1 and thyroglobulin, but not by TSH, sodium iodide or insulin [18, 21, 22].
The pendrin gene, SLC26A4, belongs to a larger family of ion transporters
that is currently thought to include 10 members, SLC26A1–11 (SLC26A10 is a
pseudogene). Early homology studies suggested the pendrin may function as a
sulfate transporter [4], but this was soon proven unlikely, since sulfate transport
was shown to be entirely normal in thyroid cells obtained from Pendred syn-
drome patients [23]. In vitro expression studies subsequently documented that
the protein forms a channel that can function either as a chloride-iodide trans-
porter in the thyroid [24] or a Cl/OH/HCO3exchanger in the kidney [25].
The functional importance of pendrin in the placenta is not known, although no
abnormality in reproductive function has been reported in women with Pendred
syndrome.
More than 100 different PDS (SLC26A4) mutations have been reported in
patients with Pendred syndrome and nonsyndromic deafness (see below) (f ig. 4).
Most of these are seen in only a single family, although 4 specific mutations
(E384G, L236P, T416P, and 1001 1G) are commonly seen, and are estimated
to be responsible for 50–60% of the Pendred syndrome cases in the Caucasian
population [26, 27]. Haplotype analysis suggests that these are founder mutations
in the Northern European Caucasian population and not mutation hot spots.
Another founder mutation, a single base deletion causing a frame shift and trun-
cated protein (1220delt), was identified in a large Bedouin tribe from Northern
Israel with more than 35 patients diagnosed with Pendred syndrome.
All forms of mutations have been found, including deletions, insertions,
missense and nonsense mutations. Elegant work by Rotman-Pikielny et al. [28]
demonstrated that at least some of the missense mutations result in defective
peptide processing, causing the protein to be trapped in the Golgi apparatus or
in the endoplasmic reticulum. Although of little clinical relevance at the present
time, this could become important in the future, since it may be possible to
develop chaperone proteins that can correct the secondary structure of these
mutant proteins, thus allowing them to be transported to the membrane, thereby
recovering at least some function.
Pendrin’s Function in the Thyroid
The exact mechanism by which pendrin functions in the thyroid is still debated.
Based on homology with sulfate transporters, it was initially hypothesized that

Kassem/Glaser 160
pendrin belongs to this family of channels [4]. Scott et al. [24] induced the
expression of pendrin in Xenopus laevis oocytes and Sf9 cells and reported 3
major findings: firstly, there was no increase in sulfate transport; second, the
rates of transport for iodide and chloride were significantly increased and third,
pendrin transports iodide and chloride in a competitive manner. Yoshida et al.
[29] reported that pendrin is responsible for iodide efflux from the follicular
cells into the colloid. They also report that in the thyroid, iodine is transported
in exchange for chloride, whereas in other tissues, it is hypothesized that pen-
drin’s main function is to transport chloride through exchange with other anions
[30].
In normal thyroid, pendrin is expressed at low levels on the apical mem-
brane of follicular cells. Thyroids from patients with Graves’ disease display a
similar, albeit more extensive, expression of pendrin when compared to normal
thyroid tissue, especially in areas with increased proliferation of the follicular
cells. In contrast, immunohistochemical staining was absent and mRNA levels
were significantly lower in papillary carcinoma when compared to normal and
other neoplastic diseases of the thyroid. These findings suggest a correlation
between pendrin expression and hormonogenesis [31].
Fig. 4. Structure of the pendrin protein showing 12 transmembrane domains as pro-
posed by Royaux et al. [18]. Circles show some of the more than 100 different mutations
identified in patients with Pendred syndrome and DNFB4. The black circles indicate
missense and non-sense mutations whereas the gray circles indicate other mutations types
including splice-site mutations and micro deletions or insertions. The 4 large circles
indicate 4 most common mutations. Together, these 4 mutations are responsible for up to
60% of the Caucasian Pendred syndrome patients diagnosed to date. The diagram is modi-
fied from that on the University of Iowa Otolaryngology Research Laboratories Web-site
(http://www.medicine.uiowa.edu/pendredandbor/slc26a4_mutations.htm).
L236P IVS81 g a
T416P
E384G COOH
NH2
123456789101112

Pendred Syndrome 161
Why, then, does the thyroid follicular cell require a second iodide trans-
porter, and why in the apical membrane? The sodium iodine symporter (NIS),
cloned in 1996 [32], and located on the basolateral membrane of the thyrocyte,
actively transports iodide against a concentration gradient into the cytoplasm of
thyroid cells. However, the iodination of thyroglobulin is carried out by the
enzyme thyroid peroxidase (TPO) located on the colloidal side of the follicular
cell apical membrane. Therefore, before the iodide can be organified, it must be
transported out of the cytosol into the colloid space (f ig. 5). Studying thyroid
plasma membrane vesicles, Golstein et al. [33] proposed the existence of a
channel in the apical plasma membrane that accomplishes this function.
Subsequent studies in polarized monolayers showed that iodide exited the cell
via the apical membrane and that this process was rapidly accelerated by thy-
rotropin [34, 35]. The identification of pendrin and the protein product of PDS
gene provided a mechanism for iodine transport from the thyroid cells into the
colloid space [36]. It is proposed that pendrin promotes the transfer of iodide
across the apical membrane (f ig. 4), and that its absence or dysfunction leads to
insufficient delivery of iodide to the iodination site and thus to an organi-
fication defect [30]. Both TPO and NIS are absolutely required for successful
Fig. 5. Schematic diagram showing iodide transport within the thyrocyte. The Sodium-
Iodide Symporter (NIS) pumps iodide into the cell against a concentration gradient. The
cytosolic iodide must exit the cell to interact with thyroid peroxidase on the extracellular side
of the apical membrane. This task is accomplished, at least in part, by pendrin.
Thyroid follicle
Colloid
Extracellular fluid
Thyroglobulin
TPO
K
Na
I
I
I
Pendrin
Na/K ATPase
Na/l symporter
Iodinated
thyroglobulin

Kassem/Glaser 162
iodination of thyroglobulin and formation of thyroid hormone. Thus, patients
with severe mutations in either will have severe congenital hypothyroidism. In
contrast, in the total absence of pendrin, organification is only partially inhib-
ited and most patients remain clinically euthyroid. Thus, an alternative, as yet
unidentified, pathway, or pathways, must exist by which iodide can exit the api-
cal border of the cell. It is possible that mutations in the components of these
other pathways may explain the disease in patients with clinical Pendred syn-
drome, but without PDS mutations.
Pendrin and the Ear
Since its initial description in 1896 [1], the mechanistic connection
between the defective thyroid function and sensorineural deafness was not
clear. Thyroid dysfunction per se clearly could not be blamed, since most
patients with congenital hypothyroidism do not have significant hearing loss
[37] and, as described above, most patients with Pendred syndrome are born
with normal or near-normal thyroid function. The high incidence of deaf-
mutism in patients with neurologic cretinism is thought to be related to mater-
nal hypothryoidism early in the pregnancy and not directly to fetal thyroid
dysfunction [38]. With the identification of the Pendrin gene in 1997 [4], it
became possible to begin to study this connection.
Soon after the discovery of pendrin, it became apparent that not all patients
with PDS mutations have thyroid abnormalities. Nonsyndromic congenital deaf-
ness previously linked to the same region of chromosome 7 (DFNB4), was
shown to be caused by PDS mutations [39]. In some cases, this apparent dissoci-
ation of clinical findings may be temporary, since the deafness typically is pre-
sent at birth, or shortly thereafter, while the goiter may appear later in life, often
during adolescence or even later [40]. The converse may also be true, since in
some patients with proven PDS mutations, the hearing loss may fluctuate, or
may occur abruptly later in childhood, associated with an acute illness or surgery
[3]. Cremers et al. [41] described 14 patients with Pendred syndrome in whom
hearing loss was first suspected as early as 6 months or as late as 6 years, and
was progressive in all. Goiter was diagnosed before the hearing loss in 4 patients.
The incidence of PDS mutations in patients with non-syndromic deafness
is not known. Scott et al. [39] screened 20 such patients and identified 3 with
novel PDS mutations. Functional analysis of these mutations and comparison
with mutations found in Pendred syndrome patients, showed that mutations that
cause Pendred syndrome have no in vitro function at all, whereas those associ-
ated with non-syndromic deafness retain some, albeit much reduced, function.
This suggests that the ear is more sensitive to changes in pendrin expression

Pendred Syndrome 163
and action than is the thyroid. Hearing loss may also be partial and progressive.
Sugiura et al. [11] tested 17 patients with bilateral enlarged ventricular aque-
ducts, a hallmark of Pendred syndrome (see below) and identified PDS muta-
tions in 14. Many of these patients had fluctuations in hearing loss that were
associated with vertigo. Hearing loss was first diagnosed after the age of
3 years in 3 of the patients, the oldest being 17 years old at the time of diagnosis.
Six of the 14 patients had moderate hearing loss or better at the beginning of the
study (aged 3–18 years). In 5 of these, hearing deteriorated significantly over
5–25 years of follow-up. Only 1 patient had a goiter, but in 8 of the 11 patients
studied there was an indication of abnormal iodine organification demonstrated
by an abnormal perchlorate discharge test. Thirteen of the patients had a single
mutation H723R that has been previously been associated with a higher rate of
goiter in other populations. The patients reported by Sugiura were Japanese,
and the relatively high iodine intake in the typical Japanese diet may explain the
lack of goiter. Of the 14 patients with PDS mutations in this study, in 8 only a
single mutant allele was identified. This finding is difficult to explain, since the
mutations identified were previously associated with recessive disease. It is
possible that a mutation or mutations in the regulatory regions of the gene,
which were not analyzed in these patients, may have been missed by the genetic
analysis. Alternatively, mutations in other genes may interact with recessive
PDS mutations to cause hearing loss.
What, then, is the cause of the hearing loss in patients with PDS gene muta-
tions? The structural abnormality of the inner ear associated with Pendred syn-
drome is variable. A particularly malformation of the cochlea, known as the
Mondini malformation, has been reported in some, but not all ears of patients
with Pendred syndrome. Enlargement of the vestibular aqueduct (EVA) appears
to be a more constant finding [41–43]. Significant differences can be seen
between the 2 ears of a single patient with profound bilateral hearing loss. Using
high-resolution CT to evaluate a cohort of Pendred syndrome patients from a
genetic isolate in the Middle East, we recently showed that the most common
structural abnormalities were an enlarged vestibulum and abnormal modiolus,
both of which were found in 100% of affected ears (f ig. 6). In contrast, an enlarged
aqueduct and an absent interscalar septum were found in only 80 and 75% of
affected ears, respectively [44].
Pendrin is expressed in cells lining the endolymphatic duct and sac, the
organ of Corti and in distinct areas of the utricle, saccule and cochlea suggest-
ing that the hearing defect is cause by a primary defect within the ear [19, 45].
In order to better understand the precise mechanism causing the profound hear-
ing loss, Everett et al. [36] generated a mouse with targeted disruption of the
mouse PDS gene. These animals are completely deaf and have vestibular dysfunc-
tion. Interestingly, the middle ear develops normally until embryonic day 15,

Kassem/Glaser 164
after which endolymphatic dilatation occurs. Sensory cell degeneration and
malformation of the inner ear develop during the 2nd postnatal week. Mice
deficient in pendrin show evidence of vestibular dysfunction. In contrast, this is
not clinically evident in most patients with Pendred syndrome, although only a
minority of patients have undergone rigorous testing of vestibular function.
Mice lacking the transcription factor Foxi1 have a similar phenotype and
lack pendrin expression in the ear during development, suggesting that this is an
upstream regulator of PDS expression. Mutations in this gene could conceiv-
ably cause a Pendred-like phenotype in man.
The clinical findings described above, along with the data from the mouse
model provide evidence that the structural defect of the inner ear may not be
directly genetically defined, but could be a secondary phenomenon. Taken
together with the presumed function of pendrin as an ion transporter or channel,
these findings suggest that the structural anomalies and hearing defect caused
by mutations in this gene may be caused by abnormal endolymphatic pressure
leading to dilatation of the vestibulum and vestibular aqueduct and degeneration
of the sensory cells. This may explain the variability in structural malformations
seen in man, and may explain the occasional occurrence of postlingual deafness
in patients with PDS mutations. More importantly, this finding may have thera-
peutic implications, since there may be a window of opportunity during which
therapy could be given to correct endolymphatic pressure and rescue the sen-
sory cells from destruction.
Fig. 6. High-resolution thin section CT image of inner ear. Note the markedly enlarged
vestibular aqueduct (white arrow), the enlarged vestibule (thin black arrow) and the abnor-
mal modiolus (thick black arrow) in the Pendred patient (a). Corresponding structures are
shown in a normal individual for comparison (b). Images provided by Dr. Moshe Goldfeld,
Western Galali Hospital, Nahariya, Israel [9].
a b
Vestibule
R
Vestibular
aqueduct

Pendred Syndrome 165
Pendrin’s Function in the Kidney
Intercalated cells are located in the distal nephron of man and rodents, rep-
resenting a minority cell type that appears to be important for acid-base bal-
ance. Three types of intercalated cells have been identif ied, type A, type B and
non-A/non-B. The major differences between these cell types relates to the
expression and sub-cellular localization of several specific ion channels [see 46
for a recent comprehensive review]. Type A intercalated cell excrete protons
through the apical H-ATPase. Disruption of this channel results in a net
decrease in Hsecretion. Type B intercalated cells express pendrin, which acts
as a HCO/Clexchanger, on their apical membrane [25, 47]. Disruption of
this channel results in decreased bicarbonate secretion and a tendency toward
metabolic alkylosis [47]. In the mouse kidney, pendrin expression is regulated
and can be modified by changes in acid-base status [48].
Mice deficient in pendrin (slc26a4/) have normal pH, renal function and
fluid balance under non-stimulated conditions. However, during NaCl restric-
tion, slc26a4/mice have elevated urinary volume and Clexcretion and
develop metabolic alkylosis, volume depletion and relative hypotension [49].
Stimulation with the aldosterone analogue diozycorticosterone pivalate
(DOCP) results in weight gain and hypertension in normal mice, but not in
scl26a4/mice [50]. These findings suggest that pendrin may play a role in the
pathogenesis of mineralocorticoid-mediated hypertension.
To date, no fluid or electrolyte abnormality has been reported in patients
with Pendred syndrome, although rigorous studies have yet to be reported, and
it seems likely that subtle abnormalities will be found under certain stress con-
ditions. Common polymorphisms have been found in PDS, including at least 2
non-synonymous coding variants. It is possible that these or other genetic vari-
ants in this gene affect the genetic risk of developing fluid and electrolyte
imbalances or hypertension. Large-scale association studies are needed to
establish or to refute this potential association between pendrin and the com-
monly seen essential hypertension.
Directions for the Future
The discovery of the genetic cause of Pendred syndrome opened up new
opportunities in the study of thyroid, ear and kidney physiology. The next chal-
lenge is to translate these findings into clinically relevant interventions. Genetic
testing can identify carriers in high-risk populations, and this information can
then be used for genetic counseling and family planning. The thyroid disease per
se does not cause overwhelming disability; however, early, complete thyroid

Kassem/Glaser 166
hormone replacement may prevent or delay the development of goiter, thus obvi-
ating the need for surgery and the morbidity associated with it. Careful prospec-
tive studies are needed to test this hypothesis. Most importantly, however, it may
be possible to develop pharmacologic interventions that can prevent or minimize
the damage to the inner ear, the most debilitating defect associated with the syn-
drome. Further basic and clinical studies are urgently needed in this direction.
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Benjamin Glaser, MD
Endocrinology and Metabolism Service
Department of Internal Medicine
Hadassah Medical Center
POB 12000, IL–91120 Jerusalem (Israel)
Tel. 972 2 677 6788, Fax 972 2 643 7940, E-Mail beng@cc.huji.ac.il

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 169–191
Treatment of Hyperthyroidism Due to
Graves’ Disease in Children
Scott A. Rivkees
Yale Pediatric Thyroid Center, Department of Pediatrics, Yale University School of
Medicine, New Haven, Conn., USA
Current treatment approaches involving antithyroid medications, surgery,
and radioactive iodine have been used for more than five decades for the treat-
ment of hyperthyroidism due to Graves’ disease in children, adolescents, and
adults [1–4]. Although additional studies are needed, the collective observations
of thousands of children with Graves’ disease have spawned a generous body of
literature detailing the natural history of Graves’ disease, along with treatment
outcome and complications [5, 6]. Based on this reported experience, the fol-
lowing generalizations can be made.
Long-term, spontaneous remission of Graves’ disease occurs in less than
30% of children. Thus, the vast majority of children with Graves’ disease will
need definitive, curative therapy, either in the form of surgery or radioactive
iodine.
•There is little evidence that use of antithyroid medications beyond 1 or 2
years increases the likelihood of spontaneous, long-term remission.
•Antithyroid medication use in children and adolescents is associated with
minor and major side effects. Although the use of antithyroid medications is
standard practice, the use of antithyroid medications involves definite risks.
•Total thyroidectomy is an effective treatment of Graves’ disease, with a low
rate of disease recurrence. Long-term complications include recurrent laryn-
geal nerve paresis in 2% or more of individuals, permanent hypoparathy-
roidism in 1% or more, and hypertrophic and non-hypertrophic scars.
Surgery is the preferred def initive treatment for the very large thyroid gland
and when the individual is considered too young for 131I.
•When used at doses that deliver 150 Gy, or more (150 Ci 131I/g thyroid
tissue), radioactive iodine is an effective cure for Graves disease and is
associated with few acute side effects. Potential long-term adverse side

Rivkees 170
effects, including thyroid cancer and genetic damage, have yet to be
observed in individuals treated as children or adolescents with 131I.
Childhood Hyperthyroidism
Hyperthyroidism occurs much less commonly in children than hypothy-
roidism, yet is a far more virulent condition [7, 8]. In children the most com-
mon cause of childhood thyrotoxicosis is Graves’ disease, which is characterized
by diffuse goiter, hyperthyroidism and occasionally ophthalmopathy [6, 9–11].
Other causes of childhood hyperthyroidism include toxic nodules, toxic multin-
odular goiters, acute and subacute thyroiditis, and the ingestion of thyroid
hormone [6, 9–11].
Untreated, hyperthyroidism is associated with excessive activity, tremor,
tachycardia, flushing, palpitations, accelerated linear growth, weight loss,
impaired skeletal mineralization, and poor school performance [6, 9–11].
Because Graves’ disease, toxic nodules and toxic multinodular goiters only
rarely spontaneously resolve within a short period, treatment of hyper-
thyroidism is essential. Current treatment options include the use of radioactive
iodine, surgery, and antithyroid medications.
Central to considering the use of radioactive iodine and other treatment
options in Graves disease in the pediatric population, is recognition of the natural
history of the autoimmune disorder. One must also consider how long antithyroid
drug therapy should be continued before moving on to definitive therapy.
Spontaneous remission of Graves’ disease in the pediatric population
occurs in the minority of individuals. Published remission rates are usually less
than 25% after several years of antithyroid therapy [5, 6, 12]. The most exten-
sive long-term study of this issue involving nearly 200 children showed that less
than 20% of children treated medically achieved remission lasting greater than
2 years [13]. In another large series of 186 children, less than 30% of children
went into remission [14]. When responses to medical therapy between prepu-
bertal and pubertal children are compared, remission rates are even less in pre-
pubertal than pubertal children, with remission occurring in fewer than 15% of
prepubescent children [15, 16].
When spontaneous remission of Graves’ disease does not occur, prolonged
drug therapy will control the hyperthyroid state and is used by some clinicians;
however, years of treatment with antithyroid drugs do not appear to increase the
likelihood of lasting remission. More than two decades ago, Greer et al. [17]
showed that the likelihood of spontaneous remission of hyperthyroidism was
similar when antithyroid medications were used for 6 or 36 months. Most recently,
Weetman [18] reviewed prospective trials comparing different durations of

Graves’ Disease in Children 171
treatment in adult subjects. In one French study involving 94 patients, following
treatment for 6 or 18 months, remission rates were 42 and 62%, respectively,
2 years after discontinuing treatment [19]. In 52 Spanish patients, following
treatment for 12 or 24 months, remission rates were 46 and 54% at 2 years after
cessation of therapy [20]. This difference was not signif icant, and by 5 years,
the relapse rate was 85%. Another study of 134 French patients found no bene-
fit of 18 vs. 43 months of treatment [21]. It is notable that remission rates in
these cohorts of adults are considerably greater than those reported in children,
suggesting that the younger one is when Graves’ disease occurs, the more last-
ing it will be.
Radioactive Iodine
Origins of 131I Therapy
The use of radioactive iodine grew out of collaborative efforts in the
1930s and 1940s of physicists at the Massachusetts Institute of Techno-
logy (MIT) and clinicians at the Massachusetts General Hospital (MGH;
Drs. J. Howard Means, Earle M. Chapman, and others) [3]. The first patient
treated with radioactive iodine alone with the intent of curing Graves’ disease,
was a 55-year-old man who received two doses in 1943 of the very short half-
life isotope 130I (t1/2 12 h). Between 1943 and 1945, an additional 22 patients
were treated with a short half-life radioactive iodine at the MGH with good out-
come [3].
When the US Atomic Energy Commission was allowed to supply uranium
fission products for medical use, 131I, with a half-life of 8 days became available
for the treatment of Graves’ disease. In 1946, a patient at Barnard Hospital in
St. Louis with thyroid cancer became the first to be treated with the long half-
life nuclide [3]. Because of the inherent advantages the longer half-life isotope,
131I rapidly became the preferred iodine isotope for treating hyperthyroidism
and thyroid cancer.
About 10 years after the first adult was treated with radioactive iodine for
Graves’ disease, Drs. John D. Crawford and Chapman at the MGH treated the
first child with Graves’ disease with radioactive iodine. The child faced
unremitting hyperthyroidism in the face of toxic reactions to antithyroid med-
ications. In the 1960s and 1970s, several groups reported their experience using
radioactive iodine to treat childhood Graves’ disease [22–24]. These reports
showed both safety and efficacy in children. When radioiodine was not associ-
ated with an increased risk of thyroid cancer or genetic damage to the offspring
of treated children and adolescents [25], radioiodine therapy use became more
widespread and extended to progressively younger children.

Rivkees 172
Iodine-131
Because the uptake of radioactive iodine by the thyroid is indistinguishable
from ordinary iodine, radioactive iodine is trapped in thyroid cells [26]. When
taken up by thyroid cells, beta emissions from radioactive iodine result in the
destruction of the trapping cell and cells in close proximity. Because the thyroid
gland has extremely high affinity for iodine in comparison with other tissues,
the use of radioactive iodine results in selective ablation of thyroid tissue [26].
About ten different isotopes of iodine have been used medically. 123I is the
most frequently used isotope for diagnostic studies of thyroid function and struc-
ture [26]. This isotope has a short half-life (13.3 h) and emits X-rays, gamma-
photons, yet no beta particles. In comparison, 131I has a half-life of about 6–8
days and emits beta particles and gamma rays. The beta particles result in local
thyroid damage; gamma emissions facilitate external diagnostic imaging.
It has been suggested that doses (administered activities) delivering
30,000–40,000 cGy (rad) to the thyroid are required to ablate the thyroid gland
[27, 28]. However, doses delivering 10,000–20,000cGy to the thyroid are more
commonly used and may result in complete or partial destruction of the thyroid
[6, 12, 29].
Administered thyroid doses of 150Ci/g (5.5 MBq/g) typically yield radia-
tion doses of 12,000 cGy to the thyroid [30]. Following 131I treatment, radiation
exposures to the stomach, marrow, liver, and gonads are about 14, 6.8, 4.8 and
2.5 cGy per organ, respectively. The total body exposure is about 4.0 cGy [30].
Because of the risk to the fetus, 131I should not be given to pregnant women.
131I Therapy
Thyroid destruction is strongly influenced by rates of iodine uptake and the
amount of thyroid tissue. Doses of radioiodine administered to the patient are
therefore based on gland size and iodine uptake using the Quimby-Marinelli
equation: dose ∃∃ (radiation; in Gy) 90 {oral iodine-131 dose (Ci) oral
24-hour uptake (%)/gland mass (g) 100%}; assuming an effective T1/2 of 6.0
days for iodine-131 [31]. Thyroid size is determined by palpation or ultrasound
(ultrasound volume 0.48 length width depth) [32]. For example, if a
dose of 300 Ci/g of thyroid tissue is desired for a patient with a 20-gram thyroid
gland and a 50% radioiodine uptake at 24 h, the dose will be 12 Ci.
When calculating 131I doses, thyroid size can be assessed clinically relative
to the size of a normal thyroid gland size (0.5–1 g per year of age; 15–20 g for
adults) or by ultrasound, which is preferred to provide a more accurate size
determination [30, 33, 34]. However, even when gland size, uptake, and effec-
tive 131I half-times are measured with a high degree of accuracy, the outcome is
still imprecise due to individual variation in the sensitivity of the thyroid to
radioiodine [32].

Graves’ Disease in Children 173
If a patient is taking antithyroid medication, as is often the case, treatment
should be stopped 3–5 days before the administration of radioactive iodine. If
antithyroid medication is stopped too soon before radioactive iodine adminis-
tration, there can be accumulation of thyroid hormones within the gland leading
to thyroid storm following radioactive iodine treatment [35]. After 131I adminis-
tration, circulating levels of thyroid hormones may then rise within 4–10 days
as thyroid hormone is released from degenerating follicular cells [36]. Progressive
decline in thyroid hormone levels will then occur.
Until the patient becomes biochemically euthyroid or hypothyroid, which
usually takes 6–12 weeks after treatment, symptoms of hyperthyroidism can be
controlled using beta-blockers [36–38]. The use of SSKI or Lugol’s solution
started one week after the administration of radioactive iodine will also attenu-
ate biochemical hyperthyroidism and not adversely affect the outcome of
radioiodine therapy [38]. In some patients, transient biochemical hypothy-
roidism can develop by 8 weeks, and hyperthyroidism will recur [39]. In up to
5–20% of patients (varying with dose), hyperthyroidism will persist; a second
dose of radioiodine is recommended for these patients [12]. Additional doses of
radioactive iodine are not usually given until 6 months after initial therapy.
Long-Term Cure Rates
Long term cure rates are generally higher in patients treated with larger
than smaller amounts of radioactive iodine [6]. In adults treated with low doses
of 131I (50–75 Ci/g), hyperthyroidism persists in 30–50% 1 year after therapy
[40–43] and hypothyroidism will develop in 7–20% of patients [40, 41]. In
comparison, after treatment with higher 131I doses (150–250 Ci/g), only
5–10% of patients are hyperthyroid at one year, and 40–80% become hypothy-
roid [30, 44, 45].
The success of radioiodine therapy is influenced by the size of the thyroid
gland and possibly by circulating levels of TRAb. Responses to 131I therapy are
lower in patients with very large glands (80 g) and high TRAb levels than in
patients with smaller glands [29, 46–49]. (At present the basis for lower effi-
cacy in the presence of high TRAb levels is not known.) Thus, surgical thy-
roidectomy should be considered with for persistently large glands. Responses
to radioactive iodine may also be less favorable after treatment with PTU
[48, 50, 51] than after MMI treatment [52].
Radioactive Iodine Use in Children
The details of 131I therapy for childhood Graves’ disease have been reported in
several studies [13, 22, 24, 53–57]. Patients as young as 1 year of age have been
treated with 131I with excellent outcomes [23, 57]. 131I doses in children and ado-
lescents have ranged from 100 to 400Ci/g thyroid tissue [6]. As in adults,

Rivkees 174
responses to 131I therapy are related to dose and gland size. In children treated with
50–100 Ci/g thyroid tissue, 25–40% are hyperthyroid several years after therapy
[58]. In children treated with a single dose of 150–200Ci/g thyroid, hyperthy-
roidism persists in 5–20%, and 60–90% become hypothyroid [6, 12, 22, 23].
We have analyzed the outcomes of 31 children (ages 7–15) treated with
radioactive iodine therapy at Yale New Haven Hospital over the past 7 years to
assess effectiveness of therapy as related to dose and gland size [59] (table 1). When
children were treated with 80–120 Ci 131I/g thyroid tissue at 6–12 months after
treatment, 28% are hyperthyroid, 28% are euthyroid, and 42% are hypothyroid.
When children are treated with 200–250Ci/g thyroid tissue, 37% are hyperthy-
roid, 0% euthyroid, and 62%. When children were treated with 300–400 Ci/g
thyroid tissue, 0% are hyperthyroid, 7% euthyroid, and 93% are hypothyroid.
When we compare these data with those of Peter and co-workers [29, 32, 59], it
appears that thyroid tissue of children and adolescents is more sensitive to 131I
than in adults, as hypothyroidism occurs at lower 131I doses (fig. 1).
We also find that gland size influences therapy outcomes, especially at
lower doses (f ig. 2). For children treated with the low or moderate doses, 53%
developed hypothyroidism when the thyroid gland is moderately enlarged
(⬃30 g) and when the thyroid gland is quite large (50–80 g), about 60% remain
eu- or hyperthyroid. Yet, when high doses are used, hypothyroidism occurs in
93% of patients, irrespective of gland size up to ⬃80 g of thyroid tissue.
Complication Rates
Acute complications of 131I therapy have been reported, but the incidence
of these is low and not well defined [6]. In children, very few acute adverse
responses to 131I therapy of Graves’ disease have been described [6].
In adults, transient nausea has been reported after radioiodine administra-
tion, and mild pain over the thyroid gland, reflecting radiation thyroiditis, may
develop one to three days after a therapeutic dose [36]. These side effects are
Table 1. Outcome of 131I treatment as related to dose
131I dose, Ci/g Radiation dose, Gy Outcome, %
mean SEM (range) mean SEM (range) hyperthyroid euthyroid hypothyroid
92.1 8.1 (80–120) 82.9 7.3 (72–108) 28.6 28.6 42.8
222.7 12.3 (200–250) 200 11.1 (180–225) 37.5 0.0 62.5
365.0 11.5 (300–405) 325 10.8 (270–364) 0.0 6.25 93.75
From Rivkees and Cornelius [59].

Graves’ Disease in Children 175
Fig. 1. Relationship between thyroid radiation dose and hypothyroidism rate in individ-
uals less than 18 years of age (left panel) as compared to outcomes observed in adults. Based
on published data of Peters et al. [32]. The shaded area shows the 95% CI; r 0.98, p 0.01.
0
0
100 200
18 years
300 400
111 222 333 444
Radiation dose absorbed by the thyroid
Hypothyroidism at 6 months
0
20
40
60
Hypothyroidism (%)
80
100
0 100 200
30 years
300 400 (Gy)
111 222 333 444 (Ci/g)0
Fig. 2. Therapy outcome as related to dose and thyroid gland size. Each character
represents an individual patient. From Rivkees and Cornelius [59].
15–30
0
2
4
6
8
10
31–60
Outcome
(number of patients)
72–108 Gy
80–120 Ci/g
180–225 Gy
200–250 Ci/g
270–364 Gy
300–405 Ci/g
61–80 15–30 31–60
Thyroid size (g)
61–80 15–30 31–60 61–80
Hypothyroid
Euthryroid
Hyperthyroid

Rivkees 176
self-limited and respond to treatment with nonsteroidal anti-inflammatory
agents [36]. Severe neck swelling and tracheal compression have been reported
rarely in patients with very large goiters after 131I administration and can be
controlled with large doses of corticosteroids [36]. However, neck swelling
after radioactive iodine treatment typically occurs with doses greater than
50,000 cGy; such doses are much greater that those needed for Graves’ therapy
[60]. Vocal cord paresis occurs very rarely [61].
Thyroid storm has been reported to develop between one and fourteen days
after 131I treatment in a small number of patients [62]. This complication is rare and
no cases were reported among 7,000 patients treated with 131I at one center [12].
Patients with severe thyrotoxicosis and very large goiters may be at higher risk for
thyroid storm. In this setting, antithyroid drugs can be administered for several
weeks before radioactive iodine therapy to deplete stores of hormones before
radioactive iodine therapy [62]. However, if medication is stopped too soon, thy-
roid hormone stores will be replenished and can lead to thyroid storm [35].
Recent discussions have focused on the association of 131I therapy of
Graves’disease with the development or progression of ophthalmopathy in adult
patients [63, 64]. In contrast to adults, children rarely develop severe ophthal-
mopathy and proptosis is generally mild [65, 66]. Of 87 children treated with 131I
for Graves’disease at one center, eye signs improved in 90% of children, did not
change in 7.5%, and worsened in 3% after treatment [23, 45]. In 45 children with
ophthalmopathy at the onset of treatment, eye disease improved in 73% and
worsened in 2% after 1 year or more of drug therapy [67]. Following subtotal
thyroidectomy in 80 children, eye disease worsened in 9% [68]. In contrast, eye
disease was stable in 60 (75%) children after total surgical thyroidectomy [68].
Thus, eye disease worsens in only a small percentage of children following med-
ical, radioactive iodine, or surgical therapy of Graves’ disease.
It has been suggested that the development and progression of ophthal-
mopathy prevented by treatment with prednisone for 3 months after radioiodine
therapy [69]. However, adjunctive prednisone therapy is not routinely recom-
mended for most children since long-term progression of ophthalmopathy
occurs infrequently and unpredictably after radioiodine [69]. Prolonged pre-
dnisone administration is also associated with weight gain, immune suppres-
sion, and growth failure in children. However, prednisone may be useful after
radioiodine therapy for the pediatric patient with severe eye disease.
Post 131I Cancer Risks
The increased risk of thyroid cancer after thyroid irradiation in childhood
has been recognized for nearly 50 years [70]. Thus, a major concern of 131I therapy

Graves’ Disease in Children 177
relates to the risk of thyroid cancer. Detractors of 131I therapy point to the
increased rates of thyroid cancer and thyroid nodules observed in young chil-
dren exposed to radiation from nuclear fallout at Hiroshima or after the
Chernobyl nuclear reactor explosion.
The thyroid gland is unique in its developmental sensitivity to malignancy
following radiation exposure. Individuals older than 20 years of age do not have
an increased risk of thyroid cancer when exposed to low-level thyroid irradia-
tion [71–73]. Yet, when individuals are less than 20 years of age at the time of
low-level thyroid irradiation, the thyroid cancer risks increases the younger one
is [71–73].
In addition to age, the radiation dose plays a major role in cancer risk [70–73].
The risk of thyroid cancer and thyroid nodules is highest with exposure to low or
moderate levels of external radiation (0.1–25 Gy), and not with the considerably
higher doses used internally to treat Graves’disease (150 Gy) [70–74].
It is important to note that iodine def iciency and exposure to nuclides other
than 131I may have contributed to the increased risk of thyroid cancer in the
young following the Chernobyl reactor explosion [70–72]. In comparison, rates
of thyroid cancer were not increased in the more than 3,000 children exposed to
131I from the Hanford reactor site in an iodine replete region [75]. An increase in
thyroid cancer has not been observed in about 6,000 children who received 131I
for diagnostic procedures [72, 76].
The Cooperative Thyrotoxicosis Therapy Follow-up Study showed that
long-term thyroid problems occur in children treated with lower, rather than
higher doses of 131I. Thyroid adenomas developed in 30% of 30 children treated
in one center with low doses of 131I estimated to result in thyroid exposure of
25 Gy [33, 50]. Yet, when children are treated with higher doses of 131I
(100–200 Gy), the incidence of thyroid neoplasms was not increased [77].
Outcomes after 131I treatment of more than 1,200 children and adolescents
treated with higher doses of radioiodine for Graves’disease have been reported [6].
The duration of follow-up in these studies ranged from 5 to 15 years, with
some subjects followed for more than 20 years. These studies have not revealed
an increased risk of thyroid malignancy. The longest follow-up studies of chil-
dren recently treated with 131I come from Read et al. [78]. When more than 100
patients were surveyed nearly four decades after receiving radioactive iodine at
ages ranging from 3 to 19 years, no adverse events or deaths could be attributed
to 131I therapy [78]. None of the patients developed thyroid cancer or leukemia.
One individual developed breast cancer, and one individual developed colon
cancer, numbers in keeping with the incidence of these malignancies in the
population at large.
We are aware of four reported cases of thyroid malignancy in children pre-
viously treated with 131I (5 years of age at treatment with 50 Ci/g; 9 years

Rivkees 178
of age at treatment with 5.4 Ci; 11 years of age at treatment with 1.25 Ci;
16 years of age at treatment with 3.2 Ci) [6]. These individuals were treated
with low doses of 131I. We are not aware of reports of thyroid cancer in patients
treated with 100 Gy of radioactive iodine for childhood Graves’ disease that
can be attributed to radioactive iodine therapy. Thus, low doses of 131I in chil-
dren should be avoided. Ablation of the thyroid gland will decrease the risks of
tumors and recurrence of hyperthyroidism. The child will need long-term thy-
roid hormone replacement, but such will be the situation if total thyroidectomy
is performed.
Although radioactive iodine is being used in progressively younger ages,
we do not know if there is an age below which high-dose 131I therapy should be
avoided. Risks of thyroid cancer after external irradiation are highest in
children less than 5 years of age and progressively decline with advancing age
[70, 72, 78, 79]. If there is residual thyroid tissue in young children after
radioactive iodine treatment, there is a theoretical risk of thyroid cancer. It may
therefore be prudent to avoid radioactive iodine therapy in children less than
5 years. However, children as young as 1 year have been treated with radioac-
tive iodine with excellent outcomes [6, 23].
Radiation exposure of the gonads during 131I therapy approximates
2.5 cGy, which is comparable to the gonadal exposure from a barium enema or
an intravenous pyelogram [80]. The literature contains data on 500 offspring
born to approximately 370 subjects treated with 131I for hyperthyroidism during
childhood and adolescence [6]. The incidence of congenital anomalies reported
among the offspring of patients treated with radioiodine does not differ from
the incidence in the general population. In addition, there was no increased
prevalence of congenital anomalies in the offspring of 77 patients treated
for thyroid cancer in childhood with 80–700 Ci of 131I [81]. There is also no
evidence of an increased rate of birth defects in survivors of the Hiroshima and
Nagasaki atomic bomb blasts who were exposed to higher levels of external
irradiation of the gonads than are associated with radioactive iodine therapy
[25, 82].
In addition to thyroid cancer, potential influences of 131I therapy on other
cancers need to be considered. Follow-up from the large cohort of the
Cooperative Thyrotoxicosis Therapy Follow-up Study did not find increased
risks of leukemia in the 131I-treated group, as compared with the drug and
surgery treated groups [83]. No increase in overall cancer mortality was seen in
the 131I-treated patients either [84]. In other studies, excess thyroid cancer mor-
tality following 131I therapy for Graves’ disease was observed during early, but
not later, years of follow-up [85]. This observation is believed to reflect mytho-
logical issues related to increased cancer surveillance and detection, rather than
131I effects [85].

Graves’ Disease in Children 179
Total-body radiation doses after 131I vary with age, and the same absolute
dose of 131I will result in more radiation exposure to a young child than to an
adolescent or adult [10, 59, 80, 86]. At 0, 1, 5, 10, 15 years of age, and in adult-
hood, respective total body radiation doses are 11.1, 4.6, 2.4, 1.45, 0.90, and
0.85 rem per Ci of 131I [80]. Based on the Biological Effects of Ionizing
Radiation Committee V (BEIR V) analysis of external radiation exposure, the
theoretical risk of cancer death following acute radiation exposure is 0.16% per
rem for children and 0.08% per rem for adults [87–89], although there is uncer-
tainty associated with these projections [87–89]. Thus, if the same 10-Ci dose
is given to a 10-year-old child and an adult, total-body doses will be 14.5 and
8.5 rem, respectively, and the theoretical risks of cancer mortality will be 2.2
and 0.68%. These values can be compared with the natural life-time risk for
cancer death of 20% [87, 89].
We do not have good dosimetry information regarding 131I use in children
with Graves’ disease to assess actual total body exposure and the long-term the-
oretical risks associated with this exposure, especially in young children. At
present, data are not available to assess actual lifetime cancer risks in children
treated with 131I or medication for Graves’ disease.
Health of Offspring
Radiation exposure of the gonads during 131I therapy approximates 2.5 cGy,
which is comparable to the gonadal exposure from a barium enema or an intra-
venous pyelogram [25]. The literature contains data on 500 offspring born
to approximately 370 subjects treated with 131I for hyperthyroidism during
childhood and adolescence [6]. The incidence of congenital anomalies reported
among the offspring of patients treated with radioiodine does not differ from
the incidence in the general population. In addition, there was no increased
prevalence of congenital anomalies in the offspring of 77 patients treated in
childhood with 80–700 Ci of 131I [81]. Furthermore, there was no evidence of
an increased rate of birth defects in survivors of the Hiroshima and Nagasaki
atomic bomb blasts who were exposed to higher levels of external irradiation of
the gonads than are associated with radioactive iodine therapy [82].
Thyroidectomy
Surgery is the oldest form of definitive therapy of Graves’ disease with the
Nobel Prize in Physiology and Medicine awarded to Koker in 1909 for develop-
ments in this field [90]. Whether total or subtotal thyroidectomy should be per-
formed has been the focus of past and recent debate. The higher relapse rates
seen with subtotal thyroidectomy have resulted in the recommendation that

Rivkees 180
total thyroidectomy is the procedure of choice for Graves’ disease [68, 91, 92].
New surgical techniques, such as minimally invasive thyroidectomy and mini-
mally invasive video-assisted thyroidectomy have recently been described [93].
Whereas it can take several months for the hyperthyroid state to remit after 131I
treatment, the hypothyroid state occurs much sooner after surgery, being depen-
dent on the clearance of circulating thyroid hormone.
In preparation for surgery, the child should be rendered euthyroid. This is
typically done with either PTU or MMI. One week before surgery, adding
iodine to the treatment 5–10 drops, t.i.d. may be desirable. This treatment
causes the gland to become firmer and less vascular, facilitating surgery.
Following subtotal thyroidectomy, relief of hyperthyroidism is achieved in
about 80% of children and adults, and hypothyroidism develops in about 60%
of individuals [94, 95]. Hyperthyroidism recurs in about 10–15% of patients
after subtotal thyroidectomy [68, 94, 95]. In comparison, hyperthyroidism
recurs in less than 3% of children and adults who undergo total thyroidectomy,
and hypothyroidism is nearly universal [68, 94–96].
Even in centers with considerable experience in thyroid surgery, acute
and long-term complications are reported. Acute complications include
hypocalcemia (40%), hematomas (2%), and recurrent laryngeal nerve paresis
(2%) [68, 91, 93]. Long-term reported complications include permanent
hypoparathyroidism in 1% of patients, which is treatable with vitamin D or vit-
amin D analogues, and recurrent laryngeal nerve injury in 2% [97]. Surgery is
associated with a neck scar ranging from about 2.5–7.0cm, that we find socially
conscious teenagers and young adults try to hide with necklaces, scarves and
high collars. Hypertrophic scars can also occur following thyroidectomy.
Associated with surgery are the acute postoperative pain or discomfort, and
time lost from school, work or activity. Surgery is expensive with collective
costs of thyroidectomy often topping USD 7,000.
Of considerable importance in evaluating surgical outcome of Graves’ dis-
ease, is the experience and expertise of the surgical center and surgeon. The
above complication rates pertain to expert surgical centers. We know little about
current complication rates following pediatric thyroidectomy performed by
non-endocrine surgeons.
Antithyroid Drug Therapy
Medical treatment in the f irst half of the century consisted of bed rest,
quinine, and iodine in the form of Lugol’s solution [98]. Partial thyroidectomy
was used to provide permanent cures [98]. With the advent of thiouracil and
propylthiouracil (PTU) in the mid-1940s, medical therapy of Graves’ improved

Graves’ Disease in Children 181
markedly [99]. Because of the relatively high incidence of toxic reactions that
developed following the administration of thiouracil including agranulocyto-
sis, leukopenia, and drug fever, PTU became the mainstay of medical therapy
[99] and was later joined by methimazole (MMI) as an effective treatment
option.
PTU and MMI reduce thyroid hormone synthesis by inhibiting the oxida-
tion and organic binding of thyroid iodide [100, 101]. These medications are
not curative. Rather, they palliate the hyperthyroid state until it spontaneously
resolves or definitive treatment is rendered.
MMI is tenfold more potent than PTU and has a longer half-life [100, 101].
Recommended doses for initial therapy are 5–10 mg/kg per day for PTU and
0.5 to 1.0 mg/kg per day for MMI [102]. Yet, even lower doses of PTU or MMI
may be effective for induction or maintenance therapy.
To control the hyperthyroid state, PTU and MMI are typically given every
eight hours. However, once-a-day dosing may bring remission as rapidly as
divided doses [102–104] and is well suited for maintenance therapy [105, 106].
Because MMI pills (5 or 10mg) are smaller than PTU tablets (50mg), and
fewer MMI pills are generally need, MMI may be more convenient.
In contrast to oral iodine therapy (see below), thiouracil drugs do not pre-
vent thyroid gland hyperplasia. Thus, thyroid enlargement may occur during
therapy. The thyroid gland may become softer and the outlines of the gland
more difficult to distinguish [99]. Because radioactive iodine is less effective in
large than in small glands [59, 99, 107], thyroid size should be continuously
monitored for progressive thyroid enlargement that may make the patient an
unsuitable candidate for radioactive iodine treatment. If the gland enlarges, this
may also be due to hypothyroidism. Thus, patients should be monitored for TSH
elevations.
Although MMI and PTU promptly inhibit hormone formation, they do not
inhibit hormone release. Thus, levels of circulating thyroid hormones may
remain elevated for several weeks as stored hormone is released. Until circulat-
ing levels of thyroid hormones normalize, the signs and symptoms of hyperthy-
roidism may be controlled with beta-blockers such as atenolol (25 or 50 mg,
QD or BID) or propranolol (2.5–10 mg b.i.d. or t.i.d.). If the child has reactive
airway disease, beta-blocker therapy may trigger acute exacerbations of asthma.
In this setting we have had success using metoprolol, which is a cardiac-selective
beta-blocker.
Thyrotoxicosis can be controlled more quickly than with thionamides
using solutions of saturated potassium iodine (SSKI or Lugol’s solution; 1–3
drops t.i.d.) which blocks the release of stored hormones. Side effects of iodine
are uncommon and include acneiform eruptions, fever, coryza, and salivation
[99]. Severe and fatal allergic reactions to iodine have also been observed [99].

Rivkees 182
When combined thionamide and iodine therapy is used, PTU or MMI should be
given a few hours before iodine to prevent iodine-induced increases in thyroid
hormone synthesis [99].
After initiation of treatment with PTU or MMI, maximal clinical responses
are seen after 4–6 weeks, at which time biochemical hypothyroidism develops.
The thionamide dose can then be reduced 30–50%. To achieve a euthyroid state,
the dose of MMI or PTU can either be reduced further, or supplementation with
L-thyroxine started.
Complications of PTU and MMI
An apparent difference between the adult and pediatric populations is the
higher incidence of adverse side effects of antithyroid medications in the
young. Published studies including 500 children [6, 13, 59, 108, 109], show that
complications of drug therapy include increases in liver enzymes (28%) and
leukopenia (25%). Up to 0.5% of propylthiouracil (PTU) or methimazole
(MMI)-treated children will develop serious complications [6, 10]. By 1998, 36
serious adverse events and two deaths from liver failure (from PTU) due to
antithyroid drug therapy of childhood Graves’ disease had been reported to the
FDA MedWatch Program, which is very prone to under reporting [6]. In addi-
tion, at least five other deaths related to antithyroid medication therapy in chil-
dren have been reported to me by professionals. Other rare and serious adverse
effects of thionamide drugs include periarteritis nodosa, other forms of vasculi-
tis, nephrotic syndrome, hypothrombinemia, and aplastic anemia [6].
Most side effects of antithyroid drugs develop within eight weeks of start-
ing therapy. However, adverse effects may develop later. Parents should be
instructed to contact their physician promptly if fever, sore throat, oral ulcera-
tion, rash, joint pain, nausea, abdominal pain, or any other unusual symptoms
develop, and stop medical therapy.
When an adverse event related to either PTU or MMI occurs, some phy-
sicians will switch to another thionamide. Published data about the risks
of changing to another medication following the occurrence of toxic reactions
in children are limited [16]. Thus, faced with major or minor side effects in
up to 20% of patients in the midst of a course of drug therapy, physicians
will be faced with either electing for definitive therapy or an alternative
medication.
Serious side effects of antithyroid drugs often develop within the f irst few
months of therapy onset; however, adverse effects may develop after several
years of antithyroid therapy. Increasing reports describe the development of
anti-neutrophil-cytoplasmic antibodies (ANCAs) with prolonged medical ther-
apy of Graves’ disease [110–112], which are associated with vasculitis. In
adults, up to 15% of individuals treated with PTU, develop ANCAs after 2 years

Graves’ Disease in Children 183
of therapy [110, 111]. MMI use is associated with the occurrence of ANCAs,
albeit with a lower incidence than PTU [110, 111]. In the pediatric population,
ANCA-mediated disease has been observed in patients treated with PTU or
MMI [113, 114]. Because these antibodies can trigger serious vasculitis events,
elimination of the trigger of ANCA induction, i.e. antithyroid medications,
must be considered [115].
Long-Term Efficacy of Antithyroid Drugs
In children, published remission rates after several years of drug therapy
are usually less than 25% [13, 59, 67, 95, 116–118]. It has been suggested that
after 2 years of treatment remission rates are 25%, that 4 years of drug therapy
are needed to achieve 50% remission rates [109], and that 10 years of drug ther-
apy can achieve remission in 75% of children [109]. However, although widely
cited, these theoretical projections have not been substantiated. The most exten-
sive long-term study of this issue involving near 200 children with Graves’ dis-
ease shows that less than 20% of children treated medically achieve remission
lasting greater than 2 years [13]. When responses to medical therapy between
prepubertal and pubertal children are compared, 1 year remission rates are also
less in prepubertal than in pubertal children [15, 16].
The efficacies of antithyroid drugs appear to be inversely related to serum
levels of thyroid-stimulating antibodies (TSAb) or thyrotropin receptor anti-
bodies (TRAbs) [119–123]. After several years of antithyroid therapy, remis-
sion rates in adults range from 15% in individuals with high levels of TRAb at
the time of diagnosis, to 50% in individuals with low pretreatment TRAb levels
[119]. In our experience, if remission occurs with medical therapy (about 15%
of our patients; n 30 patients), it is in the setting of patient with a small thy-
roid gland (20 g) and low levels of TRAbs (110% of control).
It has been suggested that long-term remission rates can be predicted
by observing responses to short-term (ca. 6 months) antithyroid drug therapy
[17, 124, 125]. Short-term therapy appears to work as well as long-term therapy
in patients with mild hyperthyroidism and small goiters, but neither short- nor
long-term antithyroid drug therapy is likely to lead to a lasting remission in
patients with severe thyrotoxicosis and a large goiter [17, 124, 125]. Although
most of the evidence supports the efficacy of short term therapy, some investi-
gators have noted higher relapse rates after short-term than long-term treatment
[126, 127].
Risks of Cancer after Drug Therapy
Antithyroid drugs are preferred to radioactive iodine therapy by many clin-
icians based on the assumption that cancer risk is less after drug therapy than
after radioactive iodine. However, data do not support that this assumption.

Rivkees 184
The largest long-term follow-up study of thyroid cancer risks after treat-
ment of Graves’ disease by the (CTSG), revealed that the incidence of thyroid
carcinomas over 10–20 years of follow-up (not lifetime incidence) is fivefold
higher in adults with Graves’ disease treated with thionamide drugs (follow-up
period normalized incidence rate 1 case per 332 individuals) than in patients
treated with 131I (1/1,783), and eightfold higher than in patients treated surgically
(1/2,820) [77]. The incidence of thyroid adenomas are also 10 and 20 times
higher among the adults treated with antithyroid drugs (1/76) than in patients
treated with 131I (1/802) or surgery (1/1,692), respectively [77]. Rather than
reflecting a causative role for medical therapy in the pathogenesis of thyroid neo-
plasia, these observations may reflect the persistence of more thyroid tissue in
patients treated with drugs than in individuals treated with radioactive iodine or
surgery.
Although CTSG data show an increased rate of thyroid cancer in the drug-
treated patients [77], it is important to note that thyroid cancer mortality rates
were not increased in the CTSG patients treated with drugs [84]. We are also
unaware of thyroid cancer cases in the large numbers of children treated with
antithyroid drugs alone.
Treatment Approaches for Children
Based on what is now known about the risks and benefits of different
treatments and the pathogenesis of Graves’ disease, we can now be more
selective in our approach to therapy. To reduce treatment risks and expe-
dite cures, the treatment of the child or adolescent with Graves’ disease can
be guided by the patient’s age and the nature of the intrinsic autoimmune
disease.
For children less than 5 years of age, we consider antithyroid medi-
cations as a first line therapy. Although radioactive iodine has also been
successfully used in this age group without an apparent increase in cancer
rates, it may be best to defer radioactive iodine therapy because of the possible
increased risks of thyroid cancer after radiation exposure in very young
children in the event that any thyroid tissue remains after radioactive iodine
therapy.
Because young children are less likely to have remission than older chil-
dren on drug treatment [15, 16], prolonged drug therapy may be needed. If there
are no toxic effects, continuing antithyroid drugs is reasonable until the child is
considered old enough for radioactive iodine therapy. Alternatively, thyroidec-
tomy or ablative radioactive iodine therapy can be considered if reactions to
medications develop or there is the desire to avoid prolonged drug use.

Graves’ Disease in Children 185
Fortunately, less than 5% of children with Graves’ disease present at 5 years of
age or younger [8].
Fifteen percent of children with Graves’disease will present between 6 and
10 years of age [8]. Considering drug therapy as a first-line measure for this age
group is reasonable. Yet, as 10 years of age are approached, either radioactive
iodine or drug therapy can be considered as initial therapy, as the risks of thy-
roid cancer in remaining irradiated thyroid tissue is expected to be less at 10
than at 5 years and there will be lower whole-body radionuclide exposure at 10
than at 5 years.
Children 10 years of age and older account for 80% of the pediatric cases
of Graves’ disease. For this age group, radioactive iodine or antithyroid drugs
can be considered as f irst-line treatment options. In determining if drug therapy
is likely to be successful, TRAb levels and thyroid size may be predictive of
remission rates. The presence of low TRAb levels and a small thyroid suggests
the possibility of remission on medical therapy. Yet, if TRAb levels are high and
the thyroid is large, the odds of spontaneous remission are low [119, 121, 123].
However, TRAb levels and thyroid size may not always be indicative of remission
likelihood.
The critical issue about drug therapy is whether a lasting cure can be
achieved after using medications to palliate the hyperthyroid state. Thus, for
patients with normal TRAb levels and a small thyroid size, it seems reasonable
for to treat for 6–12 months and stop the drug when a clinical remission has
been achieved. If a relapse occurs, medical treatment can be resumed or an
alternative form of therapy chosen. For patients with elevated TRAb levels and
a large thyroid, it is much less likely that remission will occurs after short-term
or long-term medical therapy, and consideration should be given to definitive
treatment after euthyroidism is achieved.
When radioactive iodine is used, it is important that higher doses of 131I be
used in children. The goal of radioactive iodine therapy in children should be to
ablate thyroid gland and achieve hypothyroidism. If no thyroid tissue remains,
the risk of thyroid cancer will be very small if present at all. To achieve this goal
we now use doses of 131I of 250–300 Ci/g thyroid tissue.
Finally, irrespective of the treatment option selected, careful follow-up is
needed for all patients treated for Graves’ disease. Long-term follow-up should
include regular examination of the thyroid gland and measurement of circulat-
ing levels of thyroid hormones once or twice a year. All newly appearing
thyroid nodules should be biopsied or excised.
Choosing a treatment approach for childhood Graves’ disease is often a
difficult and highly personal decision. Discussion of the advantages and risks of
each therapeutic option by the physician is essential to help the patient and fam-
ily select a treatment option (table 2).

Rivkees 186
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Medical Surgery Radioactive iodine
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Minor side effects 20–30% 100% pain 5% pain
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arthralgia hypocalcemia
leukopenia
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severe hepatitis paresis
agranolocytosis 1–5%
hypoparathyroidism
Reported mortality 13 children 1/1,000 children none
Long-term thyroid cancer risks 0.3% 0.03% 0.05%

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Scott A. Rivkees, MD
Yale Pediatric Thyroid Center, Department of Pediatrics
Yale University School of Medicine
PO 208081
New Haven, CT 06520 (USA)
Tel. 1 203 737 5975, Fax 1 203 737 5972, E-Mail Scott.Rivkees@Yale.edu

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 192–209
Thyroid-Associated Ophthalmopathy in
Juvenile Graves’ Disease: Clinical,
Endocrine and Therapeutic Aspects
Gerasimos E. Krassas, Apostolos Gogakos
Department of Endocrinology, Diabetes and Metabolism,
Panagia General Hospital, Thessaloniki, Greece
Thyroid-associated ophthalmopathy or Graves’ ophthalmopathy (GO), or
thyroid eye disease (TED) refers to the eye changes observed in Graves’ disease
(GD). The orbital involvement is characterized by lymphocytic inf iltration and
edema of the retrobulbar tissues, resulting in marked swelling of extraocular mus-
cles and orbital fat. Due to the increased volume or orbital contents the retrobul-
bar pressure rises, interfering with venous drainage (causing lid swelling) and
pushing the globe forwards (causing proptosis or exophthalmos) [1, 2]. In severe
cases, direct pressure on the optic nerve may result in loss of visual functions. The
swelling of eye muscles hampers muscle motility, associated with double vision.
The clinical manifestations of GO can thus be understood from a mechanistic
point of view. However, the immunopathogenesis of GO remains largely
unknown despite considerable progress made in this field in the last decade [3]. In
this communication we review the pediatric aspects of GO and provide the latest
information regarding the therapeutic approach of this disease.
Immunopathogenesis of Thyroid Eye Disease
The orbital fibroblasts are widely viewed as the target cells of the autoim-
mune attack in GO. During the early stages of the disease, macrophages, highly
specialized T cells, mast cells, and occasional plasma cells infiltrate the orbital
connective, adipose, and muscle tissues [4, 5]. Activation of T cells directed
against a thyroid follicular cell antigen(s) that then recognizes and binds to
a similar antigen(s) in orbital tissue is a probable but yet unproven theory [2].

Pediatric Thyroid Ophthalmopathy 193
Alternatively, macrophages and dendritic cells may nonspecifically initiate the
orbital immune response, which is then propagated by recruitment of sensitized
T cells. Several cytokines have been associated with the evolution of the orbital
tissue changes in TED [6, 7]. These include interferon-[8], tumor necrosis
factor-, interleukin-1 (IL-1), and transforming growth factor- [9] as well as
other growth factors such as insulin-like growth factor-I (IGF-I) [10, 11] and
platelet-derived growth factor [12, 13]. These compounds are now known to
be produced both by infiltrating immunocompetent cells and by residential
fibroblasts, adipocytes, myocytes, and microvascular endothelial cells. These
cytokines and growth factors stimulate cell proliferation, glycosaminoglycan
(GAG) synthesis, and expression of immunomodulatory molecules in orbital
fibroblasts and microvascular endothelial cells [13–15]. An increase in connec-
tive tissue and extraocular muscle volume within the bony orbits caused by
accumulating hydrophilic compounds (predominantly GAG, the hydrophilic
nature of which can attract water by osmosis) leads to the clinical manifest-
ations of TED and causes proptosis, extraocular muscle dysfunction, and peri-
orbital edema [1, 2].
The orbital fibroblasts do express functional TSH receptors (TSH-R). This
recent finding has led to the currently favored view that the TSH-R is the
long sought after shared antigen between the thyroid and the orbit and that the
TSH-R is the autoantigen involved in GO. Indeed, cytokine-induced differenti-
ation of a particular subset of orbital fibroblasts into adipocytes is associated
with increased TSH-R expression and adipogenesis [16].
Furthermore, TSH-R immunization of experimental animals results in his-
tological changes in orbital tissues resembling GO [17].
A causative role of stimulating TSH-R antibodies (TSI) in the develop-
ment of GO is very attractive as it allows a unifying hypothesis for the various
clinical manifestations of GD: Graves’ hyperthyroidism (GH), GO and thyroid
dermopathy. Arguments against such a hypothesis cannot, however, be dis-
missed. TSI, in contrast to T cells, cross the placenta and may cause fetal and
neonatal hyperthyroidism. GO, however, has never been observed in neonatal
thyrotoxicosis TSI are almost always present in GH, but clinically apparent GO
develops only in a subset of the patients. Lastly, serum TSI are only slightly
related to the severity of GO, although more so to the activity of the eye dis-
ease [18]. Whereas TSI might contribute to further progression of GO, it
remains doubtful if TSI act as the primary mediator in the immunopathogene-
sis of GO.
Consequently, the search for other antigens and antibodies involved in GO
continues. Graves’ IgG added to a culture of human skin fibroblasts increased
the synthesis of collagen. The effect was not mimicked by TSH and rather
specific for GO as IgG of Graves’ hyperthyroid patients without GO were not

Krassas/Gogakos 194
active in this respect [19]. Another study demonstrated that Graves’ IgG was
able to induce the release of T-cell chemoattractants from cultured orbital
fibrobasts, notably IL-16 (a CDligand that activates T cells) and RANTES
(a C-C type chemokine) [20]. The authors postulated IgG binding to a surface
receptor of the fibroblasts distinct from the TSH-R, because TSH had no effect
and there was no relation with TSH-R antibodies. The induction of IL-16 and
RANTES could be blocked by rapamycin and the authors speculated the sur-
face receptor could be the IGF-I receptor as IGF-I post-receptor signaling is
also blocked by rapamycin.
Several antibody markers of immune-mediated damage to eye muscle have
also been identified and the great majority of patients with active ophthalmopa-
thy have antibodies against one or more eye muscle antigens. However, none of
the target antigens are localized exclusively in the eye muscle and all are intra-
cellular, indicating that their exposure to the immune system would be a conse-
quence of eye muscle fiber damage rather than its cause [21].
Activity and Severity of TED
The majority of Graves’ patients have a mild and nonprogressive ocular
involvement that does not require any specif ic or aggressive treatment, also
because non-severe GO often tends to improve spontaneously. When evaluating
a patient with TED, two basic questions have to be addressed. First, does the
patient needs treatment for TED and, in a positive answer, which kind of treat-
ment is indicated.
The decision of whether ophthalmopathy must be treated should rely on
the assessment of two different parameters, the activity and severity of the dis-
ease. The activity of the disease is neither synonymous nor coincident with the
severity of the disease. In other words, an individual patient may have severe
ocular manifestations but the disease may be inactive (fig. 1). To assess the
activity of ophthalmopathy, Mourits et al. [22] proposed a clinical activity score
(CAS), which in its original formulation included 10 different items (table 1)
mainly, but not solely, reflecting inflammatory changes: giving one point to
each manifestation, a score is obtained, with a range from 0 (no activity) to 10
(highest activity). A slightly modified CAS which does not include some of the
items originally proposed by Mourits et al. [22] was proposed by an ad hoc
committee of the four thyroid societies as a tool to record ocular changes over
time after treatment of ophthalmopathy [23] (table 1). Definition of severity of
GO is somehow arbitrary (table 2). Undoubtedly, optic neuropathy which can
be subclinical and heralded only by changes in the visual evoked potentials,
depicts per se a situation that can be sight threatening, especially if it is associated

Pediatric Thyroid Ophthalmopathy 195
with an evident reduction of visual acuity. It has to be remembered that
immunosuppression treatment is effective only in patients with active disease.
Juvenile Graves’Ophthalmopathy. Incidence and Symptomatology
The most accurate data on the incidence of GO is derived from a population-
based cohort study in Olmsted County, Minn., USA [24]. The overall age-adjusted
incidence rate was 16.0 cases for women and 2.9 cases for men per 100,000
population per year. Peak incidence rates were observed in the age groups
Fig. 1. Hypothetical relationship between disease activity and severity in the natural
history of TED [60].
Disease
activity
A
0
50
100
%
B Time
Disease
severity
Table 1. Clinical activity score
Original formulation [22] Revised formulation [23]
Painful, oppressive feeling on or behind the globe spontaneous retrobulbar pain
Pain on attempted up, side, or down gaze pain on eye movements
Redness of the eyelids eyelid erythema
Diffuse redness of the conjuctiva conjuctival injection
Chemosis chemosis
Swollen caruncle swelling of the caruncle
Edema of the eyelids eyelid edema or fullness
Increase of 2 mm or more in proptosis in the last 1–3 months
Decrease in visual acuity in the last 1–3 months
Decrease in eye movements of 5 degrees or more in the last 1–3 months

Krassas/Gogakos 196
40–49 and 60–69 years. The incidence rates start to increase as of the age of
20 years. Below the age of 20 years the occurrence of GO is a rare event.
Incidence rates (cases per 100,000 population per year) are in the age groups
5–9, 10–14, and 15–19 years for females 3.5, 1.8 and 3.3, respectively, and for
males 0, 1.7 and 0, respectively. Only 6 of the 120 incident cases of GO
observed in this cohort study were below the age of 20 years. A more detailed
study published recently from the same department found that of 1,662 cases
ages 18 years, with thyroid-related abnormalities, evaluated at the Mayo
Clinic in Rochester, Minn., USA, during the 15-year interval (1985 to 1999),
35 children with GO were identified. Of these, 6 had received radioactive iodine
(RAI), 1 patient had RAI plus antithyroid drugs, 9 had partial or total thy-
roidectomy, and the rest antithyroid medications for their thyroid problem. Four
patients did not require treatment. Of the 35 children with GO, 31 required no
therapy with only supportive measures, 1 had eyelid surgery, and 3 had orbital
decompression. None of the patients received steroids or external radiotherapy.
They concluded that although the pediatric population has similar clinical mani-
festations of GO to adults, the disorder is less severe in children [25]. The low
incidence of childhood GO might be related to the low incidence of Graves’
disease during childhood. To analyze this further, we compared the prevalence
Table 2. Assessment of severity of Graves’ ophthalmopathy
Degree of involvement Parameter
proptosisadiplopiaboptic neuropathy
Mild 19–20 intermittent subclinicalc
Moderate 21–23 inconstant visual acuity 8/10–5/10
Marked 23 constant visual acuity 5/10
Severe ophthalmopathy: at least one marked, or two moderate, or one moderate and two
mild manifestationsd
aProptosis by exophthalmometer readings or CT/MRI measurements. Median normal value
in our Italian population is 15 mm. Normal values show racial variation; accordingly, abnor-
mal values should be considered those 4 mm or more above the respective median value.
bDiplopia: intermittent, present only when fatigued; inconstant, present in secondary posi-
tions of gaze; constant, present in primary and reading positions.
cAbnormal visual-evoked potentials or other tests, with normal or slightly reduced (9/10)
visual acuity.
dPatients with severe GO will need either medical or surgical treatment depending on the
activity of eye disease.
Reproduced from Bartalena et al. [61].

Pediatric Thyroid Ophthalmopathy 197
of clinically apparent GO in young or adult consecutive patients with GH. Lid
retraction by itself did not qualify for the diagnosis of GO, as this sign can be
attributed to the hyperthyroid state, disappearing spontaneously once the euthy-
roid state has been reached. GO was present in 42 of 182 (23%) patients with
childhood GH [26–29] and in 118 of 1,050 (18%) adult patients with GH
[30–33]. It follows that children have about the same risk (or slightly increased)
as adults to develop GO once they have contracted Graves’ hyperthyroidism.
The severity of childhood GO appears to be less than that of adulthood
GO. This is evident from a comparison of the relative frequency of the various
eye changes between children and adults with GO. Taking together the 42 child-
hood GO cases from the four studies published so far [26–29] and contrasting
then with 152 new consecutively referred adult GO patients [34], it is clear that
soft tissue involvement and proptosis are the predominant changes in childhood
GO whereas the more severe manifestations of restricted eye muscle motility and
optic nerve dysfunction almost never occur in children (table 3). Remarkable
is the high frequency of corneal involvement in children. This was, however,
limited to punctate epithelial erosions and all cases originated from one study
on Chinese children [29], whereas corneal involvement was absent in the three
other studies on childhood GO [26–28].
Very recently, we embarked on a questionnaire study among members of
the European Society for Paediatric Endocrinology (ESPE) and the European
Thyroid Association (ETA) with the following specific aims. First, we wanted
to know the proportion of GO cases among patients with Graves’ hyperthy-
roidism in the age group of 18 years and younger. Second, we were curious
whether childhood GO could be related to smoking prevalence. Third, we
wanted to record the diagnostic and therapeutic approaches to a standard case
(and some variants) of a 13-year-old girl with Graves’ hyperthyroidism and
Table 3. Relative frequencies (%) of eye changes in patients with
Graves’ ophthalmopathy with onset in childhood or adulthood
Childhood Adulthood
onset [26–29] onset [34]
(n 42) (n 152)
Soft tissue involvement 48 75
Proptosis 36 63
Extraocular muscle involvement 2 49
Corneal involvement 26 16
Optic nerve involvement 0 21

Krassas/Gogakos 198
moderately severe active GO [35]. The study design allowed evaluating any dif-
ferences in approaches between pediatricians and endocrinologists.
For this purpose, questionnaires were sent between November 2004 and
January 2005 to approximately 300 members of ESPE and ETA who had an
electronic address. The questionnaire contained three general questions and a
standard case of a 13-year-old girl with Graves’ hyperthyroidism and moder-
ately severe active GO (table 4) [35].
Physicians were asked to outline their diagnostic and therapeutic approaches
to the standard case according to a list of given biochemical thyroid-function
tests, imaging techniques, specific eye investigations and various therapeutic
options. Five variants of the standard case were presented, and physicians were
asked whether case variants would change their therapeutic approach chosen
for the standard case.
Table 4. The childhood Graves’ ophthalmopathy questionnaire (reproduced from
Krassas et al. [35])
General questions
(1) How many cases of childhood Graves’ ophthalmopathy (patients up to 10 years old in
prepubertal stage) have been seen in your institution in the last 10 years and how many
among adolescents (11–18 years old)?
(2) How many cases of Graves’ hyperthyroidism (up to 18 years old) have been seen in
your institution in the last 10 years?
(3) Is there an official figure on the percentage of smokers among teenagers in your country?
Standard case
A 13-year-old Caucasian girl developed over the last 6 months lack of ability to concentrate
in school, failure in school, weight loss and nervousness. Pulse rate of 120/min, diffuse
goiter around 30 g, and signs of moderately severe and active thyroid ophthalmopathy.
Specifically, she had moderately severe eyelid swelling, some chemosis and redness of
the eyes, but not caruncle swelling, no pain behind the eyes and no redness of the eyelids.
Exophthalmometer reading was 21 mm for both eyes. She also had impairment of
elevation for both eyes with inconstant diplopia. She is not a smoker.
(1) What is your diagnostic approach?
(2) What is your therapeutic approach?
Case variants
Is your therapeutic approach to the standard case changed in case of:
(1) Slight worsening of GO after 4 months
(2) Age of 7 years
(3) Age of 15 years, recurrent hyperthyroidism after a course of antithyroid drugs, still active GO
(4) Age of 15 years, euthyroid, active GO
(5) Driving problems, because of mild diplopia

Pediatric Thyroid Ophthalmopathy 199
119 questionnaires were returned but 52 respondents indicated they had no
experience with the treatment of Graves’ disease in childhood. The analysis was
thus restricted to 67 returned and completed questionnaires, originating from 23
ESPE members (called paediatricians) and 44 ETA members (called endocrinolo-
gists). It should be noted that the ETA membership list does not discriminate
between basic scientists and clinicians, so in reality the response rate was much
higher. Respondents came from 25 countries, predominantly from Europe but also
included one from Brazil, three from the USA and two from Japan. Leaving out
the results from these six respondents from outside Europe did not make any real
difference in the overall results. A total of 1,963 patients with juvenile Graves’
hyperthyroidism had been encountered by respondents over the last 10 years; on
average 4.6 cases per year by each pediatrician and 2.3 cases per year by each
internist. One-third of the patients with Graves’ hyperthyroidism had GO. Among
the patients with GO, one-third were 10 years old (77% of them being seen by
pediatricians) and two-thirds were in the age group of 11–18 years (56% of them
being seen by pediatricians). The answers of respondents with regard to smoking
prevalence among teenagers in their country were incomplete and mostly based
educated guesswork. Therefore, we grouped countries of respondents according to
smoking prevalence among teenagers as given by official data from the World
Health Organization [WHO; regional office for Europe, tobacco control database,
2003]. A higher prevalence of smoking was associated with a higher frequency of
GO among juvenile patients with Graves’ hyperthyroidism (p 0.0001 by 2
test). Whereas in countries with a smoking prevalence among teenagers of 25%
the distribution of GO cases was 36.6% (236 cases), in countries with a smoking
prevalence of 20% the distribution was 25.9% (117 cases; table 5) [35].
Regarding the diagnostic approaches to the standard case, on average, five
biochemical thyroid function tests were requested by respondents, paediatri-
cians asking one test more than internists (5.6 compared with 4.6, p 0.005).
Thyroid-stimulating hormone (TSH), free thyroxine (FT4) and TSHR-Ab were
almost universally ordered, and thyroperoxidase antibodies (TPO-Ab) and FT3
by about 60%. Thyroid imaging was requested by 56 of 67 respondents (84%),
with ultrasound by 46 and with scan by 10. Orbital imaging was asked by 59 of
67 respondents (88%), with magnetic resonance imaging or computed tomog-
raphy by 42, with ultrasound by 14 and with octreoscan by 3. The preferred
treatment of Graves’ hyperthyroidism of the standard case was clearly antithy-
roid drugs, chosen by 94% of respondents. A wait-and-see policy was recom-
mended for the co-existing GO of the standard case by 70%, and corticosteroids
by 28%. The therapeutic approach did not differ between paediatricians and
internists. With regard to the therapeutic approach of case variants, a younger
age of 7 years did not affect management very much. Antithyroid drugs were
still the treatment of choice (66%) for recurrent hyperthyroidism, whereas

Krassas/Gogakos 200
131I therapy was now chosen by 25% and thyroidectomy by 9%. Worsening of
GO after 4 months or still-active GO when euthyroid was viewed by 68 and
63% of respondents, respectively, as an indication to start specific eye treat-
ment, mainly with steroids. In case of driving problems, 36.5% recommended
eye muscle surgery and 21% prisms. One respondent remarked that diplopia in
his experience is never seen in childhood GO [35].
From all the above data it is clear that the incidence of ophthalmopathy in
childhood GD is more or less the same as in adults. However, it is less severe and
more likely to remit completely [26–29, 34]. The question then arises why child-
hood GO is less severe. The female preponderance is similar between children
and adults with GH (87 and 83%, respectively), but the prevalence of smoking is
much lower in children than in adults (4 and 47%, respectively) [29, 35].
Smoking is a risk factor for GO, and the odds increase significantly with
increasing severity of GO [36]. One study observes that the manifestations of
GO begin to resemble more closely the adult f indings when adolescence
approaches [26]; conceivably this could be explained by increasing smoking
prevalence with age.
Our recent study [35] supports the above data and provides a very interesting
clue: the difference might be caused by exposure to tobacco smoke. Specifically,
of 1,914 patients with childhood GH seen by respondents 576 (30%) had GO.
When grouped according to smoking prevalence among teenagers in the country
of origin, it became evident that the proportion of GO patients among children
Table 5. Occurrence of childhood Graves’ ophthalmopathy in Graves’hyperthyroidism
as a function of smoking prevalence among teenagers in their country of origin (reproduced
from Krassas et al. [37])
Smoking prevalence Graves’ Graves’ Graves’ ophthalmopathy
among teenagers hyperthyroidism ophthalmopathy
(%) (%) (%) 10 years 11–18 years
(%) (%)
25a644 (100) 236 (36.6) 52 48
20–25b818 (100) 223 (27.3) 15 85
20c452 (100) 117 (25.9) 24 76
Data per country based on WHO regional office for Europe, tobacco control database,
2003. Internet: http://data.euro.WHO.int/tobacco
aTurkey, Bulgaria, Germany, Czech Republic, Spain, Hungary, France.
bSwitzerland, UK, The Netherlands, Romania, Belgium, Canada, Russia, Portugal, Poland.
cDenmark, Italy, Serbia, Sweden, USA, Brazil, Greece.

Pediatric Thyroid Ophthalmopathy 201
with GH is highest in countries in which teenagers smoke most (table 5). What is
striking is that 52% of the children with GO in these countries (smoking preva-
lence 25%) are 10 years old or younger, whereas the figure (19%) is much lower
in countries in which smoking prevalence among teenagers is less than 25%. It is
unlikely that children 10 years of age smoke themselves; the high proportion of
GO in this group is thus best explained by passive smoking as a result of living in
an environment in which 25% or more of their peers smoke. It is of interest that,
based on the WHO regional office for Europe, tobacco control database, 2003, all
the countries (100%) that are included in the first group have a smoking preva-
lence higher than 25% among adults, while only 50 and 40% of the countries in
the second and third groups exhibit such a prevalence (table 5) [37].
The conclusion is that passive smoking may also have a deleterious effect
on childhood GO [37].
Treatment of Thyroid Eye Disease in Childhood
Corticosteroids
As the expectation remains that the expression of GO in children is, in most
instances, both mild and transient most of the physicians who are dealing with
such cases prefer the ‘wait-and-see’ policy. Indeed, in our recent study [35] 70%
of the respondents recommended such a policy for the eye changes. Active inter-
vention (predominantly with steroids) is considered appropriate in case of wors-
ening of eye changes or no improvement of eye changes when the patient has
become euthyroid [35]. Doses between 5 and 20 mg prednisone daily are used
depending on the severity of the case. Our policy in moderately severe cases is to
start with 20 mg daily for 4–6 weeks when usually a beneficial effect is expected
and then we tapering the dose accordingly. We are reluctant to use higher doses
of glucocorticoids (GC) as well as intravenous glucocorticosteroids. It has to be
kept in mind that prolonged prednisone administration, which should be used in
some severe cases of TED, is associated with weight gain, immune suppression
and growth failure in children [38]. Retrobulbar irradiation, which has been
proved beneficial in adult cases with TED [2], has no place in the treatment of
juvenile GO in view of the theoretical risk of tumor induction [3].
One important issue is the use of steroids in patients with TED who received
radioiodine treatment (RAI) for hyperthyroidism. Two randomized, prospective,
controlled clinical trials by Tallstedt et al. [33] and Bartalena et al. [39] clearly
demonstrated in adults that radioiodine administration may be associated with a
progression of ophthalmopathy in a small proportion of patients (⬇15%). GC can
prevent, at relatively low doses and for short periods of time, exacerbation of eye
disease and can effectively cure pre-existing ocular manifestations.

Krassas/Gogakos 202
Recently, Perros et al. [40] showed that RAI is not associated with deterio-
ration of TED in patients with minimally active eye disease when post radioio-
dine hypothyroidism is prevented. The message from all relevant studies
published so far is that RAI in adults can cause TED progression in a certain
proportion of Graves’ patients [41]. Patients who smoke or have active
(although mild to moderate) TED or severe hyperthyroidism are good candi-
dates for receiving GC coverage. Unfortunately, similar data are not available
for adolescents for two main reasons. First, RAI as treatment of hyperthy-
roidism in the pediatric age is unpopular in Europe and some other continents
and second the incidence of GO during childhood is low which might be related
to the low incidence of GD during childhood.
Somatostatin Receptors in Retrobulbar Tissues
Somatostatin and somatostatin receptor gene transcripts can be detected in pri-
mary cultures of fibroblasts obtained from retrobulbar connective tissue samples of
Graves’ ophthalmopathy and controls patients (table 6). Somatostatin receptor sub-
types 2 and 3 were present in GO and control fibroblasts, but sst1 and SST5 only in
GO f ibroblasts. Somatostatin-14 and octreotide inhibited the binding of radiola-
beled somatostatin-14 with half-maximal inhibition of binding (IC50) of
0.80 0.37 and 33.7 33.1 nmol/l respectively in GO fibroblast cultures [42].
Octreotide (107M) significantly decreased forskolin-induced but not basal cAMP
accumulation. It inhibited cell growth and induced apoptosis of the fibroblasts [42].
Lymphocytes recovered from retrobulbar tissues of GO or control patients
also express sst transcripts (table 6). All five sst subtypes were present in GO
lymphocytes, in contrast to control lymphocytes which expressed preferentially
sst3 [43].
The presence of somatostatin receptors in retrobulbar tissues of GO
patients and the inhibitory effects of octreotide on immune functions and
Table 6. Relative abundance of somatostatin receptor mRNA expression in retrobulbar
fibroblasts and lymphocytes obtained from Graves’ ophthalmopathy and control patients
(reproduced from Pasquali et al. [42, 43])
Fibroblasts [42] Lymphocytes [43]
GO (n 10) controls (n 6) GO (n 10) controls (n 2)
sst1  – –
sst2    /
sst3    
sst4 /– /
sst5  ––

Pediatric Thyroid Ophthalmopathy 203
fibroblasts growth and activity provide a sound biologic rationale for the appli-
cation of somatostatin analogues in the diagnosis and treatment of GO.
Orbital Octreoscan for Assessment of Disease Activity
By radiolabeling octreotide, tissues that express somatostatin receptors can
be visualized. By applying [111In-DPTA-D-Phe] octreotide scintigraphy, specif ic
uptake of the radiolabel was observed in the orbits of some but not all patients
with GO [44]. The orbital uptake can be explained from binding of somatostatin
receptors on activated T lymphocytes and fibroblasts in the orbit and from local
blood pooling due to venous stasis. Systemic hypercirculation seems only
partly responsible, as evident from the rather low orbital uptake in Graves’
hyperthyroid patients without GO.
Some but not all studies report a direct relation between orbital octreotide
accumulation and the severity of GO [44–46]. In contrast, the activity of the eye
disease is always found to be related to orbital octreotide uptake. This is evident
from a direct relation between orbital uptake and various parameters of disease
activity in GO like the clinical activity score [44, 46] and the T2 relaxation time of
the inferior rectus muscle on MRI [47]. The lower uptake in patients with inactive
GO is close to that in controls subjects in whom no specific uptake is observed
[45]. A positive orbital octreoscan might thus indicate active GO which – unlike
the inactive end stage of the disease with fibrosis – is susceptible to immunosup-
pressive treatment [48]. Indeed, successful immunosuppression is associated with
a fall in orbital octreotide uptake. Orbital octreoscan could consequently be used to
select those GO patients, who are likely to benefit from immunosuppression [48].
Potential Role of IGF-I
IGF-I immunoreactivity is increased in eye muscle cells, fat cells and retrob-
ulbar inflammatory cells of GO patients [10]. IGF-I stimulates the synthesis of
collagen and glycosaminoglycans by orbital fibroblasts in vitro [49]. Graves IgG
inhibit the binding of radiolabeled IGF-I to orbital fibroblasts in culture, although
without discrimination between IgGs obtained from Graves’ patients with or
without GO [50]. This finding is reminiscent of the inhibition of radiolabeled
TSH to the TSH-R by Graves IgG, suggesting the possibility that there might be
IGF-I receptor stimulating autoantibodies in GD. These findings on IGF-I in GO
have so far not been confirmed by others. In patients with active GO – all euthy-
roid while receiving methimazole treatment – serum concentrations of free and
total IGF-I and IGF-II and of the three IGF binding proteins 1, 2 and 3 were all
similar to those of matched controls [51], thus excluding serum as the origin of
any upregulated IGF-I in orbital tissues of GO patients. The increased IGF levels
in retrobulbar tissues may represent autocrine and/or paracrine activity, in theory
susceptible to reduction by somatostatin analogues [52].

Krassas/Gogakos 204
Therapeutic Approach of TED by using Somatostatin Analogs
Somatostatin (SM), a peptide inhibiting the release of GH, is present and
plays an inhibiting role in the regulation of several organ systems in men
and other species. Various SM analogs (SM-as) have been developed and used in
clinical practice because the short half-life of SM makes it unsuitable for routine
treatment [53]. Recently, it has been shown that SM-as might be of therapeutic
value in the treatment of active TED in adults. However, most of the initial studies
were uncontrolled, not randomized, and included only small number of patients.
We had the opportunity to treat 3 adolescents (2F, 1M) with moderate severe TED
with SM-a aged 14, 15 and 16 years old [54]. All had an increased clinical activ-
ity score (CAS) – 4, 5 and 6, respectively. All were on antithyroid therapy and
euthyroid at the time of the initiation of treatment. They received 20mg octreotide
(sandostatin-LAR) i.m. one injection every 30 days for 4 months. Their ophthal-
mopathy improved substantially and CAS decreased in all patients [54].
Recently, 4 double-blind, randomized, placebo-controlled clinical studies
were published. In the first [55], 50 euthyroid patients (11 males, 39 females, age
22–74 years, median 50 years) with active TED (clinical activity score [CAS] 3,
NOSPECS 2a–5a, of median duration 0.9 years) received either 30 g LAR or
placebo every 4 weeks for 16 weeks. Both groups then received 30 g LAR for
weeks 16–32 and were followed-up without treatment for a further 24 weeks.
Objective assessments included all individual parameters of TED, CAS, and
derived scores for soft tissue inflammation (STI) and ophthalmopathy index (OI).
During weeks 0–16 there was significant reduction in STI, subjective diplopia,
and CAS in LAR treated patients; STI and CAS were also reduced with placebo.
The OI reduced by –1.12 in LAR (p 0.0017) vs. 0.23 in placebo (p 0.33),
giving a barely significant treatment effect by Wilcoxon’s rank sum test
(p 0.043), but analysis of covariance failed to confirm this (p 0.16). During
weeks 16–32 there was no signif icant change in OI in either group. The overall
results (weeks 0–32) showed reduction in STI and CAS in both groups. They con-
cluded that no significant therapeutic effect of octreotide LAR was seen in patients
with moderately severe TED. The improvement in both treated and placebo groups
emphasize that the results of open studies must be viewed with caution.
In the second study of a long-acting SM-a (16 weeks of long-acting release
formulation of octreotide [octreotide-LAR]), which was conducted in 51
patients with mild active TED and aimed in preventing deterioration and
precluding the need for more aggressive therapeutic modalities, such as gluco-
corticoids or radiotherapy, no treatment effect was observed for the primary end
point [56]. The clinical activity score was reduced for patients treated with
octreotide-LAR, but without any signif icant difference with respect to patients
receiving placebo. However, octreotide-LAR significantly reduced proptosis
(as measured by exophthalmometry). This was associated with non-significant

Pediatric Thyroid Ophthalmopathy 205
differences in favor of octreotide-LAR in a series of proptosis-related parame-
ters. These included class III grade, opening of the upper eyelid, the difference
in ocular pressure before primary position and upgaze, and extraocular muscle
involvement. Evaluating the extraocular muscle volume by magnetic resonance
imaging showed a nonsignificant reduction. No significant correlation between
the initial uptake of octreoscan and the response to treatment was observed.
The inference was that in this study, octreotide-LAR did not seem suitable
to mitigate activity in mild TED. However, proptosis, one of the most debilitat-
ing symptoms of TED, was significantly reduced. The sustained effect on prop-
tosis of just 16 weeks of octreotide-LAR treatment is an encouraging
preliminary result in light of the serious lack of therapeutic options for this
condition.
Very recently a third similar study was published, in which lanreotide 20
mg every 2 weeks was used in a randomized fashion. A total of 60 patients were
investigated. The inference was that lanreotide had no effect on CAS in patients
with TED [57]. Finally, in a randomized controlled study from the Endocrinology
Department of the Mayo Clinic, Minn., USA, which has just been published, 29
patients with moderately severe TED were investigated and a signif icant
improvement in clinical activity score and lid fissure width in patients who
received sandostatin LAR 20 mg was found [58].
Future Perspectives of Somatostatin Analogs
One may raise the question why the efficacy of long-acting SM-a is not so
strong, given the well established biologic rationale for this therapeutic modality
in GO. One of the answers might be that octreotide and lanreotide have a high
affinity only for sst2, a low affinity for sst3 and sst5 and an almost absent affin-
ity for sst1 and sst4 (table 6) [59]. This is unfortunate in view of the expression
of all five subtypes of the somatostatin receptors in retrobulbar f ibroblasts and
lymphocytes of GO patients. The newly developed SM-a SOM 230 has, in con-
trast, a rather high affinity for all sst subtypes except sst4 (table 6) [59]. It is thus
plausible to assume that SOM230 might be much more effective in the treatment
of GO. If so, this might be especially relevant for the treatment of GO in chil-
dren, in whom one might be reluctant to administer high doses of glucocorti-
coids (in view of the adverse effects of longitudinal bone growth) or retrobulbar
irradiation (in view of the theoretical risk of tumor induction).
Conclusions
Children have about the same risk (or slightly increased) as adults to
develop GO once they have contracted Graves’ hyperthyroidism. The severity of

Krassas/Gogakos 206
childhood GO appears to be less than that of adulthood GO. The female prepon-
derate is similar between children and adults with GH (87 and 83%, respec-
tively), but the prevalence of smoking is much lower in children than in adults (4
and 47%, respectively). Smoking is a risk factor for GO, and the odds increase
significantly with increasing severity of GO. It has also been shown that the
manifestation of GO begin to resemble more closely the adult findings when
adolescence approaches. This could be explained by increasing smoking preva-
lence with age. Our recent study supports the above data and provides a very
interesting clue: the difference might be caused by exposure to tobacco smoke.
Regarding treatment of TED in childhood, most physicians who are deal-
ing with such cases prefer the ‘wait-and-see’ policy. Indeed, in our recent study
70% of the respondents recommended such a policy for the eye changes.
Pharmacological intervention, predominantly with steroids is considered
appropriate in case of worsening of eye changes or no improvement of eye
changes when the patient has become euthyroid. Doses between 5 and 20 g
prednisone daily are used depending on the severity of the case. It has to be kept
in mind that prolonged prednisone administration, which should be used in
some severe cases of TED, is associated with weight gain, immune suppression
and growth failure in children. Retrobulbar irradiation has no place in the treat-
ment of juvenile GO in view of the theoretical risk of tumor induction.
SM, a peptide inhibiting the release of GH, is present and plays an inhibit-
ing role in the regulation of several organ systems in men and other species.
Various SM-as have been developed and used in clinical practice because the
short half-life of SM makes it unsuitable for routine treatment. Recently, it has
been shown that SM-as might be of therapeutic value in the treatment of active
TED in adults. However, most of the initial studies were uncontrolled, not
randomized, and included only small number of patients. Very recently four
double-blind, placebo-controlled clinical studies were published, which have
demonstrated only a modest improvement in proptosis and lid fissure width.
However, it is encouraging that some benefit may be derived from SM-as. The
current range of SM-as drugs target two of four somatostatin receptors present
in orbital fibroblast and two of five receptors found in the lymphocytes of TED
patients. Therefore, there is a reason to believe that newer generations of SM-as
that target a wider range of somatostatin receptors may show markedly superior
results in the treatment of TED. SOM230 is a SM-a, that is still being tested,
which targets a greater range of somatostatin receptor seen in TED patients.
Currently, the available assortment of SM-as should be considered in those
patients with persistent proptosis that is unresponsive to other therapies. The
generally mild variety of adverse effects that SM-as elicit indicates that concur-
rent use with other therapies may be palatable from the patients’ perspective,
even though current benefits are small.

Pediatric Thyroid Ophthalmopathy 207
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Prof. G.E. Krassas, MD
Department of Endocrinology, Diabetes and Metabolism
Panagia General Hospital
Tsimiski 92
GR–54622 Thessaloniki (Greece)
Tel. 30 2310479633, Fax 30 2310282476, E-Mail krassas@the.forthnet.gr

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 210–224
Differentiated Thyroid Carcinoma
in Pediatric Age
Wilmar M. Wiersinga
Department of Endocrinology and Metabolism, Academic Medical Center,
University of Amsterdam, Amsterdam, The Netherlands
Epidemiology
Differentiated thyroid carcinoma (papillary and follicular thyroid carci-
noma) is rare during childhood and adolescence. It comprises 90–95% of all
pediatric thyroid cancers; medullary thyroid carcinoma is present in 5–8%, and
undifferentiated anaplastic carcinoma is extremely rare. The annual incidence
of differentiated thyroid carcinoma in children below 16 years of age is between
0.02 and 0.3 cases per 100,000, whereas the annual incidence per 100,000 in
the general population ranges from 1.2 to 2.6 in men and from 2.0 to 3.8 in
women [1]. In large retrospective surveys of differentiated thyroid carcinoma,
72 of 1,500 cases (4.8%) occurred in children of 16 years at the Institut
Gustave-Roussy in Villejuif [2], and 140 of 1,599 cases (8.8%) in children of
19 years at the M.D. Anderson Cancer Center in Houston [3]. Most affected
children are older than 10 years, and the occurrence of differentiated thyroid
cancer below the age of 10 years is exceptional [1, 4]. Although juvenile thyroid
cancer is rare, it accounts for about 35% of all carcinomas in children [5].
In the USA about 350 subjects younger than 20 years are diagnosed with
thyroid carcinoma every year [5].
Differentiated thyroid carcinoma is in general 2–4 times more frequent in
females than in males [1], but the sex difference in frequency is less marked in
children below the age of 10 years [3, 4]. Age-specific incidence rates diverge
for males and females starting at the age of 10 years, and increase substantially
for females from age 13–14 years [5–7].
Over the past 60 years pediatric thyroid cancer incidence has had two dis-
tinct peaks [4]. The first occurred around the mid-20th century and was due to
irradiation of benign conditions like tinea capitis, acne, chronic tonsillitis and

Childhood Differentiated Thyroid Carcinoma 211
thymus enlargement. Thyroid cancer incidence rates decreased when external
neck irradiation for benign conditions was abandoned in view of its recognized
causal relationship [8]. The second peak occurred in the early 1990s caused by
environmental contamination with radioactive iodine from the 1986 Chernobyl
nuclear power plant catastrophe, reaching its maximum in the mid 1990s [9].
Thyroid cancer developed mainly in children ⬍5 years at exposure, with onset
before the age of 14 years. Girls were at greater risk than boys, with a 30-fold
increase of thyroid cancer. Others also observed that children under 5 years of
age at the time of exposure are the most vulnerable to the effects of ionizing
radiation, girls more so than boys [10]. This may be due to age- and sex-related
differences in metabolic activity of the thyroid gland: follicles less than 100 m
in size are presumably active and more prevalent in children 12 years old,
whereas follicles 200 m considered to be hypofunctional are more frequent
in adults up to the age of 40 years [11]. A comparative study on differentiated
thyroid carcinoma among children and adolescents living in either Belarus or
France/Italy demonstrated that the post-Chernobyl thyroid carcinomas in
Belarussian children were less influenced by sex, occurred in younger children,
had greater aggressiveness at presentation, were more frequently papillary, and
were more frequently associated with thyroid autoimmunity than the naturally
occurring thyroid carcinomas in French and Italian children [12].
Thyroid cancer can occur after other childhood malignancies that involve
radiation to the neck region, including tumors of the central nervous system,
acute lymphoblastic leukemia, non-Hodgkin lymphoma, Ewing’s sarcoma and
Wilms’ tumor [13]. The median latent interval between therapeutic irradiation for
childhood malignancy and diagnosis of thyroid cancer is 13 years (range 6–30
years) [14]. Total body irradiation before allogeneic bone-marrow transplantation
carries also a risk for thyroid cancer [15]. The risk of thyroid cancer after child-
hood exposure to thyroid irradiation increases with doses up to 20–29 Gy (odds
ratio 9.8, 95% CI 3.2–34.8) [16]. At dosis 30 Gy a fall in the dose-response rela-
tion is seen, consistent with a cell-killing effect. Both increased and decreased
risks are more pronounced in children diagnosed with a f irst primary malignant
disease before age 10 years than in those older than 10 years.
In approximately 5% of children there is a family history of papillary thy-
roid carcinoma. In some families this is related to adenomatous polyposis or
Cowden’s disease, but in other families there are no associated lesions.
Pathology
Combining three large surveys of differentiated thyroid carcinoma in chil-
dren and adolescents, 107 of the 137 cases had papillary carcinoma (78%) and

Wiersinga 212
30 had follicular carcinoma (22%) [1, 17, 18]; these figures are remarkably
similar to 81% papillary and 19% follicular carcinomas among differentiated
thyroid cancers in the general population [1, 3]. The data do not support a
higher prevalence of papillary thyroid carcinoma in children than in adults, as
stated by some authors [19].
Papillary thyroid carcinomas from children and adolescents contain more
numerous lymphocytes than those from adults: nearly half contain CD4T
helper cells, CD8killer cells or CD19B cells [20, 21]. This may be related
to the more favorable prognosis of differentiated thyroid cancer in children and
adolescents than in adults, in line with the notion that the immune response to
thyroid cancer appears to be important in preventing metastasis and recurrence.
Pediatric papillary thyroid carcinomas with the most numerous proliferating
lymphocytes have indeed the longest disease-free survival [20]. Consistent with
this effect is the greatest risk of recurrence in those pediatric papillary thyroid
carcinomas which intensely express the B7–2 coactivator: B7–2 suppresses T
cell growth by binding to the CTLA-4 receptor on T cells [22].
Differentiated thyroid carcinomas in general have a lower expression of the
sodium iodide symporter (NIS) than normal thyrocytes, but this appears less so
in childhood: NIS expression is absent or subnormal in about 90% of adult
patients, in contrast to undetectable NIS expression in about 60% in patients
⬍20 years of age [11, 23]. The greater NIS expression in juvenile than in adult
cancer implies greater differentiation and radioiodine responsiveness at a
younger age; indeed recurrence risk in young patients is lower in NIS-positive
than in NIS-negative tumors [23].
Tumorigenesis of thyroid carcinomas is explained mainly by two mecha-
nisms: activation of proto-oncogenes (e.g. the RET gene in papillary thyroid
carcinoma) and inactivation of tumour suppressor genes (e.g. p53 and PTEN in
follicular thyroid carcinoma). Pediatric differentiated thyroid carcinoma differs
in many aspects from carcinomas in adults: in children, the cancer has a larger
size and is already more widespread at presentation than in adults (vide infra).
The difference calls for a biologic explanation. RET mutations can initiate pap-
illary thyroid carcinoma, and they occur nearly always already in childhood;
these mutations are less likely to be transmitted to later generations of cells
after puberty in view of the early expiration of the potency of thyrocytes to
divide [4]. Thus the papillary carcinomas with the fastest onset become
detectable in children.
Many studies have looked after molecular-biologic differences between
pediatric and adult thyroid cancers. In papillary thyroid carcinoma, mutations in
RET, NTRK, BRAF (and rarely RAS) activate the MAP kinase cascade, resulting
in increased transcription of growth and proliferation genes and thereby initiating
tumorigenesis. RET rearrangements result from the fusion of the RET tyrosine

Childhood Differentiated Thyroid Carcinoma 213
kinase domain with the N-terminus part of different proteins, creating chimeric
oncogenes with constitutive activity, named RET/PTC. At least 15 different
RET/PTC variants have been described so far involving rearrangements with
10 different genes. A higher frequency of rearrangement of the RET/PTC
oncogenes [24–26] and lower frequency of BRAF mutations [27] have been
observed in childhood than in adult papillary thyroid cancer, but these data have
not been confirmed by others [28, 29]. The higher frequency of RET rearrange-
ments in radiation-induced cancer may be linked to the particular effectiveness
of radiation in causing double-strand breaks (and thereby in gene rearrange-
ments) rather than point mutations [30]. RET-PTC and BRAF mutations are
mutually exclusive in papillary carcinomas, both activating constitutively the
RET/PTC-RAS-BRAF-MAP pathway. Gene expression in post-Chernobyl cancer
is similar to that in sporadic papillary carcinoma as analysed by cDNA and
Affymetric microarrays [30]. Radiation-induced thyroid cancers and sporadic
papillary carcinomas thus most likely represent the same disease. A relationship
between RET and NTRK positive cases and more advanced disease or worse
prognosis is found in some [24] but not all studies [26, 29]. Likewise, increased
expression of the tyrosine kinase receptor cMET and its ligand hepatocyte
growth factor/scatter factor in papillary thyroid carcinoma in children and young
adults is associated with a high risk for metastasis and recurrence [31], but later
studies observed overexpression of MET in the majority of papillary thyroid car-
cinomas [4, 32]. RAS and PPARG are involved in follicular thyroid carcinogene-
sis, and it has been claimed that PPARG rearrangement is more frequent in
cancers at a younger age [33]. Taken together, it is clear that much still has to be
learned on the biology of these tumors in order to fully understand differences in
the clinical course of these tumors between pediatric and adult age.
Clinical Presentation
The most common clinical presentation of childhood thyroid cancer is a
palpable thyroid nodule; it is the first sign of the disease in 73–87% of the cases
[8, 18]. Most thyroid cancers in children are asymptomatic, but palpable thyroid
nodules are more frequently malignant in children than in adults [19, 34]. As
with adults, hoarseness, dysphagia or a hard fixed nodule may be indicative of an
underlying thyroid malignancy. Fine-needle aspiration cytology of the nodule
should confirm the diagnosis. The size of newly diagnosed papillary thyroid
tumors in childhood is larger than in adulthood: a size of 4 cm is found in 36%
of children vs. 15% of adults, and a size of 1 cm occurs in 9% of children vs.
22% of adults [35]. Invasion of contiguous structures in papillary thyroid carci-
noma is also more frequent in children than in adults (24 vs. 16%) [35].

Wiersinga 214
Neck node involvement is quite common in childhood papillary thyroid
carcinoma, in the order of 60–90% [2–4, 8, 35]; palpable cervical lypmph-
adenopathy occurs usually in the presence of a palpable thyroid nodule,
whereas palpable lymph nodes in the absence of a palpable thyroid nodule is
uncommon [18]. Neck node involvement is much more frequent in children
than in adults. Among 1,039 consecutive patients with papillary thyroid carci-
noma treated in the Mayo Clinics, nodal metastases were present in 90% of
children vs. 35% in adults, and the same was true for distant metastases (7% in
children vs. 2% in adults) [34, 35]. Similar findings have been reported in other
large series [2, 3]. The distant metastases occur almost always in the lungs; they
are rare outside the lungs. In contrast to adult lesions, pediatric pulmonary
metastases are overwhelmingly miliary and seldom nodular; they may not be
detected on standard chest radiographs or even on spiral computed tomography
scans, becoming visible only at postablation 131I whole-body scans [36–39];
they are almost always functional [4].
It might well be that children with differentiated thyroid carcinoma nowa-
days present with less advanced disease than in the past, possibly reflecting
increased awareness on the part of pediatricians and family physicians [34].
Nevertheless, one must conclude that differentiated thyroid carcinoma in chil-
dren and adolescents is associated with a much higher frequency of cervical
lymph node and distant (pulmonary) metastases at clinical presentation than in
adults. The paradox of this more widespread disease in children is its associa-
tion with a better prognosis than in adults (vide infra).
Management
The goals of primary treatment of differentiated thyroid carcinoma are to
eradicate disease and extend recurrence-free survival [4]. Childhood differenti-
ated thyroid carcinoma is, however, a rare disease, and it may take decades even
at large referral centers to accumulate large series from which meaningful con-
clusions on the most appropriate treatment regimen can be derived. No ran-
domized controlled trials are available. Guidelines consequently rely on adult
and more specifically pediatric outcomes literature, which has been summa-
rized in two recent publications [4, 34].
Thyroidectomy
The general consensus is that total or near-total thyroidectomy is the best
operation in experienced hands. Reasons to perform a complete thyroidectomy
are first the high prevalence of multifocality and bilaterality in papillary
thyroid carcinoma, due to intrathyroidal lymphatic spread or de novo tumors

Childhood Differentiated Thyroid Carcinoma 215
arising in a synchronous or metachronous (possible due to RET/PTC
rearrangements) fashion [34]. A second compelling argument is the longer
recurrence-free survival after total vs. less than total thyroidectomy (table 1)
[4, 40]. Completion thyroidectomy has been associated with lower mortality
rates in adults with papillary thyroid carcinoma and children and adolescents
with radiation-induced papillary thyroid carcinoma as well [41]. Less exten-
sive surgery has been supported by the outcome of an American multi-institu-
tional cohort of 329 patients diagnosed when ⬍21 years old: progression-free
survival did not differ in relation to the extent of surgery [42]; however, total
thyroidectomy was more often applied to later-stage patients, jeopardizing the
claim of no benefit from more intense treatment [4]. Lobectomy for microcar-
cinomas (⬍1 cm) remains a controversial issue, and is better avoided in radia-
tion-induced cancer.
Thyroidectomy should be accompanied routinely by en bloc dissection of
the central neck compartment with clearing of lymphatic and soft tissue.
Modified lateral neck dissection is advocated in case of metastases to lateral
lymph node compartments (as diagnosed clinically, by ultrasound or intraoper-
ative biopsy). Mere ‘berry picking’ does not alter long-term survival, and may
actually increase the risk of nodal recurrence [34]. There seems never a need for
radical neck dissection in a child with papillary thyroid carcinoma [43]. Care
should be taken to protect the laryngeal nerves and the parathyroid glands;
devitalized parathyroids must be autotransplanted.
Thyroid Remnant Ablation
Meaningful 131I uptake (0.3% at 24 h) by thyroid remnants can usually be
demonstrated even after the most meticulous ‘total thyroidectomy’. Reasons to
Table 1. Predictors of recurrence-free survival in 274 patients with differentiated
thyroid carcinoma (103 children 18 years old and 171 adults 19–28 years old) [4, 40]
Predictor RR (95% CI) p value*
Age at diagnosis (19–28 vs. 18 years) 0.99 (0.92–1.0) NS
Gender (male vs. female) 0.97 (0.38–2.4) NS
Histology (follicular vs. papillary) 0.51 (0.23–1.1) NS
Lymph node metastases (present vs. absent) 3.1 (1.3–7.2) 0.027
Thyroidectomy (less than total vs. total) 6.2 (2.8–13.7) 0.001
Radioiodine ablation (no vs. yes) 5.8 (2.4–14.1) 0.001
*Cox multiple regression analysis.

Wiersinga 216
apply routine 131I remnant ablation are: (1) a longer recurrence-free survival in
comparison with no ablation (table 1); (2) increased sensitivity of subsequent
diagnostic 131I whole-body scans to detect (pulmonary) metastases; (3) render
serum thyroglobulin (Tg) a highly sensitive marker for residual recurrent dis-
ease during long-term follow-up [4, 40, 44]. Consequently, radioiodine remnant
ablation in children is the rule rather than the exception at most centers world-
wide. However, some authors advocate a more conservative approach, restrict-
ing the procedure to selected high-risk patients [34]. Most children should be
included in the high-risk group in view of the frequent extrathyroidal invasion,
lymph node metastases and distant metastases, but most staging systems
because of the good overall survival of children will classify them as stage I and
only as high-risk stage II in case of distant metastases [4]. A recent paper on 60
children and adolescents with differentiated thyroid carcinoma reinforces the
benefits of radioiodine remnant ablation: local relapse was reduced from 42%
to 6.3% when 131I was administered postoperatively, 10-year locoregional failure-
free survival (in children without distant metastases at diagnosis) was 86.5 vs.
71.9% without ablation (p 0.04), and distant failure-free rate was 100 vs.
94% without ablation (not significant) [45]. According to a recent meta-analysis,
remnant ablation improves outcomes in patients with differentiated thyroid car-
cinoma of all ages by reducing locoregional and distant recurrence risk [46].
Current recommendations are to perform ablation 6 weeks after surgery.
Children are placed on T3 1 g/kg/day in two or three divided doses for the first
4 weeks, followed by a 2-week period of withdrawal [44]. By doing so, serum
TSH will rise to levels of 25mU/l allowing maximal radioiodine uptake by the
thyroid remnant. Recent studies suggest that adequate hyperthyrotropinemia can
be reached in 14 days after total thyroidectomy. In adult patients serum TSH con-
centrations of 30 mU/l were reached in 74% after 9–11 days, in 93% after
15–17 days, and in 98% after 22 days after total thyroidectomy; these f igures
were 16, 65 and 97%, respectively, after withdrawal of suppressive T4 therapy
[47]. Compared with adults, T4 clearance rates and serum TSH to free T4 ratios
are higher in children, implying the possibility of shorter T4 withdrawal periods.
Indeed in children on suppressive T4 therapy (mean TSH 0.26 mU/l, range
0.01–1.37 mU/l) the mean interval to reach a serum TSH 30 mU/l after thyrox-
ine withdrawal was 12.4 0.8 days; serum TSH 25 mU/l was documented in
all patients by day 14 of withdrawal [48]. In this study, T4 was stopped on day
14, low-iodine diet was instituted as of day 7, TSH was measured on days
14, 7 and 1, a diagnostic whole-body scan with 123I was done on day 0,
dose determination on day 1, and the therapeutic 131I dose was given on day 2.
A low iodine diet – at least in adults – improves the efficacy of thyroid remnant
ablation [49]. The diagnostic whole-body scan just prior to remnant ablation
should employ 300–400 mCi 123I or 0.5–2.0 mCi 131I; higher doses of 131I might

Childhood Differentiated Thyroid Carcinoma 217
be associated with thyroid stunning, i.e. a lower uptake of a subsequent (thera-
peutic) dose of 131I [44]. The ablation dose in adults varies between 25 and
100 mCi 131I. A large randomized clinical trial in 509 patients (mostly adults but
also including children) concludes that doses between 25 and 50 mCi are equally
effective for remnant ablation, which was successful in 82%. In pediatric patients
thyroid remnant ablation is successful in the majority after a single dose of
30 mCi 131I [34, 44], but others use higher doses of ⬃60 mCi in view of the high
frequency of locally advanced disease and distant metastases in children [4].
Still others use body weight-based formulas, like 1mCi/kg with a range of
0.5–2 mCi/kg [2, 44]. Most institutions treat pediatric patients with fixed empiric
doses of 131I, and do not apply dosimetry to determine minimally effective doses
[34]. But all centers agree to perform a postablation or posttherapy whole-body
scan 5–7 days later, especially to detect pulmonary metastases. In a study of 28
children and adolescents with pulmonary metastases, whole-body scan revealed
the pulmonary metastases in all patients but chest X-rays only in 7 cases (25%);
18 of the 21 children with normal chest X-rays underwent chest CT scan, which
detected micronodular pulmonary shadows only in 5 children (28%) [51].
Follow-Up
Following radioiodine remnant ablation, patients are placed on TSH-
suppressive doses of levothyroxine aiming at serum TSH levels of 0.1 mU/l. In
patients with low risk papillary thyroid carcinoma and no evidence of remaining
disease the target could be TSH values between 0.1 and 0.4 mU/l for several
years, followed by replacement doses of levothyroxine [34, 44]. These recom-
mendations have been extrapolated from adults to children and adolescents
because scientific data at the pediatric age are lacking. High risk patients should
be maintained at TSH levels of 0.1 mU/l, but children may suffer from
headaches, insomnia and attention deficit disorders which should be taken into
account in delineating the levothyroxine dose. Children require higher L-T4 doses
per kg body weight to reach TSH levels of 0.1 mU/l: 3–4 g/kg/day in children
below the age of 10 years, but at the age of 16–18 years 2.4–2.8 g/kg/day may be
sufficient [19]. Growth rate and puberty are usually normal, with the expected
height reached at adult age.
The success of radioiodine remnant ablation is judged about 6 months later
by a diagnostic whole-body scan (uptake should be ⬃0.1%) or increasingly
by TSH-stimulated serum Tg (Tg should be undetectable). The protocol for a
diagnostic whole-body scan after T4 withdrawal has been given above [48].
Prolonged T4 withdrawal is often poorly tolerated by children, and for this rea-
son the use of recombinant human TSH (rhTSH) may be particularly beneficial.
rhTSH is licensed in Europe and the USA as an adjunct to diagnostic whole-
body scan or serum Tg testing and (in Europe only) as an adjunct to radioiodine

Wiersinga 218
ablation, but in both settings the licensing covers only adults; thus, rhTSH
administration in children is ‘off-label’ [4]. rhTSH has been successfully used
in a limited number of children so far [4, 52]. Serum peak TSH levels after
rhTSH are negatively related to body surface area (r 0.72, p ⬍0.0001),
implying the need for a personalized rhTSH dose [53]. Mean TSH levels
achieved in children after rhTSH, however, appear to be remarkably similar to
values previously reported in adults [54]. The data suggest that no alterations in
dose (0.9 mg intramuscularly on two consecutive days) may be necessary when
rhTSH is used in children and adolescents.
Neck ultrasonography should be included in the follow-up, as it can detect
lymph node metastases that are not suspected by palpation, diagnostic whole-
body scan, or serum Tg determination [55]. When no evidence of still existing
disease is found at 6 months using palpation, neck ultrasonography, whole-
body scan and serum Tg, the patient can be followed under a lower levothyrox-
ine dose. Serum Tg under levothyroxine treatment and neck ultrasonography
should be repeated every year, and with longer time intervals after ‘no evidence
of disease’ status for 2 years. Follow-up should probably be life-long.
Neck lymph node metastases are approached surgically, in which the extent
of excision depends on the extent of the disease; complete resection of neoplas-
tic foci is obtained in the majority of patients [19]. Microscopic neck metastases
can be treated with 131I. 131I treatment should always be administered for inoper-
able functional distant metastases. Pulmonary metastasis are typically treated
with 175–200 mCi 131I. Others apply 1mCi/kg body weight to be repeated every
6 months until the posttreatment scan no longer shows any uptake. This schedule
diminishes the risk on pulmonary fibrosis, and after four to six courses of 131I
80% of children seem to be cured [19]. Therapy is carried out following thyroid
hormone withdrawal on a low-iodine diet [4, 34, 44]. Total cumulative doses of
131I should be kept below 500 mCi in children and 800 mCi in adolescents. All
care is best delivered by a multidisciplinary specialized team.
Prognosis
In 1994, Mazzaferri and Jhiang [56] already noticed a very high recur-
rence rate but low mortality rate in children and adolescents with differentiated
thyroid carcinoma. This was confirmed by Samaan et al. [3] in 1992 in a com-
parative study on 140 patients below 20 years of age and 1,459 patients of 20
years with differentiated thyroid carcinoma. In both groups the frequency of
papillary carcinoma (86 vs. 80%), thyroidectomy (73 vs. 65%) and 131I therapy
(48 vs. 45%) was similar, but extrathyroidal spread was more prevalent in
the younger age group (74 vs. 57%). Recurrences were more frequent at age

Childhood Differentiated Thyroid Carcinoma 219
⬍20 years than in the older group (37 vs. 22%), but mortality was lower (3.6 vs.
11.3%). The number of actual recurrences in the children was higher than
expected (48 vs. 30, p ⬍0.001) but not so in the adults (301 vs. 319), and the
number of actual deaths in the children was lower than expected (5 vs. 18,
p⬍0.001) but not so in the adults (166 vs. 153). The median follow-up in this
study was 11 years, with a range of 1–43 years.
Although the above findings are reconfirmed by many other smaller series,
the low mortality rate of pediatric differentiated thyroid carcinoma might to
some extent reflect relatively short follow-ups compared with patients’ lifes-
pans [4]. Most reports have a median follow-up of 15 years, but cause-
specific deaths may occur after longer time intervals [57]: e.g. mortality was 10%
in 34 patients followed up for 20 years [6], and 15% of 40 patients diagnosed
at age 12 years died after 12–33 years [2]. The relatively short follow-up also
may lead to underestimation of the recurrence rate. The median time to recur-
rence is 7 years, but events occur up to 44 years after presentation [58, 59]. In
the historical series of the Royal Marsden Hospital the median overall survival
was 53 years; presentation with distant metastases predicted poorer survival,
and recurrences had also a higher risk of death with a median survival of 30
years [58]. A 100% survival at 10 years’ follow-up seems to be the rule rather
than the exception. Disease-free survival at 5 and 10 years follow-up is 80 and
61%, respectively [40]. The majority of children with lung metastases achieve
complete remission, and even partial responders rarely progress [2, 36, 40].
Over a 20-year follow-up, few if any cause-specific deaths were noted in pedi-
atric patients with lung metastases, in contrast to the 10-year mortality rate of
30–60% in adults with lung metastases [4, 59].
The risk of developing recurrent disease is increased by lymph node
metastases at presentation, less than total thyroidectomy, and no radioiodine
ablation as observed in many studies (table 1). In the recent multivariate regres-
sion analysis by Jarzab et al. [4] presented in table 1, age is not an independent
risk factor in this respect. In contrast, age is a major determinant of recurrence
risk in many other reports [19, 40, 43, 45, 58]: e.g. 20-year recurrence-free
interval was 10% in patients aged 10 years and 48% in patients aged 10–18
years at diagnosis [60]. Among 137 cases of papillary thyroid carcinomas 21
years of age with a median follow-up of 6.6 years, univariate analysis demon-
strated recurrence to be more common in patients with multifocal disease (OR
7.5) or large tumors 2 cm (OR 4.1), and in those with palpable cervical lymph-
adenopathy (OR 3.0) or distant metastases at diagnosis (OR 2.8); by multivari-
ate analysis the only signif icant predictor of recurrence was multifocality,
which was also true for the 38 patients with follicular carcinoma (OR 22) [61].
Most of the outcome studies described so far, refer to patient series col-
lected in the distant past. The outcome of patients who were diagnosed more

Wiersinga 220
recently might be different in view of the recommendations to perform (near)
total thyroidectomy and radioiodine ablation postoperatively. This was evalu-
ated by summarizing seven studies on children and adolescents with differenti-
ated thyroid carcinoma published after 2000 (table 2) [18, 62–67]. Sex
distribution and histology type are in agreement with previous series. At clini-
cal presentation, the cancer was already widespread as evident from a high fre-
quency of extrathyroidal invasion, lymph node and distant metastases, again
confirming more advanced disease in children with differentiated thyroid carci-
noma than in adults. Remarkably in comparison with past figures is the higher
frequency of near-total, total or completion thyroidectomy (80%) and of direct
postoperative 131I therapy for thyroid ablation and metastases (64%). The out-
come after a median follow-up is reassuring: only one child died and 83% had
become disease-free. It can be concluded that the prognosis of children and
adolescents with differentiated thyroid carcinoma is in general rather good.
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Long-term outcome (n 281)
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Wiersinga 224
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with differentiated thyroid carcinoma. Ann Surg Oncol 2003;10:15–20.
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Prof. Wilmar M. Wiersinga
Department of Endocrinology and Metabolism
Academic Medical Center, Room F5–171
University of Amsterdam
Meibergdreef 9
NL–1105 AZ Amsterdam (The Netherlands)
Tel. 31 20 566 6071, Fax 31 20 691 7682, E-Mail w.m.wiersinga@amc.uva.nl

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 225–269
Imaging of the Normal and Affected
Thyroid in Childhood
Finn N. Bennedbæka, Laszlo Hegedüsb
aDepartment of Endocrinology and Metabolism, Herlev University Hospital, Herlev,
and bDepartment of Endocrinology and Metabolism, Odense University Hospital,
Odense, Denmark
Imaging has undergone major advances over the past three decades and has
revolutionized the evaluation of patients with thyroid disease. However, the use
of thyroid imaging is in general not evidence-based, and there have been few
cost-benefit evaluations of medical imaging [1].
The thyroid gland can be evaluated by several imaging techniques: (1) radionu-
clide imaging, and (2) nonisotopic imaging comprising (a) ultrasonography
(US); (b) computed tomography (CT), and (c) magnetic resonance imaging
(MRI). A recent development has been the combination of PET (positron emis-
sion tomography) and CT for oncologic imaging. Each has advantages and
limitations, and there is no absolute clinical indication for performing any of
them in the majority of patients [1, 2]. In this chapter emphasis will be on the
clinical use of US in childhood.
Radionuclide Imaging
In regions with adequate dietary iodine intake, the 24-hour uptake of oral
radioiodine is 10–35%. The trapping mechanism is the sodium-iodide symporter
(NIS), which is regulated by thyrotropin (TSH) [3]. There are more than 20
radionuclides of iodine, but only 123I and 131I are in widespread clinical use. 123I
has a relatively short half-life and emits only photons and is used for thyroid
uptake measurements and scintigraphy. In contrast, 131I has a half-life of 8 days
and emits particles as well as high-energy photons. 131I is therefore suited for
therapy, but the photons can be imaged, which explains why 131I is used
for diagnostic and post-treatment whole-body scanning in patients with thyroid

Bennedbæk/Hegedüs 226
cancer. The use of 131I for routine thyroid scintigraphy is discouraged because
the radiation dose is about 100 times greater than that of 123I. Based on low cost,
availability and an even lower radiation dose, technetium (99mTc) pertecnetate is
an attractive alternative to 123I and consequently recommended for routine thy-
roid imaging by authorities in most European countries. 99mTc is administered
intravenously, and uptake and scan are obtained after 15–20 min. In children the
radiation exposure to the gland is three- to fivefold higher than in adults.
For routine imaging a gamma camera with a pin-hole collimator is most
often used. The patient lies in the supine position with the neck extended.
Markers can be used to identify anatomic sites, such as the manubrium, or can
be placed at the edge of a palpable nodule. Additional SPECT (single photon
emission computed tomography), where the camera head rotates 180–360
around the patient, improves resolution and can provide volumetric estimates,
but is not performed routinely [4, 5].
Thyroid uptake is influenced by the serum inorganic iodine level, which is
dependent on the intake of iodine. A number of factors can influence the
uptake. Thus, it is generally increased in hyperthyroid patients with Graves’ dis-
ease or toxic nodular goiter, and decreased in patients with subacute or silent
thyroiditis as well as in those with hypothyroidism (table 1) [6].
Indications for Thyroid Uptake and Imaging
When patients are referred for uptake and/or scan, it is important to ensure
that they are not taking thyroid hormone. However, in congenital hypothy-
roidism, L-thyroxine therapy need not be delayed while awaiting scintigraphy,
since scintigram validity depends on a normal or elevated TSH level, which is
the case for many days after onset of treatment, during which time scintigraphy
can be performed. It is also important to avoid the ingestion of excess iodine,
and to secure that female adolescents are not pregnant.
Measurements of thyroid uptake and imaging give valuable information in
several clinical situations (table 2). A known activity of tracer is administered
orally, and the percentage accumulated at designated times is measured using
either a probe or a gamma camera. It is almost standard procedure to obtain a
24-hour measurement, but the early 4- to 6-hour measurements allows the clin-
ician to identify a thyroid with rapid turnover. Some obtain only an early mea-
surement and by extrapolation calculate the 24-hour value [7]. The uptake is
often used to determine therapy doses of 131I to treat patients with Graves’ dis-
ease or toxic nodular goiter [8].
Only few studies, all retrospective, that describe the role of scintigraphy in
the evaluation of the spectrum of pediatric thyroid disorders, have been pub-
lished. In one study, comprising 280 children, indication for scintigraphy
included hypothyroidism, neck masses, and hyperthyroidism [9] and was

Thyroid Imaging in Childhood 227
Table 1. Factors that influence thyroid radioiodine uptake
Causes of increased uptake
Hyperthyroidism
Iodine deficiency
Rebound after withdrawal of antithyroid medication
Rebound after suppression of thyrotropin
Recovery phase of subacute, silent, or postpartum thyroiditis
Inborn errors of thyroid hormogenesis (apart from trapping defects)
Pregnancy (use of radiopharmaceuticals contraindicated during pregnancy)
Lithium carbonate therapy
Some patients with Hashimoto’s thyroiditis
Causes of decreased uptake
Primary hypothyroidism
Destructive thyroiditis (subacute thyroiditis, silent thyroiditis, postpartum thyroiditis)
Thyroidectomy, 131I treatment or external neck irradiation
Thyroid hormone
Antithyroid drugs
Excess iodine, including dietary supplements with iodine
Radiological contrast media
Amiodarone
Topical iodine
Perchlorate, thiocyanate
Sulphonamides, sulphonylurea
High-dose glucocorticosteroids
Table 2. Indications for thyroid uptake and imaging
Indications for measuring thyroid uptake
Confirm the diagnosis of hyperthyroidism
Differentiate different types of thyrotoxicosis
Provide data for calculation of a therapeutic dose of 131I
Detect intrathyroidal defects in organification
Follow-up of patients treated for thyroid cancer
Indications for thyroid scintigraphy
Depict structure and function of the thyroid
Differentiate different types of thyrotoxicosis
Determine whether a nodule is functioning
Determine whether a cervical or mediastinal mass contains functioning thyroid
Identify ectopic thyroid
Aid in the diagnosis of congenital hypothyroidism
Identify thyroid metastases
Determine whether ablation therapy of thyroid cancer has been successful

Bennedbæk/Hegedüs 228
considered helpful in the work-up. Scintigraphy added little to the management
of children with post-irradiation hypothyroidism, Hashimoto’s thyroiditis, or
Graves’ disease, when the clinical diagnosis was straightforward.
The Normal Thyroid Scintigraphy
The thyroid gland is located in the antero-inferior part of the neck
(infrahyoid compartment) (fig. 1). There are two lobes and an isthmus. 10–40%
have a small pyramidal lobe, arising from the superior part of the isthmus,
which is occasionally identified on scintigraphy.
Congenital Defects
Congenital defects include anatomic and inherited disorders [10].
Anatomic defects comprise agenesis (fig. 2), hemiagenesis and maldescent of
the gland, which is positioned along the tract of the thyroglossal duct. Rarely,
congenital cysts of the thyroid are seen. The clinical consequences are highly
variable, from severe hypothyroidism due to thyroid agenesis to moderate
hypothyroidism due to ectopic (usually lingual) (fig. 3) thyroid rudiments or
thyroid hypoplasia (f ig. 4) and, finally, to subclinical hypothyroidism (high
serum TSH with normal serum free T4 and free T3 concentrations) in patients
with thyroid hemiagenesis. Imaging is valuable in defining agenesis of the thy-
roid. On 99mTc scintigraphy, the thyroid is not identified, but there is uptake by
salivary glands [11]. Anatomic defects such as hemiagenesis are infrequently
identified because they are rare and seldom result in subclinical or clinical
hypothyroidism. Rare cases of coexisting hyperthyroidism [12], including TSH
Fig. 1. Normal thyroid gland in a 4-year-old girl 15 min after intravenous administra-
tion of 50 MBq 99mTc pertechnetate. Left panel: lateral view; right panel: anterior view.

Thyroid Imaging in Childhood 229
Fig. 2. 99mTc pertechnetate thyroid scintigraphy demonstrating absence of thyroid
uptake in a 10-day-old girl with congenital hypothyroidism due to thyroid agenesis (lateral
and anterior view).
Fig. 3. 99mTc pertechnetate thyroid scintigraphy showing uptake in the lingual region
in a neonate (lateral and anterior view) with congenital hypothyroidism.
receptor antibodies resulting in Graves’ disease have been described [13]. Most
often congenital defects are found incidentally in patients having imaging of the
neck for other reasons.
The introduction of neonatal screening programs has enabled early diagno-
sis and treatment of infants with congenital hypothyroidism (CH) and the
prevention of mental retardation [14]. Patients with CH are classified as having
developmental abnormalities of the thyroid gland in 85% of the cases. These
include ectopic thyroid tissue, aplasia or hypoplasia of the thyroid or a normally
located gland with hypothyroidism caused by dyshormogenesis [15] (fig. 5).

Bennedbæk/Hegedüs 230
Although thyroid imaging with 123I or 99mTc has been available for
decades, these techniques are not routinely used in newborn infants diagnosed
by screening as having CH. Guidelines on CH have described thyroid imaging in
newborns as optional [16, 17] and some argue that presence, absence, or abnor-
mal location of a thyroid does not alter management of CH. Others believe that
optimal counseling of parents, and management, implies obtaining a scintigra-
phy [18]. The latter authors recommend 123I rather than 99mTc in cases of CH,
arguing that 99mTc is valid only in cases of absent or normal-appearing thyroid
glands and more often misdiagnoses ectopic thyroid tissue [18]. However, these
results have not been conf irmed by others [19, 20]. Thyroglobulin (Tg) has been
Fig. 4. 99mTc pertechnetate thyroid
scintigraphy (lateral view) showing reduced
uptake in a cervical thyroid in a 13-day-old
boy with mild congenital hypothyroidism.
Additional US demonstrated a 5 5mm
large normoechoic thyroid in the midline,
not divided into two lobes – findings com-
patible with thyroid hypoplasia.
Fig. 5. 99mTc pertechnetate thyroid scan in an 11-day-old girl with diffuse goiter on
palpation and congenital hypothyroidism due to dyshormogenesis. Increased and diffuse
uptake in an enlarged cervical thyroid gland can be seen (lateral and anterior view).

Thyroid Imaging in Childhood 231
found in varying concentrations in infants and children with congenital hypothy-
roidism. While a comparative study found that Tg was a more reliable marker for
the presence or absence of a thyroid gland it cannot substitute scintigraphy as a
first line diagnostic tool in the management of CH [20].
Inborn errors of synthesis of thyroid hormones can be diagnosed by clini-
cal findings, biochemical results and uptake and scintigraphy. Future improve-
ments in obtaining a definite diagnosis will be based on genetic testing. Absent
trapping, due to mutations in the NIS gene, results in absent thyroid uptake, and
additionally lack of trapping in salivary glands. A defect in thyroid peroxidase
can be identified by active trapping by the thyroid and a positive perchlorate
discharge test [21] (fig. 6).
An ectopic thyroid, located at the base of the tongue, is called a lingual thy-
roid and occurs in 1 in 100,000 persons [22]. It can be seen with or without
other functioning thyroid tissue located at the usual site of the thyroid gland or
anywhere else between the foramen cecum and the normal position. One third
of the patients with an ectopic thyroid have hypothyroidism at the time of diag-
nosis [23]. In the majority it is often asymptomatic until physiologic stress, such
as severe systemic disease or pregnancy [24], causes enlargement of the ectopic
tissue. It may be associated with hypothyroidism, with or without thyroid
Fig. 6. 99mTc pertechnetate thyroid scintigraphy in a 7-year-old boy with congenital
hypothyroidism and a palpable diffuse goiter (scan performed without preceding thyroxine
withdrawal). Diffuse uptake in an enlarged gland can be seen. Two weeks later an additional
perchlorate discharge test was performed: injection of 10 MBq 123I showed diffuse uptake
after 60 min at which time sodium perchlorate (20 mg/kg) was administered. Uptake mea-
surements every 15 min the following hour showed increased discharge reaching a level of
43% of the maximum uptake after 30–45 min. Results are compatible with a partial thyroid
peroxidase defect explaining the goiter and concomitant hypothyroidism.

Bennedbæk/Hegedüs 232
enlargement, or in case of swelling, with dysphagia, dysphonia, or dyspnea
[25]. Ectopic thyroid tissue, including lingual thyroid disease, can be diagnosed
efficiently by 99mTc scintigraphy [26, 27].
Congenital Goiter
Congenital goiters may be secondary to a number of diseases. Goiters sec-
ondary to enzyme deficiencies [28] (fig. 6) may be present at birth. However, most
of these develop in the early months and years of extrauterine life [28]. In the
absence of maternal thyroid autoantibodies, further evaluation of goiter in the
newborn is based on thyroid function tests in addition to 123I or 99mTc scintigraphy.
Infants born to mothers with hyperthyroidism secondary to TSH receptor antibod-
ies can have goiter [29] and do not warrant imaging. Other causes include maternal
prenatal ingestion of excess iodine (f ig. 7), antithyroid medication, lithium and
other goitrogens [29, 30]. Scintigraphy is of limited value in these cases.
Hypothyroidism
Hashimoto’s thyroiditis is the most common cause of thyroid disease in
children and adolescents and also the most common cause of acquired hypothy-
roidism with or without goiter [31]. Often a continuum from normal to slightly
reduced homogeneous distribution of tracer on thyroid scintigraphy is found
(fig. 8a), unlike the heterogeneous distribution (fig. 8b) more often reported in
Fig. 7. 99mTc pertechnetate thyroid scintigraphy in an 11-day-old girl with a small pal-
pable goiter and mild hypothyrodism due to maternal prenatal ingestion of excess iodine.
Normal uptake in the gut and the bladder. Image cannot distinguish between thyroid aplasia
and iodine contamination, but additional US demonstrated a normal thyroid gland.
Thyroxine could be withdrawn 3 months postpartum.

Thyroid Imaging in Childhood 233
adults [32]. However, in children and adolescents, thyroid scintigraphy is not
helpful in the diagnosis of typical Hashimoto’s thyroiditis [33].
Hyperthyroidism
In children, hyperthyroidism is a result of Graves’ disease or an
autonomous hyperfunctioning thyroid nodule [34]. The latter is extremely rare
in childhood. Figure 9 shows the typical scintigraphic appearance of Graves’
Fig. 8. 99mTc pertechnetate thyroid scintigraphy in a 15-year-old girl with Hashimoto’s
thyroiditis (hypothyroidism and high concentrations of thyroid peroxidase antibodies)
(a) – slightly reduced homogeneous distribution of tracer in a small thyroid gland, and a
10-year-old girl with Hashimoto’s thyroiditis (elevated thyroid peroxidase antibodies and
hypothyroidism) (b) – heterogeneous distribution of tracer in a normal-sized thyroid gland.
a b
Fig. 9. 99mTc pertechnetate thyroid
scintigraphy showing diffuse and increased
uptake in a thyroid gland with enlarged and
symmetric lobes.

Bennedbæk/Hegedüs 234
Fig. 10. 99mTc pertechnetate thyroid
scan of a hyperfunctioning nodule in the
right lobe with complete suppression of
uptake in the remainder of the thyroid.
disease. Compared with a normal thyroid, the thyroid lobes are slightly larger in
all dimensions, and the early and late uptakes are higher. Figure 10 shows an
autonomous hyperfunctioning nodule with suppression of extranodular thyroid
tissue. If thyrotoxicosis is confirmed biochemically, in addition to elevated lev-
els of TSH receptor antibodies and a nonpalpable thyroid gland, there is no
absolute indication to measure uptake or obtain a scan.
Subacute thyroiditis is rare in childhood [35] and most often presents with
thyrotoxicosis and elevated erythrocyte sedimentation rate and is associated
with neck pain and tenderness. Reduced or no thyroid uptake on a scintiscan
supports the diagnosis (fig. 11).
Single and Multiple Thyroid Nodules
In general, diffuse enlargement of the thyroid is of benign origin, whereas a
solitary nodule must be evaluated carefully. Discrete thyroid nodules are uncom-
mon in children, especially in the prepubescent child [36]. Figure 12 shows a
multinodular goiter in a euthyroid prepubescent girl with familial occurrence of
nontoxic and toxic multinodular goiter in several female probands. The preva-
lence of thyroid nodularity in children is considerably lower than in an adult pop-
ulation and has been estimated to be approximately 1.8% [37]. In both
nonpalpable (incidentally found by neck imaging for other reasons) and palpable
nodules larger than 1 cm, a 99mTc scintigraphy is recommended by the authors
[37]. A solitary nodule with low-uptake (cold) and a nodule with normal uptake
are shown in figure 13. In the adult population the likelihood of a cold nodule
being malignant is low (5% in a recent review [38]) and in the view of many clin-
icians it adds little valuable information to a US-guided fine-needle aspiration

Thyroid Imaging in Childhood 235
biopsy [39]. However, the a priori risk of a solitary nodule being malignant is
higher in childhood, with an estimated risk of 18–46% [37, 40]. This risk
increases if there is a history of previous radiation therapy to the cervical region
[41], or if the patient is a male [42]. Therefore, the functional status of a solitary
nodule should be evaluated, and non-functioning nodules are biopsied. A rare
cause of a solitary cold thyroid nodule in childhood is the thyroglossal duct
cysts, which often appears as a palpable neck mass [43].
Fig. 11. 99mTc pertechnetate thyroid
scintigraphy of a 14-year-old girl with tran-
sient thyrotoxicosis and painful swelling of
the thyroid gland following an episode of
flu-like symptoms. Low tracer uptake, com-
patible with subacute thyroiditis, is seen.
Fig. 12. 99mTc pertechnetate thyroid
scintigraphy in an 11-year-old girl with non-
toxic multinodular goiter. Heterogeneous
uptake, bilaterally.

Bennedbæk/Hegedüs 236
PET and PET/CT
Cancer-seeking radiopharmaceuticals have been evaluated for more than a
decade to improve differentiation between benign and malignant thyroid nodules.
Positron emission tomography with fluorine 18-fluorodeoxyglucose (FDG) is
well established as a functional imaging tool for diagnostic oncologic imaging.
It yields metabolic information about lesions that is not provided with conven-
tional morphologic imaging modalities such as US, CT and MRI [44]. Studies
using FDG PET for tumor staging and restaging, monitoring treatment, and
predicting the prognosis in patients with head and neck cancers, have been pub-
lished [45, 46]. To interpret PET images accurately, it is essential to be fully
familiar with the normal patterns, intensities, and frequencies of FDG distribu-
tion in the head and neck area. PET evaluations of physiologic tracer uptake in
the head and neck region, with or without image fusion techniques involving
the use of conventional cross-sectional modalities to assist in locating structures
and lesions seen on PET images, have been described [47, 48].
Combined PET/CT scanners that enable highly precise localization of the
metabolic abnormalities seen on PET and high-spatial-resolution CT images
have been developed [49]. The PET/CT fusion imaging is a novel multimodal-
ity technology that allows the correlation of findings from two concurrent
imaging modalities in a comprehensive examination (f ig. 14). The CT demon-
strates exquisite anatomic detail but does not provide functional information,
Fig. 13. a A nonfunctioning nodule in the left lower pole is shown. The patient, an
8-year-old boy, had a benign solitary 3 3cm large cyst as evidenced by US and US-guided
aspiration. bAn enlarged right lobe and normal uptake in a 2 2 cm large nodule can be
seen in the right lower pole. An 11-year-old boy with a palpable solitary solid homogeneous
well-defined nodule. Biopsy was performed due to previous neck irradiation and showed
benign cytology.
a b

Thyroid Imaging in Childhood 237
whereas FDG PET reveals aspects of tumor function and allows metabolic
measurements.
In a recent retrospective review of PET/CT images, obtained in 78 patients
with non-head and neck cancers, the accumulation of FDG was described [46].
Intense tracer uptake is usually seen in the palatine tonsils, soft palate, and lin-
gual tonsils. In the normal thyroid gland, the tongue, and inferior conchae the
uptake is minimal. FDG accumulation is variable in the sublingual, sub-
mandibular and parotid glands [46]. Thus, the normal thyroid shows very low-
grade FDG uptake, and is usually not visualized on the whole-body FDG-PET
scan. Diffuse thyroid FDG uptake is usually an indicator of chronic autoim-
mune thyroiditis, as supported by the presence of thyroid autoantibodies and
changes on sonography in one study [50]. Occasionally, focally or diffusely
increased FDG uptake is seen as an incidental finding in the thyroid. The
dilemma is to differentiate physiologic from pathologic FDG uptake [51].
Although a high FDG uptake in a thyroid tumor suggests malignancy even low
levels of FDG uptake cannot completely rule out malignancy [52–54]. A cyto-
logic diagnosis of focal thyroid FDG uptake in incidentalomas is mandatory, as
cancer is confirmed in a signif icant number [55]. Despite limited data, PET and
PET/CT have proved valuable in the evaluation of recurrent thyroid carcinoma
[56]. So far, implementation of PET/CT in the routine evaluation of thyroid
nodules in children awaits larger studies because of the considerable overlap in
uptake between malignant and benign nodules.
In hereditary thyroid cancer the role of imaging in gene carriers is contro-
versial. In one study CT and MRI failed to locate tumors 5 mm in diameter
but whole-body FDG PET and adjunctive cervical US helped stage individuals
Fig. 14. Left panel: PET image 45 min after injection of 400 MBq 18 FDG shows
increased focal uptake on the left side of the neck. Right panel: PET/CT fusion image shows
that the increased uptake is localized in the left thyroid lobe. At surgery a papillary carci-
noma was found.

Bennedbæk/Hegedüs 238
carrying mutant genes, thus verifying multiple endocrine neoplasia (MEN)2A
or familial medullary thyroid carcinoma (FMTC) [57].
Ultrasonography
Because of the superficial location of the thyroid gland, high-resolution
real-time gray-scale and color Doppler sonography can demonstrate the normal
thyroid anatomy and pathologic conditions with remarkable clarity [58]. With
increasing availability, this technique has come to play an ever more important
role in the diagnostic evaluation of thyroid diseases. High-frequency transduc-
ers (7.5–15.0 MHz) provide both deep ultrasound penetration (up to 5cm) and a
high-definition image, with a resolution of 0.7–1.0 mm. It can distinguish solid
nodules from cysts and allows accurate estimation of size, shows vascular flow
(Doppler), and aids in the accurate placing of needles for diagnostic or thera-
peutic purposes [59]. It is also an excellent tool for use in the follow-up for esti-
mation of changes in size of a lesion or the entire thyroid gland over time.
Finally, it allows in utero investigation of the fetal thyroid [60] and can be help-
ful in fetal diagnosis of thyroid dysfunction [61]. The major limitations of
sonography are the high degree of observer variability [62] and the inability to
identify retrotracheal, retroclavicular, or intrathoracic extension of the thyroid
[2, 59].
Examination is performed with the patient in the supine position and the
neck hyperextended. A small pillow may be placed under the shoulders to pro-
vide better exposure of the neck. The thyroid gland must be examined in both
transverse and longitudinal planes. The examination should be extended later-
ally to include the region of the carotid artery and jugular vein to identify
enlarged jugular chain lymph nodes, superiorly to visualize submandibular
adenopathy, and inferiorly to define any pathologic supraclavicular lymph
nodes.
Indications for Thyroid Sonography
It is important to remember that thyroid scintigraphy (imaging providing
information on functionality and to some degree anatomy) and sonography
(providing information on morphology and anatomy) are complementary imag-
ing modalities. Based on the lack of prospective comparative studies in child-
hood thyroid disease, indications for each will often be based on local traditions
and nuclear medicine and radiology facilities and expertise. The evasion of
ionizing radiation and sedation, in addition to a short examination time and
wide availability, makes ultrasound an ideal initial examination in children
[36]. Sonography will provide valuable diagnostic information in a number of

Thyroid Imaging in Childhood 239
clinical situations (table 3). In one series, one third of pediatric neck masses
were located in the thyroid gland [36]. Sonography, and sonography-guided
fine-needle aspiration biopsy, often has substantial impact on the final diagno-
sis of a thyroid mass (table 4). Sonographic tissue characteristics aid in classi-
fying the lesion as inflammatory, neoplastic, congenital, traumatic, or vascular,
and are diagnostic in the majority of cases [63]. In some genetic disorders atten-
tion must be drawn to the frequent involvement of the thyroid. For instance,
Cowden syndrome, a rare autosomal-dominant disease, is characterized by
multiple hamartomas of the skin and often (two-thirds of the patients) coexist-
ing benign thyroid nodules, but also increased risk of nonmedullary thyroid car-
cinoma [64]. Genetic confirmation of Cowden syndrome warrants regular
thyroid US because of the increased risk of thyroid malignancy.
Normal Thyroid Sonography
The thyroid gland is made up of two lobes located along either side of the
trachea (seen in the midline of the lower neck as a markedly echogenic area
with shadowing), and connected across the midline by the isthmus (fig. 15).
The pyramidal lobe can often be visualized in younger patients, but it under-
goes progressive atrophy in adulthood and eventually becomes invisible.
Generally, the parathyroid glands are not identified.
The size and shape of the thyroid lobes vary widely. In the newborn, the gland
is 18–20 mm long, with an anteroposterior diameter of 8–9 mm. By 1 year of age,
the mean length is 25 mm and the anteroposterior diameter is 12–15 mm [58].
Sonography is an accurate method for calculating thyroid volume. The
most common mathematical method is based on the ellipsoid formula
(length width thickness /6 for each lobe) (fig. 16). This method has an
estimated mean error of 15% [58] but the accuracy decreases with increasing
size, irregularity of the thyroid, and with retroclavicular extension [1]. The most
Table 3. Indications for thyroid US
Aid in the diagnosis of congenital hypothyroidism
Differentiate different types of thyrotoxicosis
Differentiate thyroid masses
Guide biopsy of nodules
Aspirate thyroid cysts
Guide interventional procedures (e.g. laser ablation)
Identify ectopic thyroid
Identify thyroid metastases
Identify recurrence in the follow-up of patients treated for
thyroid cancer

Bennedbæk/Hegedüs 240
precise mathematical method is the integration of partial volume estimates
obtained at cross-sectional scans of the thyroid gland through evenly spaced
sonographic scans [65]. This method has an estimated error of 5–10%. Modern
three-dimensional ultrasound technology permits the simultaneous measure-
ment of the three orthogonal planes of each thyroid lobe [66]. Planimetric three-
dimensional sonography seems less observer-dependent and is more accurate
than conventional sonography with an intraobserver variability of 5% [67].
Goiter prevalence in school-age children is an important indicator of
iodine deficiency disorders in a population. The 1994 WHO criteria provides an
acceptable estimate of goiter prevalence in areas of severe iodine deficiency,
but in areas of mild iodine deficiency sonography-determined thyroid volume
is the method of choice [68]. Thyroid volume is correlated with iodine status,
age, weight, height, sex and body surface area in non-iodine-deficient areas
[69]. Thyroid volumes increase with advancing age with a relative sudden
increase between the age of 11 and 12 in girls and between 13 and 14 in boys
Table 4. Potential causes of thyroid masses in childhood and adolescence
Acute suppurative thyroiditis
Subacute thyroiditis (DeQuervain)
Congenital goiter (often diffuse)
Diffuse goiter
Nodular goiter (uni- or multinodular):
Benign thyroid nodules
• Colloid/hyperplastic nodule
• Follicular adenoma
• Hürthle-cell adenoma
• Thyroid teratomas
• Lymphocytic thyroiditis
• Thyroglossal duct cyst
Malignant thyroid nodules
• Papillary carcinoma
• Follicular carcinoma
• Hürthle-cell carcinoma
• Anaplastic carcinoma (extremely rare in childhood)
• Medullary carcinoma
• Lymphoma
• Cancer metastatic to the thyroid
Nonthyroid lesions (clinically mistaken for being of thyroid origin)
• Branchial cleft cyst and other epithelial cysts
• Parathyroid adenoma or cyst (rarely palpable)
• Lymph node

Thyroid Imaging in Childhood 241
Fig. 15. Anatomy of the neck. Transverse section through the thyroid at the level of the 7th
cervical vertebra CVII. Strap muscles: sternohyoid and sternothyroid muscles. aAnatomic draw-
ing (modified from [58]). bCorresponding transsectional sonogram. C Common carotid
artery; E esophagus (often deviating to the left at this level); J jugular vein; Tr trachea.
Strap muscles Trachea
Thyroid
Internal jugular vein
Esophagus
Longus colli m.
Sternocleidomastoid m.
Common carotid a.
a
b
Fig. 16. Volume measurement of the thyroid gland. Transverse (a) and longitudinal
(b) images show callipers at the boundaries of the right thyroid lobe. The calculated thyroid
volume is based on the ellipsoid formula with a correction factor (length width thick-
ness /6 for each lobe). C Carotid artery; J jugular vein.
ab

Bennedbæk/Hegedüs 242
[70]. Thyroid volume is sex-independent up to the age of about 11, but at ages
12 and 13, girls have a slightly larger thyroid volume (associated with an
increase in body surface area). The subsequent larger increase in body surface
area in boys results in larger thyroid volumes from the age of 14. The sex dif-
ference in thyroid volume is less marked if expressed by body surface area than
by age, but both indicate larger thyroid glands in 14 year old males than in
females [70]. In a study of Dutch schoolchildren, median US-determined thy-
roid volume was approximately 3 ml at the age of six, 5 ml at the age of ten, 9 ml
and 12 ml at the age of 18 in girls and boys, respectively (table 5).
Normal thyroid parenchyma has a characteristic homogenous medium-level
echogenicity (fig. 15b), whereas that of the muscles anterior (m. sternothyroideus
and m. sternohyoideus) and anterolateral (m. sternocleidomastoideus) to the
thyroid appear hypoechoic (fig. 15b). The thin hyperechoic line that bounds the
thyroid lobes is the capsule which is often identif iable by sonography. The rich
vascularity of the gland is easily detected with currently available high-sensitivity
Doppler instruments (fig. 17).
Congenital Defects
Congenital hypothyroidism is one of the more common congenital
endocrine disorders, with an incidence of around 1 in 3,800 live births. Patients
are classif ied as: (1) having developmental abnormalities of the thyroid gland
(85% of cases) [15], which include ectopic thyroid tissue, aplasia, or hypoplasia
Table 5. Median thyroid volume in a cohort of Dutch
schoolchildren
Age Thyroid volume, ml
boys girls
6 years 3 3
8 years 4 4
10 years 5 5
12 years 6 8
14 years 10 9
16 years 10 9
18 years 12 9
Median thyroid size determined by ultrasound in Dutch
schoolchildren (408 boys and 529 girls) according to age.

Thyroid Imaging in Childhood 243
of the thyroid gland, or (2) having a normally located gland mostly related to
thyroid dyshormogenesis. It is generally accepted that scintigraphy is indis-
pensable in the correct diagnostic work up of congenital hypothyroidism
[21, 71]. However, scintigraphy has to be performed within the first week after
starting thyroxine treatment, to prevent an inhibited uptake of the isotope, and is
not always performed. Sonography has been evaluated and found valuable for
obtaining an etiologic diagnosis [72, 73], but not reliable for detecting ectopia
or for differentiating ectopia from aplasia [74]. This was confirmed in a recent
study of 66 neonates with an established diagnosis of congenital hypothy-
roidism resulting in a diagnosis of ectopic thyroid tissue in 42 of them (64%).
Confirmation was obtained by scintigraphy, but sonographically confirmed in
only 9 of 42 cases [75].
More recent advances in US technology, including color Doppler and high-
resolution gray-scale US, have led to a reevaluation of US in congenital
hypothyroidism. In a recent study from Japan color Doppler US was found
superior to gray-scale US and MRI (sensitivity 90, 70 and 70%, respectively)
[76]. In a comparative study of US and scintigraphy in 88 patients with congen-
ital hypothyroidism, it was confirmed that sonography failed to distinguish
between thyroid aplasia and ectopia but did distinguish between presence and
absence of thyroid tissue [77]. The authors conclude that sonography is an accu-
rate method to establish the presence of dysgenesis of the thyroid gland and
might be used as the first imaging tool in patients with CH, whereas scintigra-
phy should be used mainly to distinguish agenesis from ectopia, whenever there
is no thyroid tissue present at US [77].
Fig. 17. Normal thyroid vascularity on color Doppler US. C Carotid artery;
Jjugular vein; Tr tracheal air shadow.

Bennedbæk/Hegedüs 244
Ectopic thyroid tissue is the most frequent cause of congenital hypothy-
roidism (two-thirds of cases) and although sonography results in a low detec-
tion rate compared to radionuclide scanning, it adds etiological information
based on location, echogenicity and vascularity [78]. Figure 18 shows ectopic
thyroid tissue in the lateral neck, conf irmed by scintigraphy (fig. 18a) as well as
by US (fig. 18b, c), in a neonate with congenital hypothyroidism. The presence
of cysts, detected by sonography, within the empty thyroid area in two-thirds of
patients with thyroid dysgenesis, is a novel observation [79] but does not alter
management.
Syndromes like Williams’ syndrome (incidence of 1:10,000 live births,
characterized by facial dysmorphisms, heart defects, short stature and mental
retardation) can show thyroid disorders including thyroid ectopia, hemiagenesis
and thyroid hypoplasia in addition to subclinical or overt hypothyroidism. In
Fig. 18. a 99mTc pertechnetate scintigraphy demonstrating heterogeneous and reduced
uptake in the lateral neck, primarily on the right side. Additional trans-sectional US demon-
strated well-defined thyroid tissue (arrows) lateral to the jugular vein on both the right (b)
and the left side (c).
c
ab

Thyroid Imaging in Childhood 245
this syndrome, abnormalities of thyroid morphology are best detected by US
[80]. Thyroid hemiagenesis is often an incidental f inding on sonography with a
higher incidence of agenesis of the left lobe [81].
Seventy percent of congenital anomalies in the neck are thyroglossal duct
remnants or cysts [82, 83]. In the young child, thyroglossal duct cysts often
appear as a firm midline mass with a variable sonographic appearance. The
majority are pseudosolid rather than anechoic and closely related to the hyoid
bone [84]. Cysts can be located anywhere from the base of the tongue to the
thyroid isthmus [82], but also at the level of the hyoid or infrahyoid.
Congenital Goiter
Congenital goiters may be secondary to a number of diseases [28]. Goiters
secondary to enzyme deficiencies, e.g. mutations in the thyroid peroxidase
gene resulting in iodide organif ication defects, may be present at birth. In a
cohort study of newborns with congenital hypothyroidism and normally located
thyroid, 50% were classified as having goiter [85]. In the group with permanent
congenital hypothyroidism and goiter, one-third had an iodine organification
defect, one-fourth a defect of thyroglobulin synthesis and 5% had Pendred’s
syndrome.
Sonography can be used to differentiate goitrous hypothyroidism (gland
enlargement) from agenesis (absent gland). Morphology in congenital goiters
will often show homogeneous normal or slightly reduced echogenicity.
Most of the congenital goiters develop in the early months and years of
extrauterine life. Infants born to mothers with Graves’ disease (circulating TSH
receptor antibodies that cross the placenta) can have fetal goiter [86]. Other
causes include prenatal ingestion of iodine [87], including administration of
amiodarone during pregnancy [88], lithium [30] and antithyroid drugs [89].
Diffuse Thyroid Disease
Inflammatory disorders of the thyroid include acute (suppurative), sub-
acute (de Quervain), and chronic autoimmune (Hashimoto’s) thyroiditis. Even
with less evident clinical signs of local infection, a complex hypoechoic mass
seen sonographically raises the suspicion of acute suppurative thyroiditis with
abscess formation [90]. When the left lobe of the thyroid is involved, the possi-
bility of a remnant of the left third pharyngeal pouch, which results in a fistula
between this lobe and the ipsilateral piriform sinus, should be considered
[91, 92]. When acute symptoms have subsided, a barium swallow should be per-
formed to identify any hypopharyngeal fistula [90]. Thyroglossal duct remnants
or cysts pose a risk of fistulas that may develop with infection and should be
evaluated with fistulograms [93]. Still, the ability of the thyroid gland to with-
stand infection is well known and abscess formation is rare [94].

Bennedbæk/Hegedüs 246
Subacute thyroiditis is extremely uncommon during childhood [35] and
the incidence is lower than that of acute suppurative thyroiditis. However, it is
an important differential diagnosis even with a unilateral painful enlargement
of a lobe presenting as a solitary cold thyroid nodule [95]. A radionuclide scan
showing ‘no uptake’supports the diagnosis (fig. 11), as does sonography, show-
ing marked hypoechogenicity – focal or diffuse – with reduced vascularity
(fig. 19) [96]. With recovery, size decreases, but areas of hypoechogenicity may
be detected for many months [96].
The majority of patients in the pediatric age group, mostly older children,
have an autoimmune chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis)
and it is also the most common cause of acquired hypothyroidism with or with-
out goiter [31]. This condition is often associated with other autoimmune disor-
ders, e.g. type 1 diabetes mellitus, celiac disease and also Turner’s syndrome
and Down’s syndrome. Conversely, in a high proportion of young patients with
type 1 diabetes without any clinical signs of thyroid disease, markers of thyroid
autoimmunity have been found [97]. More than 40% showed degrees of thyroid
hypoechogenicity on sonography and 16% had thyroid autoantibodies. The
typical sonographic signs in Hashimoto’s thyroiditis are marked diffuse or
inhomogeneous hypoechogenicity or patchy echo pattern (fig. 20) [1, 98].
Sonography cannot differentiate between goitrous autoimmune thyroiditis and
lymphoma. Therefore, growth of a goiter, especially in euthyroid subjects on
L-thyroxine therapy, should raise suspicion of lymphoma and lead to large-
needle biopsy [99].
Fig. 19. Trans-sectional gray-scale US of the right lobe showing marked hypoe-
chogenicity. A 14-year-old girl with subacute thyroiditis (for a corresponding scintigraphy of
the patient, see fig. 11).

Thyroid Imaging in Childhood 247
In conjunction with presence or absence of thyroid autoantibodies the clin-
ical utility of US is imperative. In contrast to the abnormal echogenicity in all
patients with Hashimoto’s thyroiditis, patients with a diffuse colloid goiter have
normal echogenicity [100, 101].
In patients with Graves’ disease, the thyroid is usually enlarged and the
echo pattern is homogeneous and diffusely hypoechoic (fig. 21a). Color
Doppler sonography demonstrates a hypervascular pattern often referred to as
‘thyroid inferno’ (fig. 21b). A significant decrease in flow velocities after
Fig. 20. Longitudinal US image of a 15-year-old girl with Hashimoto’s thyroiditis,
depicting reduced and diffuse echogenicity in an enlarged thyroid.
Fig. 21. Graves’ disease. aLongitudinal US showing an enlarged and diffusely hypoe-
choic thyroid lobe. bCorresponding Doppler image with increased vascularity indicating an
acute stage (debut) of the disease. There are multiple linear bright echoes throughout the
hypoechoic parenchyma with coarse septations.
ab

Bennedbæk/Hegedüs 248
medical treatment is often seen. However, there is no correlation between the
degree of biochemical hyperfunction and the degree of hypervascularity or
blood flow velocity. On the other hand, preliminary data suggest that quantifi-
cation of blood flow can predict recurrence following withdrawal of medical
treatment with a sensitivity of 71% [102].
Routine thyroid imaging (radionuclide scanning and US) is not indicated
in all disorders accompanied by diffuse thyroid enlargement, when there is no
clinically detectable focal thyroid abnormality, unless presence of features sug-
gestive of acute or subacute thyroiditis or malignancy, e.g. a history of radiation
exposure.
Nodular Thyroid Disease
In children, nodular thyroid disease may appear clinically as either a single
thyroid nodule (more common) or as a multinodular thyroid gland (less common)
[103, 104]. Nodular thyroid disease in childhood differs from that in adulthood
in two aspects. First, it is far less common in younger individuals and increases
in frequency with age. Second, thyroid carcinoma is much more likely to be
present in children than in adults with thyroid nodules. US is very helpful in
differentiating multinodular goiters (f ig. 22) from single thyroid nodules and
diffuse thyroid disease.
Multinodular thyroid disease in children is often associated with other dis-
orders, e.g. renal or digital anomalies, McCune-Albright syndrome and
Hashimoto’s thyroiditis, but equally important with a non-negligible incidence
of thyroid malignancy [103]. Furthermore, there are several families in whom
multinodular goiter has been described and the genetic loci identified [105],
Fig. 22. Multinodular goiter. Transverse US shows two small (less than 1cm in diame-
ter) cystic nodules. E Esophagus; Tr tracheal air shadow.

Thyroid Imaging in Childhood 249
including the rare autosomal-dominant Cowden disease [106]. The echographic
structure of multinodular or adenomatous goiter may be heterogeneous without
well-defined nodules (can have the same appearance of inhomogeneity as with
Hashimoto’s thyroiditis), or there may be two or more nodules within an other-
wise normal-appearing gland. Often patients evaluated for a solitary nodule
have additional small thyroid nodules detected by US but this finding does not
exclude carcinoma [107]. A solitary (by palpation) low-uptake thyroid nodule
with or without coexisting nodules warrants US-guided fine-needle aspiration
biopsy and a lower, compared with adults, threshold for diagnostic surgery [38].
Thyrotoxicosis in children is most often a result of Graves’ disease or
rarely an autonomous hyperfunctioning nodule but almost never due to toxic
multinodular goiter [108]. Toxic multinodular goiter in childhood has also been
described in association with nonautoimmune activating TSH receptor muta-
tions [109]. In the absence of thyroid autoantibodies, scintigraphy and US are
helpful in establishing a f inal diagnosis in order to guide treatment. The sono-
graphic appearance most often is that of multiple (two or more) discrete nod-
ules with increased blood flow on color Doppler sonography.
Single Thyroid Nodules
Although most single thyroid nodules in childhood are benign (e.g. colloid
nodules, follicular adenoma), thyroid carcinoma has been reported in 7–30% of
nodules in this population [104]. The clinical challenge is to distinguish the
malignant nodules from the many benign ones, and thus, to identify those
patients for whom surgical excision is indicated. The combination of sonogra-
phy with fine needle aspiration biopsy provides a sensitive and specific
approach to the child with a single thyroid nodule [110] and can at best avoid
unnecessary thyroid surgery [111].
Thyroid nodules on US may have one of three echo patterns: solid
(echogenic), cystic (echo-free), or a mixed solid-cystic appearance (fig. 23).
Mixed solid-cystic nodules are more likely to be neoplasms (follicular adenoma
or carcinoma) than are purely cystic lesions [112]. The majority of thyroid nod-
ules are due to hyperplasia, and are often referred to as hyperplastic, adenoma-
tous, or colloid nodules. Most of the cystic lesions are hyperplastic (colloid)
nodules that have undergone liquefactive degeneration. Most solid colloid nod-
ules appear iso- or hypoechoic on US (fig. 24) often with a thin peripheral
hypoechoic halo.
The benign follicular adenoma is a true thyroid neoplasm that has a fibrous
encapsulation, often appears as a solid iso- or hypoechoic mass (fig. 23a) but
without specific sonographic features to distinguish it from carcinoma. Various
subtypes include fetal adenoma, Hürthle cell adenoma, and embryonal ade-
noma. The cytologic features of follicular adenomas are indistinguishable from

Bennedbæk/Hegedüs 250
Fig. 23. Longitudinal US images of young patients with (a) a solid homogenous, oval
and well-defined hypoechoic thyroid nodule (benign follicular adenoma); (b) a small (hypo-
echoic) well-defined cyst, and (c) a mixed solid-cystic nodule.
a
c
b
Fig. 24. A benign colloid thyroid nodule. Longitudinal image of a homogeneous iso-
echoic round to oval mass with a thin halo surrounding the nodule.

Thyroid Imaging in Childhood 251
those of follicular carcinoma. Vascular and capsular invasion are the hallmarks
of follicular carcinoma and implies surgical excision for complete histological
investigation. Preoperative selection of these patients based on TPO immunos-
taining of biopsies has been proposed to improve sensitivity (more than 80%
staining suggesting a benign nodule) [113], but others have found that TPO
expression has limited value for the differential diagnosis of follicular thyroid
carcinoma from the thyroid adenoma [114].
Rare cases of primary thyroid teratomas have been described and are
important in the differential diagnosis because of the potential of malignant
transformation [115].
Since the extent of primary surgical treatment is closely related to the over-
all prognosis, preoperative diagnosis becomes essential in the management of
thyroid neoplasms in young patients. The preoperative workup of children and
adolescents with thyroid nodules requires the collaboration of an experienced
team of professionals, and US and US-guided FNAB are important in the initial
evaluation [116].
Thyroid Carcinoma
In childhood the most common malignant tumors in the head and neck
region are lymphomas and rhabdomyosarcomas whereas thyroid cancer in
childhood is rare, representing 1.4% of all pediatric malignancies in the USA
[117]. Its incidence rises after the age of 5 and its overall incidence in children
in England and Wales is 0.5 per million per year [118]. Papillary carcinoma
accounts for more than 90% of all pediatric thyroid cancers and 75% of these
have metastasized at presentation [119]. The commonest clinical presentation
of a thyroid malignancy is a palpable, asymptomatic, solitary nodule in the thy-
roid [120]. A solitary thyroid nodule in a child is alarming, since the incidence
of malignancy in such a nodule is higher than in adults and, at least in older
series, varies from 18 to 46% [37, 40].
A thyroid nodule that clinically appears solitary, solid or mixed solid-
cystic on ultrasound and hypofunctioning on scintigraphy is highly suspicious
for malignancy and warrants US-guided FNAB. Ultrasound guidance is recom-
mended because it facilitates accurate sampling of the lesion and reduces the
risk of false-negative results [121].
Sonographically, most carcinomas appear hypoechoic compared with the
remaining gland but so do the majority of colloid nodules. No single sono-
graphic criterion distinguishes benign thyroid nodules from malignant nodules
with complete reliability [122]. However, certain sonographic features are more
commonly found in benign or malignant nodules and thus can be suggestive of
either (table 6). The fundamental morphological features recorded on high-
resolution and color Doppler sonography should include:

Bennedbæk/Hegedüs 252
•internal consistency (solid, mixed solid-cystic, or purely cystic)
•echogenicity hyper (increased), iso (same), or hypoechogenicity
(decreased) relative to the adjacent thyroid parenchyma
•halo (present or absent, complete or incomplete)
•margin (well-defined vs. poorly defined)
•presence and pattern (coarse or fine) of calcifications
•presence and distribution of blood flow signals
•location (subcapsular or intervening thyroid parenchyma)
•lymphadenopathies
•invasion of adjacent structures
A nodule that has a signif icant cystic component is usually a benign col-
loid nodule that has undergone degeneration or hemorrhage. FNAB of both the
cystic and the solid part is mandatory. Papillary carcinomas may exhibit partly
cystic degeneration [123] and cervical lymph nodes with metastases may also
show a cystic pattern.
A peripheral sonolucent halo that completely surrounds a thyroid nodule
may be present in 60–80% of benign nodules and 15% of thyroid cancers [58].
The vast majority of benign thyroid nodules tend to have a sharp and well-
defined margin, whereas malignant lesions tend to have irregular or poorly
Table 6. Sonographic features suggestive of a benign versus a malignant
thyroid nodule
Feature Pathologic diagnosis
benign malignant
Purely cystic content  
Mixed solid-cystic  
Hypoechoic  
Thin halo  
Well-def ined margin  
Poorly defined margin  
Microcalcifications  
Increased peripheral flow  
Increased intranodular flow  
Subcapsular location  
Lymphadenopathies  
Invasion of adjacent structures 
Rare (1%); low probability (15%); intermediate probability
(16–84%); high probability (85%).
Adapted from [58, 125, 126].

Thyroid Imaging in Childhood 253
defined margins, but nevertheless a finding with poor predictive value. Intra-
nodular calcif ications are detected in more than 10% of thyroid nodules in the
adult population [58]. Although indicative of malignancy it is also frequently
seen in benign nodules as reported in one study of 159 adult patients operated
on. In this study a preoperative US detected calcifications in three fourths of the
malignant and one third of the benign nodules [124]. In thyroid cancer in chil-
dren it is a less frequent f inding and in one study of 103 consecutive pediatric
patients with solid thyroid nodules, microcalcification was found in only 5 and
3% of malignant and benign nodules, respectively [125]. In the same study,
increased intranodular vascularity (sensitivity of 70% and specif icity of 88%),
a subcapsular location (sensitivity of 65% and specificity of 86%) together with
an irregular outline were the most reliable diagnostic markers for cancer in
smaller nodules (diameter less than 15 mm). The only sonographic features with
a very high probability of malignancy are pathological appearing ipsilateral
lymph node(s) and features of invasion of adjacent structures [126]. Certain fea-
tures of enlarged cervical lymph nodes are indicative of malignancy and include
round shape (rather than oval), absent hilus, intranodal necrosis, calcif ication,
matting, soft-tissue edema, and peripheral vascularity (fig. 25) [127].
Papillary carcinoma has specific histologic (fibrous capsule, microcalcif i-
cations) and cytologic features (‘ground glass’ nuclei, cytoplasmic inclusions in
the nucleus) that often allow a relatively easy pathologic diagnosis. Some of the
US characteristics of papillary carcinoma include hypoechogenicity (90%),
microcalcifications, hypervascularity (often disorganized), and cervical lymph
node metastases that may contain microcalcif ications or may be partly cystic.
The minimally invasive follicular carcinoma is encapsulated, and only the
Fig. 25. a A normal oval lymph node with an echogenic linear hilus centrally.
bLongitudinal image near the carotid artery and jugular vein, showing a large hypoechoic
round metastatic lymph node with anarchic vascularization (power Doppler). C Carotid
artery; J jugular vein.
ab

Bennedbæk/Hegedüs 254
histological demonstration of focal invasion of the capsule itself, or of capsular
blood vessels, permits differentiation from follicular adenoma. Sonographically,
it will often appear solid and iso- or hypoechoic with a thick hypoechoic halo.
Often vessels pass from the periphery to the center of the nodule. The widely
invasive follicular carcinomas are not well encapsulated and invasion of the
vessels and the adjacent thyroid can sometimes be apparent on US, showing an
irregular tumor margin in addition to a chaotic arrangement of internal blood
vessels [58]. The sonographic appearance of medullary carcinoma is usually
similar to that of papillary carcinoma and is most often seen as a hypoechoic
solid mass, occasionally with more coarse calcif ications. It is important to
remember that the disease is often multicentric and/or bilateral in about 90% of
the familial cases and a high incidence of lymph node involvement is seen.
Extranodal thyroid lymphomatous involvement (non-Hodgkin’s lymphoma) is
rare in childhood and sonographically appears as a markedly hypoechoic and
lobulated mass which is mostly hypovascular. In the adult population it can
arise from a preexisting Hashimoto’s thyroiditis [128].
Routine thyroid US is recommended for surveillance of children and ado-
lescents who have had neck irradiation for other childhood cancers [129].
A baseline study one year after irradiation is recommended with ongoing fol-
low-up US depending on the radiation dose and the patient’s age at the time of
irradiation [104]. Thyroid US seems more sensitive than physical examination
or scintigraphy in the follow-up of patients exposed to head-and-neck irradia-
tion during childhood for benign conditions [130].
Computed Tomography
Computed tomography offers excellent anatomic resolution because of its
ability to identify small differences in density between different tissues [131].
It is highly sensitive for detecting thyroid nodules, but as with US, benign nodules
cannot be distinguished from carcinomas [132]. It can distinguish solid from
cystic and mixed solid-cystic nodules and thyroid volume can be determined. It
is superior to US in detecting thyroid tissue in the retrotracheal, retroclavicular
and intrathoracic regions and for evaluation of metastatic disease in the neck
and thorax [133]. The limitations of CT are cost, limited availability, length of
the procedure, need for patient cooperation, artifacts caused by swallowing or
breathing, and exposure to ionizing irradiation (1–4 rad) [132]. It has been sug-
gested that the higher doses and increased lifetime radiation risks in children
will actually produce a sharp increase, relative to adults, in estimated risk of
lifetime cancer from CT [134]. This fact may stimulate a more active approach
toward reduction of CT exposure in pediatric patients, which is definitely

Thyroid Imaging in Childhood 255
supported by the availability of equal, or in some instances superior, imaging
modalities. Furthermore, the need for sedation in newborn and smaller children
makes CT less attractive compared to US, as an initial examination of neck
masses in children. CT-guided biopsy is possible but more cumbersome than
is US-guided biopsy. It can be valuable in poorly accessible or deep-seated
lesions of the neck [135]. Neither CT nor MRI is routinely indicated in the
pediatric population with thyroid disorders, and never in case of hyper- or
hypothyroidism.
Indications for CT of the Thyroid
Localization of thyroid tissue is valuable in the workup of hypothyroidism
(including congenital hypothyroidism) during childhood or in rare cases of stri-
dor [136]. For this purpose, US is recommended as an initial screening exami-
nation in addition to scintigraphy. However, in a small series of 19 patients with
congenital hypothyroidism, enhanced CT (Omnipaque intravenously) identi-
fied ectopic (sublingual) thyroid tissue in 7 patients, which was missed by US
as well as by scintigraphy [137]. Enhanced CT seems to be of value in identify-
ing thyroid tissue when US and scintigraphy fails.
CT can estimate the extent of tracheal compression by a goiter and can
provide information on retroclavicular extension of the thyroid. Some recom-
mend preoperative US as well as CT of the neck and chest to delineate the
extent of the disease [104]. Furthermore, CT is of value in the follow-up of
patients with thyroid carcinoma because of its sensitivity for detecting recurrent
carcinoma in the neck, and metastases elsewhere. Recurrent carcinoma appears
as discrete low-density lesions within or outside the thyroid bed, and lymph
node metastases show no enhancement after contrast injection [138]. CT can
complement whole-body scintigraphy in the follow-up of these patients, espe-
cially if recurrence is suspected.
Normal Thyroid
The normal thyroid gland is easily seen on CT, and its density is always
higher than that of the surrounding tissues (fig. 26). CT density of the thyroid is
closely related to its iodine content and reduced density is the hallmark of many
thyroid disorders, but still not specific for any thyroid disorder.
Developmental Abnormalities
Ectopic thyroid tissue may be located anywhere from the foramen coecum,
at the base of the tongue, to the anterior mediastinum. Scintigraphy is the imag-
ing procedure of choice but CT can aid in localization if radionuclide uptake is
poor [1]. CT enables the differentiation of thyroglossal duct cysts from other
neck lesions based on location, CT values, and alterations in the adjacent soft

Bennedbæk/Hegedüs 256
Fig. 26. Transverse sectional computed tomography of the neck showing a normal
homogeneous thyroid gland.
tissues [139]. Carcinoma within the thyroglossal duct is a very rare pediatric
tumor and so far only 22 cases have been reported in the literature [140].
Calcification within the cyst, or a dense enhancing nodule seen on enhanced
CT, raises suspicion of a carcinoma.
Diffuse Thyroid Disease
In patients with Graves’ disease, the density is decreased by 50–70% due
to decreased iodine stores, and the tissue may be slightly inhomogeneous [141].
In patients with Hashimoto’s thyroiditis the density is reduced and is lowest in
patients with hypothyroidism [142]. Asymmetric low-density areas should raise
the suspicion of lymphoma or carcinoma [143]. In the initial phases acute sup-
purative thyroiditis shows non-specific morphological alterations, but as infec-
tion progresses loculated hypodense areas (abscess) may appear [144].
Nodular Thyroid Disease
Multinodular goiters are usually seen as an enlarged asymmetric thyroid
gland with multiple areas of varying degrees of density (f ig. 27) [1]. However,
medullary thyroid carcinoma can appear as single but also multiple low-density
lesions of variable size, in one or both lobes, and be misclassif ied as ‘benign-
appearing’ multinodular goiter [145]. Compression of the trachea (fig. 28),
esophagus, and great vessels is easily detected, and CT is ideal for estimating
the extent of tracheal compression by a goiter [146].

Thyroid Imaging in Childhood 257
Fig. 27. CT of the neck showing areas of varying degrees of density in a slightly
enlarged thyroid gland compatible with multinodularity.
Fig. 28. CT of the neck showing the trachea is displaced to the left and with compressed
lumen due to thyroid carcinoma.

Bennedbæk/Hegedüs 258
Fig. 29. Medullary carcinoma appearing as a heterogeneous and enlarged left thyroid
lobe with ipsilateral lymph node metastasis lateral to the jugular vein. The trachea is dis-
placed slightly to the right.
The complete extent of larger lesions is – in some cases – better evaluated
with CT (or MRI).
Thyroid nodules often appear as low density lesions but CT cannot differ-
entiate benign nodules from papillary and follicular carcinomas. As with US,
calcifications are easily detected and invasive growth into surrounding struc-
tures, as well as lymph node metastases (neck and mediastinum), can be
revealed by CT (fig. 29) [138].
Magnetic Resonance Imaging
MRI offers excellent anatomic resolution and generation of images in multi-
ple planes. Conventional T1- and T2-weighted imaging is highly sensitive but just
as nonspecific as US and CT in differentiating benign thyroid nodules from car-
cinomas. Sensitivity does not increase with additional gadolinium-enhancement
but primary thyroid lymphoma enhances less than other solid thyroid tumors
[147]. MRI can distinguish solid from cystic nodules (fig. 30) [132]. Like CT, it
provides highly accurate estimates of thyroid volume with a low observer vari-
ability and is useful, especially in irregularly enlarged goiters [148]. As CT, and
in contrast to US, it can identify thyroid tissue in the retrotracheal and intratho-
racic regions (fig. 31). The obvious limitations of MRI are its cost, limited

Thyroid Imaging in Childhood 259
Fig. 30. Axial MR examination with T2- (on the left side) and T1-weighted (on the right
side) scans of a cystic-solid thyroid nodule in the right thyroid lobe. In the picture on the left
side a hypointense solid component (arrow) can be seen in comparison with the relatively
hyperintense fluid. In the T1-weighted picture on the right side, the lesion can not be recog-
nized in the hypointense fluid.
Fig. 31. Coronal T1-weighted MRI of a large multinodular goiter shows compression
of trachea (white arrow) and left-sided substernal extension (black arrows).

Bennedbæk/Hegedüs 260
availability, length of the procedure, need for preparation and patient coopera-
tion – the examination cannot be carried through in 5–10% of adult patients
due to claustrophobia – and anesthesia is required in early childhood [149].
Tissue movement decreases image quality, and calcifications are better seen
with CT [150].
Indications for Thyroid MRI
MRI is rarely required to define anatomy and parenchyma of the thyroid
gland itself, but is more useful in defining the exact extension of very large
thyroid glands and large masses caused by lymphadenopathy, which may be dif-
ficult to achieve with US alone. Metastatic lymph nodes in the neck as well as
invasion of the aerodigestive tract are also in the realm of MR imaging [142]. In
this context, the extent of thyroid carcinoma can be determined preoperatively,
which may be useful in planning surgery. Another potential implication of MRI
is for the detection of the site of recurrent carcinoma in thyroglobulin-positive
patients with normal clinical examinations. Features such as asymmetry,
increased signal intensity in the thyroid bed, and invasion or displacement of
adjacent tissue, as well as enlarged lymph nodes with increased signal intensity
suggest recurrent carcinoma [151]. Additional gadolinium injection may be
useful because enhancement is seen in recurrent carcinoma and also in meta-
static nodes [152].
Acute suppurative thyroiditis and thyroid abscess are rare disorders and
congenital pyriform fistula should be suspected, especially in case of recurrent
infections on the left side. MRI or CT is valuable in addition to barium esopha-
gography in the workup of such patients [153].
Normal Thyroid
On T1-weighted images the normal thyroid gland has a nearly homoge-
neous signal with an intensity similar to that of the adjacent neck muscles
(fig. 32) [154]. Air, blood, and vessels usually appear black. On T2-weighted
images, the normal thyroid gland has a greater signal intensity than the adjacent
muscles. Blood vessels, lymph nodes, fat, and muscle are clearly identified and
distinguished from the thyroid.
Developmental Defects
Ectopic thyroid tissue may be encountered in the tongue (foramen cecum),
along the midline between the posterior tongue and the isthmus of the thyroid
gland, but also in the oral cavity, lateral neck and mediastinum. Scintigraphy is the
first-line imaging modality. MRI, however, is also useful as demonstrated in a
small series of 21 patients with submucosal lesions in the base of the tongue [155].
MRI depicted lingual thyroid and additional ectopic thyroid tissue in the floor of

Thyroid Imaging in Childhood 261
the mouth and lateral neck in concordance with the scintigraphic findings. Ectopic
thyroid glands appear isointense or hyperintense relative to muscle tissue on
T1-weighted images and show slight to moderate contrast enhancement, and the T2
signal appears low to intermediate. In the same study all ectopic thyroid tissue had
well-defined margins on MRI and in case of ill-defined margins malignancy with
invasion of adjacent structures was confirmed surgically [155]. Although rare,
goiter and malignant tumors may develop in ectopic thyroid tissue [142].
Diffuse Thyroid Disease
In Graves’ disease both T1- and T2-weighted images show a diffusely
increased but slightly heterogeneous signal [156]. Dilated vessels within the thy-
roid can often be identified [157]. In autoimmune thyroiditis the thyroid appears
heterogeneous on T1-weighted images and often with diffusely increased signal
on T2-weighted images [157]. A morphological overlap on T1- and T2-weighted
images is seen between patients with Graves’ disease, subacute thyroiditis and
Hashimoto’s thyroiditis, but additional calculation of the diffusion coefficient
can distinguish Graves’ (highest values) from the other two [158]. In subacute
thyroiditis T1-weighted images demonstrate regions of abnormality with irregu-
lar margins and slightly high intensity while on T2-weighted images, markedly
increased intensity can be seen in the same sites [159].
Infiltration of adjacent neck structures and hypointensity on T1- and T2-
weighted images are suggestive of Riedel’s thyroiditis [160].
Fig. 32. Axial MRI of the neck showing a T1-weighted image with a normal thyroid gland
appearing homogeneous and with signal intensity similar to that of the adjacent neck muscles.
Thyroid gland
Trachea
Esophagus
Sternocleidomastoid m.
Internal jugular v.
Scalenus mm.
Cervical spine
Spinal cord
Semispinalis cervicis m.
Splenius capitis m.
Nuchal lig.
Longus colli m.
Levator scapulae m.
Trapezius m.
Vertebral a.

Bennedbæk/Hegedüs 262
Nodular Thyroid Disease
Multinodular goiters have various degrees of heterogeneity and low to
increased signal intensity on T1-weighted images [154]. Focal hemorrhage and
areas of cystic degeneration, often seen in multinodular goiters, are character-
ized by high signal intensity [157]. Nodules are better visualized on T2-
weighted images [157] and simple cysts show a homogeneous high-intensity
signal (increases with increasing protein and lipid content) on both T1- and T2-
weighted images. The MR characteristics of hyper- or hypofunctioning nodules
do not differ. Hyperplastic-colloid nodules and benign adenomas appear round
or oval with a heterogeneous signal equal to or greater than that of normal thy-
roid tissue [156].
No MRI characteristics accurately distinguish between benign nodules and
carcinomas, although a nodule with a smoother, more uniform, and thicker cap-
sule is more likely to be benign [161]. Thyroid carcinomas appear as focal or
multifocal lesions of variable size, and iso- or slightly hyperintense on T1-
weighted images and hyperintense on T2-weighted images. MRI is valuable to
assess extracapsular spread, especially into the trachea, larynx, esophagus, ves-
sels, and muscles [162].
The complete extent of larger lesions is – most often – better evaluated
with MRI or CT than with US.
On MRI, metastatic lymph nodes can have low to intermediate T1- and
high T2-weighted signal intensities or high T1- and T2-weighted signal intensi-
ties, the latter reflecting primarily a high thyroglobulin content. The metastatic
nodes in papillary carcinoma may enhance markedly (hypervascular) [142].
Acknowledgments
We are indebted to Peter Oturai, Department of Nuclear Medicine and Clinical
Physiology, Glostrup University Hospital, Denmark, for providing the majority of the
radionuclide images and to Helle Hendel and Mette Nørlem, Herlev University Hospital,
Denmark, for PET, CT and MR images.
The authors thank The Novo Nordisk Foundation, The Agnes and Knut Mørk
Foundation and the A.P. Møller Relief Foundation for economic support.
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Finn N. Bennedbæk, MD, PhD
Department of Endocrinology and Metabolism, Herlev University Hospital
Herlev Ringvej 75, DK–2730 Herlev (Denmark)
Tel. 45 4488 4051, E-Mail f inobe01@herlevhosp.kbhamt.dk

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 270–277
Thyroid and Other Autoimmune
Diseases with Emphasis on Type 1
Diabetes Mellitus and Turner
Syndrome
Thomas Kapellen, Angela Galler, Roland Pfäffle, Wieland Kiess
Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
Modern diabetes management facilitates normal growth and development in
children and adolescents with diabetes. However, comorbidity including autoim-
mune disorders like autoimmune thyroiditis, adrenal insufficiency, or celiac dis-
ease may lead to disturbance of growth and pubertal development of children and
adolescents with diabetes. Such comorbidity could also have a negative impact on
metabolic control. Therefore awareness of these complications and monitoring
are mandatory in clinical diabetes management [14]. If several of autoimmune
diseases are present in a patient autoimmune polyglandular syndrome (APS)
should be considered. APS type 1 also known as autoimmune polyendocrinopa-
thy-candidiasis ectodemal dystrophy (APECED) is a rare syndrome that com-
bines mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency.
Inheritance is autosomal-recessive with a mutation of the autoimmune regulatory
gene (AIRE) on chromosome 21. In contrast, APS type 2 shows various combi-
nations of adrenal insufficiency, autoimmune thyroid disease and type 1 diabetes.
This syndrome with polygenetic inheritance has a prevalence of 1–2/100,000
[5, 13, 31]. For girls with Turner syndrome autoimmune hypothyroidism is an
even more common comorbidity. Thyroid function should therefore performed
routinely in the long term care of Turner patients. Additionally, there is evidence
for a 4- to 8-fold higher incidence of celiac disease in females with Turner syn-
drome than in the non-Turner population. The prevalence of other autoantibodies
to endocrine organs (pituitary, adrenocortical cells, gastric parietal cells) is not
increased in Turner patients [10].

Type 1 D. Mellitus and Turner Syndrome in Autoimmune Diseases 271
Thyroid Disease in Diabetes Mellitus
The most frequent autoimmune disease in type 1 diabetes affects the thyroid.
The etiology of autoimmunity in pancreas and thyroid is a T cell-mediated disease
and seems to be due to common genetic susceptibility. Two immune regulatory
genes (HLA human leukocyte antigen and CTLA-4 cytotoxic T lymphocyte-
associated protein 4) contribute to the susceptibility for both diseases [5, 23].
This locus, also known as the IDDM 12 gene, seems to play a major role in deve-
lopment of autoimmune polyglandular syndrome type 2 (APS-2).
Autoimmunthyroiditis describes a group of thyroid diseases with destruc-
tion of thyroid tissue due to an autoimmune reaction. Classification of these
diseases is not consistent in the literature. Most frequently, Hashimoto thyroidi-
tis with antibodies against thyroid antigens is found. These antibodies are
directed towards thyroid peroxidase (TPO-Ab), thyreoglobulin (TG-Ab) and/or
TSH-receptor antigen (TRAK).
Positivity for thyroid auto antibodies in children with type 1 diabetes
shows considerable variability in different countries. Incidence and prevalence
numbers vary between 3 and 50% [3, 18, 19, 33, 36] compared to a suggested
rate of 3–10% in non diabetic children and adolescents [17, 26, 38]. The largest
cohort analysis was published by Kordonouri et al. [19] reporting a rate of
21.6% of thyroid antibodies in a group of 7,097 children and adolescents with
type 1 diabetes. In this study patients with antibody positivity were older, had
longer diabetes duration and had developed diabetes later in life. 63% of
patients with positive thyroid antibodies were female.
The majority of patients with positive thyroid antibodies have normal
thyroid function. Elevated TSH levels as a marker for subclinical hypothy-
roidism are found in about 15% in the antibody positive patient group. Overt
primary hypothyroidism due to autoimmune thyroiditis is seen in 3–5% of
patients [3, 8, 19]. Clinical findings of hypothyroidism like goiter, weight gain,
fatigue, cold intolerance and bradycardia are rare because of screening for TSH
and autoantibodies in patients with type 1 diabetes (table 1).
In the study of Kaspers et al. [16], evidence for thyroid disease was significantly
more often observed in patients when celiac disease was present (6.3 vs. 2.3%).
Since screening is both efficient and cost effective there is no controversy
about thyroid antibody screening in patients with type 1 diabetes anymore.
Screening is performed in our institution once a year. In case of significant anti-
body levels (especially thyroperoxidase antibodies) a longitudinal survey of
diabetic children over 5 years showed a higher risk of later development of TSH
elevation and subclinical or clinical hypothyroidism [18]. These data were con-
firmed by a recently published study from Australia over a follow-up period of
13 years [9]. Therefore, in patients with elevated TPO/TGA antibodies thyroid

Kapellen/Galler/Pfäffle/Kiess 272
function (TSH and free T4) should be measured routinely. Ultrasound of the
thyroid gland could provide further information on the development of
Hashimoto’s disease with typical patterns like increased volume of the gland
and areas of lower echogenity within the thyroid. Hansen et al. [11] found
sonographic abnormalities in 42% of children with type 1 diabetes in compari-
son to 11% in the control group. In long-term follow-up after 3 years preva-
lence of these sonographic findings increased up to 50% in diabetic patients.
However, 9% of diabetic patients with abnormalities at baseline had a normal
ultrasound of the thyroid at follow-up.
There is no consensus on the time point of introduction of treatment with
thyroxin! In our opinion treatment with thyroxin is recommended in the case of
subclinical or clinical hypothyroidism or significant antibody levels plus ultra-
sound findings.
The impact of subclinical hypothyroidism on metabolic control in children
and adolescents with type 1 diabetes mellitus was studied by Mohn et al. [30].
In this retrospective case control study, 13 patients with subclinical hypothy-
roidism had significantly more symptomatic and severe hypoglycemic events
during 12 months prior to the diagnosis of thyroid disease. There was no difference
in HbA1c, insulin requirement or growth between the two groups as had also
Table 1. Prevalence of hypothyroidism or hyperthyroidism in patients with type 1 diabetes mellitus in
different countries
Country Number of Hypothyroidism Hyperthyroidism Follow-up Reference
patients male:female male:female years
(age, years)
UK 509 20 (3.9%) 8 (1.6%) 8 [20]
(16–45) 1:5.6 1:1
USA 58 18 (31%) 1 (1.7%) 18 [35]
1:2.6
USA 204, 28 (14%) 18 (9%) – [34]
⬍20 years 6 subclinical 3 subclinical
Germany 216 8 (3.7%) 0 4–13 [18]
(1–22) 1:1.6
all subclinical
Italy 1,419 55 (3.9%) 0 – [33]
(1–18)
Italy 212 3 (1.5%) 1 (0.5%) 3–10 [25]
(1.2–21) 9 with thyroiditis
in biopsy

Type 1 D. Mellitus and Turner Syndrome in Autoimmune Diseases 273
been found in the cohort of Kordonouri et al. [19]. After introduction of
thyroxin substitution the rate of hypoglycemia decreased rapidly and after
6 months there was no difference between the groups anymore.
Hyperthyroidism is less common than hypothyroidism in association with
diabetes but still more common than in the general population. There is less
published data available with a frequency of subclinical disease in about 2–3%
and overt hyperthyroidism or thyrotoxicosis in only a few patients [25, 34, 35].
Hyperthyroidism may be due to Grave’s disease or hyperthyroid phase of
Hashimoto’s thyroiditis. It should be considered if there is unexplained weight
loss with normal appetite, agitation, sweating, tachycardia, tremor or unex-
plained problems with metabolic control.
There is no difference in treatment strategies between patients with dia-
betes and the nondiabetic population [20]. Therefore, antithyroid drugs still
remain the initial treatment of choice. However, in non-European countries
(especially the USA) radioactive iodine is used more frequently. There is no
long-term safety data available until now and radioactive iodine has not been
shown to be superior to antithyroid drug treatment at the moment.
Thyroid Disease in Turner Syndrome
An association between Turner syndrome (TS) and thyroid disease was
first suggested by Atria et al. [1] in 1948 when they reported post mortem find-
ings of a small thyroid gland with lymphocytic infiltration in a young woman
with Turner syndrome.
Many authors reported on a higher prevalence of hypothyroidism and an
association with positive thyroid antibodies in TS patients (table 2) [2, 6, 7, 24,
29, 32, 37]. Hypothyroidism is found in up to 35% of TS patients. Thyroid
autoimmunity seems to be even more common in females with Turner syndrome
with a prevalence of up to 52% [15]. A positive family history was reported by
Wilson et al. [37]. This group found an increased incidence of thyroid antibodies
in patients with TS and their first degree relatives. The incidence of thyroid anti-
bodies was 30% in patients compared to 1.7% in an age matched control group
and 22% in the mothers of the TS patients (vs. 6.6% in the controls). Larissa et
al. [21] found a preferential parental segregation of autoimmunity in their study.
There is no clear explanation for the higher frequency of thyroid auto-
immunity in Turner syndrome. The positive family history could give a link to
genetic co-etiology. HLA association is discussed very controversially in the
literature. In the Italian study of Larizza et al. [21], an association of HLA-DR7/
DQ2 and DR7/DQ9 haplotypes with autoantibodies was detected. These haplo-
types have been reported to be associated with autoimmune disorders. Other

Kapellen/Galler/Pfäffle/Kiess 274
chromosomal aberrations like Down syndrome also tend to be associated with
thyroid autoimmunity.
In order to evaluate the functionality of the hypothamic-hypophyseal-
thyroid axis, Mazzilli et al. [28] studied 27 children and adolescents with TRH
test and compared these data with an age- and sex-matched control group.
There were no differences between the two groups in TSH levels or areas under
the curve after the injection of TRH.
The age of onset of thyroid abnormalities has been reported to a variable
degree in the literature. Many authors reported (laboratory) onset before the age
of 5 years [29, 32]. As seen in the normal population there is a rise in incidence
of thyroid autoimmunity and hypothyroidism until puberty [29, 32]. The annual
incidence is estimated to be 3.2% in females with Turner syndrome [6].
The clinical findings in Turner females in comparison to laboratory abnor-
malities were examined in a large cohort of 478 patients by Radetti et al. [32].
Of the 106 patients with positive thyroid antibodies 49 patients had a positive
ultrasound indicating autoimmune thyroid disease. Of those 49 patients 17 were
euthyroid, 27 had compensated subclinical hypothyroidism, 2 were hypothyroid
and 3 were hyperthyroid. Goiter was found on clinical examination in 16
patients. There were no symptoms of hypothyroidism in any patient. However,
Table 2. Prevalence of hypothyroidism or hyperthyroidism in patients with Turner syndrome in dif-
ferent countries
Country Number of Hypothyroidism Autoantibodies Hyperthyroidism Reference
patients (age)
Greece 84 20 (24%) 35 (42%) 2 (2.5%) [24]
(1–19)
UK 60 – 18 (30%) – [37]
UK 145 22 (15%) 60 (41%) 1 (0.7%) [7]
(16–52)
Sweden 91 23 (25%) 25 (28%) 3 (3.3%) [6]
(0–37) follow up:
34 (37%)
Brazil 71 11 (15.5%) 17 (23.9%) – [29]
(0–20)
Italy 478 29 (6.1%) 106 (22.2%) 3 (0.6%) [32]
(3–25) 27 subclinical
Germany 120 42 (35%) 43 (35.8%) – [2]
(16–23)
Total 1,049 147/989 (14.9%) 304 (29%) 9/798 (1.2%)

Type 1 D. Mellitus and Turner Syndrome in Autoimmune Diseases 275
in the three hyperthyroid patients irritability, sweatiness, diarrhea, weight loss,
tremor and sleep disorders were found [33].
Many studies tried to find an association between clinical symptoms and
the karyotype of X-chromosome [2, 7, 29, 33]. The risk of developing auto-
immune thyroid disease may be particularly high in patients with Turner
syndrome with an X-isochromosome [7, 21]. Ivarson et al. [15] also found a
higher incidence of thyroid autoantibodies in females with isochromosome X
and in patients with 45 X0 compared to mosaicism or structural disturbances of
the X chromosome. Other authors [6, 29, 33] could not f ind such associations.
The risk of developing hypothyroidism therefore appears to be high for all TS
women, independent of the karyotype.
Short stature in Turner syndrome can be successfully treated with growth
hormone. Normalization of height can be achieved when growth hormone treat-
ment is started at a young age and pharmacological doses are applied [4].
However, the growth hormone response in patients with TS seems to be rather
variable. A transient alteration of thyroid status with a slight decrease of T4 levels
after introduction of growth hormone administration has been described [27].
Bettendorf et al. [2] found an association of the gain over projected height (PAH)
after growth hormone treatment with autoimmunity. The PAH was 6.56cm in TS
patients without autoantibody titers while patients with positive TPO/TG or
tissue-transglutaminase antibodies had a PAH of only 4.16 cm (p ⬍0.01 cm). This
could indicate an association of growth hormone effects with autoimmunity and
especially subclinical hypothyroidism. On the other hand, a higher risk to develop
thyroid autoimmunity due to growth-promoting treatment has not been found.
In conclusion, screening for thyroid function and thyroid autoimmunity in
females with Turner syndrome is recommended from age 4–5 years upward.
Measurement of TSH and free T4 should be conducted annually. There is no
consensus whether or not autoantibodies should also be screened for. In our
opinion, in patients at high risk for the development of hypothyroidism elevated
autoantibody titers may precede the development of hypothyroidism.
Treatment is not different from the guidelines for the general population.
However, one should keep in mind the association of thyroid function and
autoimmunity to growth hormone response in some studies. Therefore, treat-
ment of subclinical hypothyroidism should immediately be introduced.
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Thomas M. Kapellen, MD
Hospital for Children and Adolescents, University of Leipzig
Oststrasse 21–25
DE–03417 Leipzig (Germany)
Tel. ⫹49 341 9726168, Fax ⫹49 341 9726169, E-Mail kapt@medizin.uni-leipzig.de

Krassas GE, Rivkees SA, Kiess W (eds): Diseases of the Thyroid in Childhood and Adolescence.
Pediatr Adolesc Med. Basel, Karger, 2007, vol 11, pp 278–286
Thyroid and Trace Elements in Children
and Adolescents
George J. Kahaly
Department of Medicine I, Gutenberg University Hospital, Mainz, Germany
Iodine Deficiency and Supplementation
Iodine deficiency produces a spectrum of disorders – endemic goiter,
hypothyroidism, cretinism, and congenital anomalies – that are termed the
iodine deficiency disorders. Despite substantial global progress against iodine
deficiency, it is estimated that 750 million people worldwide, or approximately
15% of the population, remain iodine deficient and goitrous. In iodine-def icient
areas, multiple nutritional and environmental influences contribute to the preva-
lence and severity of iodine deficiency disorders. Even nowadays, iodine nutri-
tion in children and iodine supplementation of pregnant women remains a
medical challenge and ought to be optimized. In Europe, nearly two-thirds of the
populations live in countries that are iodine deficient. Damage to reproductive
function and to the development of the fetus and newborn is the most important
consequence of iodine deficiency. The fetal brain is particularly vulnerable to
maternal hypothyroidism in iodine deficiency, and iodine def iciency is the lead-
ing cause worldwide of mental retardation. Even mild or sub clinical maternal
hypothyroidism during pregnancy can impair mental development of the new-
born. The recommended daily intake during pregnancy from the World Health
Organization/United Nations Children’s fund/International Council for Control
of iodine deficiency disorders (WHO/UNICEF/ICCIDD) is 0.2mg, while the
United States Institute of Medicine (IOM) suggests a recommended dietary
allowance (RDA) during pregnancy of 0.22 mg or 220 ␮g. The ‘VERA’ study in
Germany reported a median (range) iodine intake of 100 (33–284) ␮g/day in 19-
to 24-year-old women. Recent studies reporting low urinary iodine in pregnant
women in Europe reinforce the dietary intake data. Urinary iodine excretion is
an accurate indicator of dietary iodine intake as more than 90% of ingested

Thyroid and Minerals 279
iodine is excreted in the urine and urinary iodine is highly sensitive to recent
changes in iodine intake. In eight iodine-deficient countries, urinary iodine con-
centrations indicate that iodine intakes are clearly inadequate. Studies of thyroid
size in pregnancy measured by ultrasonography also indicate iodine nutrition is
suboptimal in much of Europe. In countries affected by mild or moderate iodine
deficiency (e.g. Germany, Belgium, Italy, Denmark), thyroid volume increases
14–30% during pregnancy, while in iodine-sufficient countries (Finland,
Holland), there is no increase in thyroid volume during pregnancy.
Six randomized, controlled trials of iodine supplementation in pregnancy
have been published, involving 450 women with mild-to-moderate iodine def i-
ciency. In all six trials, supplementation resulted in a significant increase in
maternal urinary iodine. Iodine doses varied between 50 and 230 ␮g/day, and
the data indicate no clear dose-response relationship for urinary iodine, TSH,
thyroglobulin, thyroid hormone or thyroid volume. For the newborn, most data
suggest supplementation is safe and efficacious. The studies also suggest an
increase in newborn thyroid volume and thyroglobulin can be prevented or min-
imized by supplementation, which has little or no impact on newborn total or
free thyroid hormone levels. There are no clinical data on the effect of supple-
mentation on birth weight or prematurity, and no data on long-term outcomes,
such as thyroid autoimmunity, or child development.
The labeled iodine content of multivitamin/minerals marketed as prenatal
supplements in Europe varies widely. Many commonly used products contain no
iodine, while others contain 200 or even 300␮g. The actual iodine content in sup-
plements is determined not only by the original amount added, but also by the sta-
bility of the compound, the time elapsed since manufacture, and the conditions
under which the product is stored. The iodine content of kelp supplements, a pop-
ular supplemental form, is highly variable. The median iodine content (range)
of the manufacturer’s recommended daily supplement regimen was 1,005 ␮g
(210–3,840 ␮g) or 1 mg. The mean measured content (as a percent of declared
content) was 137% (45–914%). For half of the kelp supplements, the manufac-
turer’s recommended daily dose was greater than 1,100␮g/day, the recommended
safe upper limit for pregnancy. In addition, bioavailability of iodine from supple-
ments has not been tested. Bioavailability can be influenced by the physical form
of the product, e.g. tablets vs. gelatin capsule, the substance used in coating and
thickness of coat, the amount of pressure used to form the tablet, the disintegra-
tion and dissolution of the tablet, and other nutrients or substances present which
may interfere with bioavailability. Until recently, there was no specific European
Union regulation of multivitamin/mineral supplements. They were classified as
foods, and had to comply with relevant EU food legislation and individual mem-
ber state’s internal legislation. In 2002, the European Parliament approved a com-
mon position which states that the label of the supplement must contain clear

Kahaly 280
instructions for daily dosage, and a warning about possible health risk from
excess use. Provisions specific for iodine state: supplements may contain iodine;
the amount present should be labeled in ␮g; the only iodine compounds permitted
are potassium iodide, potassium iodate, and sodium iodate.
Finally, 26 prospective controlled trials regarding iodine deficiency in child-
hood and related disorders, assessing 29,613 children, were recently reviewed.
The results suggest that iodine supplementation, especially iodized oil, is an
effective means of decreasing goiter rates and improving iodine status in
children. Indications of positive effects on physical and mental development
and mortality were seen. Adverse effects, noted in 1.8% only of the children
investigated, were generally minor and transient. Results for differences in cog-
nitive and psychomotor measures were mixed, with studies showing a positive
intervention effect. Most studies showed a significant increase in urinary iodine
excretion and levels recommended by the WHO were reached in most cases
after iodine supplementation [1–20].
Selenium Deficiency and Supplementation
The essential trace element selenium is involved in thyroid hormone syn-
thesis, metabolism and action. In several regions of the world people are exposed
to inadequate selenium supply because selenium contents of surface soils have
been depleted by erosion and glacial washout similar to iodine. Therefore, plant
and animal food chains contain inadequate amounts of both of these elements.
Deficiencies of selenium and iron can act in concert with iodine deficiency to
impair thyroid metabolism and modify the response to prophylactic iodine. The
effects of selenium and iron status on iodine and thyroid metabolism share
certain parallels. Selenium deficiency reduces the activity of the selenium-
dependent deiodinase and peroxidase enzymes and thereby impairs thyroid
metabolism in iodine-deficient populations [21–24]. Similarly, iron deficiency
reduces heme-dependent thyroperoxidase activity, impairs thyroid metabolism,
and influences the response to iodine in iodine deficiency disorders.
Combined selenium and iodine deficiency are etiologic factors involved in
the pathogenesis of myxedematous cretinism in central Africa. Additional fac-
tors such as dietary consumption of goitrogens, e.g. thiocyanate contained in or
released from staple foods of these regions, may contribute to the selenium and
iodide interaction. In a longitudinal intervention trial in goitrous, nonanemic
children living in an iodine- and selenium-deficient area in Cote d’Ivoire, oral
iodized oil was administered and thyroid size and thyroid hormone metabolism
was analyzed. Positive thyroid response to iodine supplementation, decreased
thyroid volume and serum TSH, at 50 weeks was signif icantly impaired

Thyroid and Minerals 281
depending on the extent of selenium deficiency, but no adverse effect of admin-
istration of iodized oil were observed. In rodent models, studies revealed necro-
sis and infiltration by mononuclear inflammatory cells in the affected selenium
deficient thyroid glands after administration of high doses of iodide. No such
destructive processes were observed when high iodide doses were given to sele-
nium adequate rats.
Relations between selenium and iodine status and thyroid hormone levels
were also examined in goitrous children in comparison to a control group.
Blood selenium and plasma glutathione activities were lower in the goitrous
group than in the controls but differences of free T4 and TSH levels were only
identified in girls belonging to the low and high selenium quartiles without evi-
dence for altered iodine status. Provided iodine supply reaches minimal critical
levels or low intake as in many parts of Europe additional selenium supplemen-
tation is not harmful as described in Zaire where selenium-enhanced degrada-
tion of thyroid hormones by deiodination occurred in treated children. Thus,
low-dose selenium administration does not cause thyroid insufficiency in sub-
jects with mild iodine deficiency.
It is known that selenium intake and plasma selenium levels decline in
infants fed selenium-poor milk formula before meat-derived food additives are
fed as ‘beikost’ compared to breastfed babies. Nevertheless, selenium supple-
mentation appears not indicated in premature babies provided adequate nutri-
tion is achieved. However, during pregnancy and the postpartum period the
maternal plasma selenium status is decreasing because of considerable transfer
of the trace element to the growing fetus via the placenta (1–4 ␮g of selenium
per day) and via breast milk (3–6␮g of selenium per day) to the feeding baby in
addition to enhanced maternal urinary losses. Therefore, adequate supplemen-
tation of both trace elements to the pregnant and lactating mother is indicated in
areas of limited or inadequate supply of selenium and/or iodine. Selenium sup-
plementation in children with congenital hypothyroidism on T4 treatment did
not affect serum thyroid hormone concentrations or the impaired T3/T4 ratio
but decreased thyroglobulin levels and normalized the TSH difference observed
between matched euthyroid controls and children with congenital hypothy-
roidism, indicating improvement of the central thyroid hormone feedback and
decreased thyroid stimulation.
Iron Deficiency and Supplementation
Worldwide, more than two billion people – mainly children and young
women – are iron deficient. In developing countries, 40–50% of school-age
children are anemic, approximately 50% because of iron def iciency. Iron and

Kahaly 282
iodine deficiencies often coexist; in regions of West and North Africa, 20–30%
of school-age children suffer from both goiter and iron-deficiency anemia. Data
from animal studies indicate that iron deficiency, with or without anemia,
impairs thyroid metabolism. Iron deficiency also impairs thyroid metabolism in
human trials. Overall, these studies suggest that iron deficiency blunts the
thyrotropic response to exogenous TRH; lowers serum T3 and T4 levels, and
lowers utilization of thyroid hormones [25–30].
Clinical trials were done in primary schools in an area of endemic goiter in
the mountains of Cote d’Ivoire. At that time, the median urinary iodine concen-
tration and the goiter rate by palpation in school-aged children in this region
were 28 ␮g/l and 45%, respectively, indicating moderate to severe iodine def i-
ciency. Goitrous, school-aged children were divided into two groups: nonan-
emic or with iron deficiency anemia. All children received an oral dose of
0.4 ml iodized poppy seed oil (Lipiodol®) containing 200 mg or 0.2 g of iodine.
At 15 and 30 weeks, thyroid volume was significantly reduced in the nonan-
emic group compared to the group with iron deficiency. A sharp difference in
goiter prevalence was apparent at 15 and 30 weeks, when goiter rates were 62
and 64% in the anemic group but only 31 and 12% in the nonanemic children.
Median TSH values were lower (p ⬍0.01), and T4 values were greater
(p ⬍0.01) in the nonanemic children. Thus, in this study, both anatomic
(thyroid size) and biochemical (TSH, T4) measures indicated that treatment
with iodized oil significantly improved thyroid function in the nonanemic chil-
dren compared to the children with iron deficiency. Goiter prevalence in the
anemic children group was reduced after iron supplementation from 64 to 20%
at 65 weeks.
In a second study, goitrous, iron-deficient children randomly received
either oral iron sulfate (60 mg elemental iron) 4 tablets per week for 16 weeks or
placebo. Thyroid volume was signif icantly reduced in the iron-treated group
(mean % delta thyroid volume –22.8 (SD 10.7%) compared to placebo
(12.7%, p ⬍0.02). The final study was done in an area of endemic goiter in
northern Morocco. In a 9-month, randomized, double-blind trial, 6- to 15-year-
old children were given iodized salt (25 ␮g iodine per gram of salt) or dual for-
tified salt with iodine (25 ␮g iodine per gram of salt) and iron (1 mg iron per
gram of salt) as ferrous sulfate encapsulated with partially hydrogenated veg-
etable oil. In the children group with dual fortified salt, hemoglobin and iron
status improved significantly compared to the iodized salt group. Addition of
encapsulated iron to iodized salt improved the efficacy of iodine in goitrous
children with a high prevalence of anemia. Taken together, these data demon-
strate that iron deficiency anemia blunts the efficacy of iodine prophylaxis
while iron supplementation improves the efficacy of oral iodized oil and
iodized salt in goitrous children with iron deficiency anemia. This suggests that

Thyroid and Minerals 283
a high prevalence of iodine deficiency anemia among children in areas of
endemic goiter may reduce the effectiveness of iodized salt programs. Iron defi-
ciency anemia may have a greater impact on iodine def iciency than previously
described goitrogens because of its high prevalence in vulnerable groups. The
data also argue strongly for the dual fortif ication of salt with iodine and iron,
not only to reduce the prevalence of iron deficiency but also to increase the eff i-
cacy of the iodine in populations that are both iron deficient and goitrous.
Vitamin A Supply and Zinc Status
In developing countries, children are at high risk for vitamin A deficiency,
a leading cause of preventable blindness in children and increased morbidity
and mortality from serious infections. In rural Cote d’Ivoire, 32–50% of
school-age children suffer from both vitamin A def iciency and goiter. In north-
ern Morocco, 41% of children have vitamin A def iciency, and 50% are
goitrous. In animals, vitamin A deficiency has multiple effects on thyroid
metabolism: it decreases thyroidal iodine uptake, impairs thyroglobulin synthe-
sis, and increases thyroid size. In the periphery, vitamin A deficiency increases
free and total circulating thyroid hormone, and vitamin A status may modulate
T4 feedback of TSH secretion. Finally, vitamin A def iciency in rats increases
pituitary TSHmRNA and TSH secretion; both return to normal after treat-
ment with retinoic acid [31].
In a double-blind, randomized clinical trial, children with vitamin defi-
ciency were given iodized salt and either vitamin A or placebo at 0 and 5
months. At baseline, increasing severity of vitamin A deficiency was a predic-
tor of greater thyroid volume and higher concentrations of TSH and thyroglob-
ulin. In children with vitamin A deficiency, the odds ratio for goiter was 6.51
(95% CI 2.94–14.41). Severity of vitamin A deficiency was also a strong pre-
dictor of higher concentrations of total T4; the odds ratio for hypothyroidism in
vitamin A def iciency was 0.06 (95% CI 0.03–0.14). During the intervention,
mean thyroglobulin, median TSH, and the goiter rate significantly decreased in
the vitamin A-treated group compared with those in the placebo group. The
findings indicate that vitamin A deficiency in severely iodine deficient children
increases TSH stimulation and thyroid size and reduces the risk for hypothy-
roidism. This effect could be due to decreased vitamin A-mediated suppression
of the pituitary TSHgene. Therefore, in children with iodine and vitamin A
deficiencies receiving iodized salt, concurrent vitamin A supplementation
improves iodine eff icacy.
Finally, zinc status also affects thyroid function [32, 33]. For example, in
zinc deficient rats decreased 5 deoidinase activity, lower T3 and free T4 serum

Kahaly 284
concentrations and marked alterations of follicle cellular architecture including
signs of thyroid cell apoptosis were found.
Conclusions
Despite significant progress, deficiencies of iodine and other trace elements,
e.g. selenium and iron, remain major public health problems affecting more than
30% of the global population. These deficiencies often coexist in children. Recent
studies have demonstrated that a high prevalence of iron deficiency among chil-
dren in areas of endemic goiter may reduce the effectiveness of iodized salt pro-
grams. These findings argue strongly for improving iron status in areas of
overlapping deficiency, not only to combat anemia but also to increase the effi-
cacy of iodine prophylaxis. The dual fortification of salt with iodine and iron may
prove to be an effective and sustainable method to accomplish these important
goals. Iron deficiency impairs thyroid hormone synthesis by reducing activity of
heme-dependent thyroid peroxidase. Iron-deficiency anemia blunts and iron sup-
plementation improves the efficacy of iodine supplementation. Combined sele-
nium and iodine deficiency leads to myxedematous cretinism. The normal thyroid
gland retains high selenium concentrations even under conditions of inadequate
selenium supply and expresses many of the known seleno-cysteine-containing
proteins. Among these selenoproteins are the glutathione peroxidase, deiodinase,
and thioredoxine reductase families of enzymes. Adequate selenium nutrition
supports efficient thyroid hormone synthesis and metabolism and protects the
thyroid gland from damage by excessive iodide exposure. In regions of combined
severe iodine and selenium deficiency, normalization of iodine supply is manda-
tory before initiation of selenium supplementation in order to prevent hypothy-
roidism. Selenium deficiency and disturbed thyroid hormone economy may
develop under conditions of special dietary regimens such as long-term total
nutrition, or may be the result of imbalanced nutrition in children.
Iodine deficiency during pregnancy adversely affects thyroid function of
the newborn and mental development of the offspring and these adverse effects
can be prevented or minimized by supplementation. Although most women in
Europe are iodine deficient during pregnancy, less than 50% receive supple-
mentation with iodine. There are no data on the effect of iodine supplementa-
tion on long-term child outcomes. The iodine content of prenatal supplements
in Europe varies widely; many commonly used products contain no iodine. This
is why the European Union is developing legislation to establish permissible
levels for iodine in food supplements. Therefore, in most European countries,
pregnant women and women planning a pregnancy should receive an iodine-
containing supplement (approximately 150 ␮g daily). Kelp and seaweed-based

Thyroid and Minerals 285
products, because of unacceptable variability in their iodine content, should be
avoided. Prenatal supplement manufacturers should be encouraged to include
adequate iodine (150␮g/day) in their products. Also, professional organizations
should influence EU legislation to ensure optimal doses for iodine in prenatal
vitamin-mineral supplements.
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15 Zimmermann M, Delange F: Iodine supplementation of pregnant women in Europe: a review and
recommendations. Eur J Clin Nutr 2004;58:979–984.
16 Park YK, Kim I, Yetley EA: Characteristics of vitamin and mineral supplement products in the
United States. Am J Clin Nutr 1991;54:750–759.
17 Zimmermann MB, Hess SY, Adou P, Torresani T, Wegmüller R, Hurell RF: Thyroid size and goiter
prevalence after introduction of iodized salt: a 5-year prospective study in schoolchildren in Cote
d’Ivoire. Am J Clin Nutr 2003;77:663–667.

Kahaly 286
18 Zimmermann MB, Moretti D, Chaouki N, Torresani T: Introduction of iodized salt to severely
iodine-deficient children does not provoke thyroid autoimmunity: a one-year prospective trial in
northern Morocco. Thyroid 2003;13:199–203.
19 Zimmermann MB, Wegmüller R, Zeder C, Torresani T, Chaouki N: Rapid relapse of thyroid dys-
function and goiter in school-age children after discontinuation of salt iodization. Am J Clin Nutr
2004;79:642–645.
20 Zimmermann MB, Ito Y, Hess SY, Fujieda K, Molinari L: High thyroid volume in children with
excess dietary iodine intakes. Am J Clin Nutr 2005;81:840–844.
21 Dumont JE, Corvilain B, Contempre B: The biochemistry of endemic cretinism: roles of iodine
and selenium deficiency and goitrogens. Mol Cell Endocrinol 1994;100:163–166.
22 Arthur JR, Beckett M, Mitchell JH: Interactions between selenium and iodine deficiencies in man
and animals. Nutr Res Rev 1999;12:55–73.
23 Berry MJ, Banu L, Larsen PR: Type 1 iodothyronine deoidinase is a selenocysteine-containing
enzyme. Nature 1991;349:438–440.
24 Köhrle J: The deoidinase family: selenoenzymes regulating thyroid hormone availability and
action. Cell Mol Life Sci 2000;57:1853–1863.
25 Zimmermann M, Adou P, Torresani T, Zeder C, Hurrell R: Persistence of goiter despite oral iodine
supplementation in goitrous children with iron deficiency anemia in Cote d’Ivoire. Am J Clin Nutr
2000;71:88–93.
26 Zimmermann M, Adou P, Torresani T, Zeder C, Hur rell R: Iron supplementation in goitrous, iron
deficient children improves their response to oral iodized oil. Eur J Endocrinol 2000;142: 217–223.
27 Zimmermann MB, Zeder C, Chaouki N, Torresani T, Saad A, Hurrel RF: Addition of microencap-
sulated iron to iodized salt improves the eff icacy of iodine in goitrous, iron-deficient children:
a randomized, double-blind, controlled trial. Eur J Endocrinol 2002;147:747–753.
28 Hess SY, Zimmermann MB, Adou P, Torresani T, Hurell RF: Treatment of iron deficiency in
goitrous children improves the efficacy of iodized salt in Cote d’Ivoire. Am J Clin Nutr 2002;75:
743–748.
29 Hess SY, Zimmermann MB, Arnold M, Langhans W, Hurrell RF: Iron def iciency anemia reduces
thyroid peroxidase activity in rats. J Nutr 2002;132:1951–1955.
30 Zimmermann MB, Zeder C, Chaouki N, Saad A, Torresani T, Hurrel RF: Dual fortif ication of salt
with iodine and microencapsulated iron: a randomized, double-blind, controlled trial in Moroccan
schoolchildren. Am J Clin Nutr 2003;77:425–432.
31 Kralic A, Eder K, Kirchgessner M: Influence of zinc and selenium deficiency on parameters relat-
ing to thyroid hormone metabolism. Horm Metab Res 1996;28:223–226.
32 Ruz M, Codoceo J, Galgani J, Munoz L, Gras N, Muzzo S, Leiva L, Bosco C: Single and multiple
selenium-zinc-iodine deficiencies affect rat thyroid metabolism and ultrastructure. J Nutr 1999;129:
174–180.
33 Zimmermann MB, Wegmüller R, Zeder C, Chaouki N, Torresani T: The effects of Vitamin A defi-
ciency and Vitamin A supplementation on thyroid function in goitrous children. J Clin Endocrinol
Metab 2004;89:5441–5447.
George J. Kahaly, MD, PhD
Department of Medicine I, Gutenberg University Hospital
Langenbeckstrasse 1
DE–55131 Mainz (Germany)
Tel. 49 6131 17 3460, Fax 49 6131 17 3768, E-Mail gkahaly@mail.uni-mainz.de

287
Bakker, O. 142
Bennedbæk, F.N. 225
Büyükgebiz, A. 128
Feldt-Rasmussen, U. 80
Galler, A. 270
Glaser, B. 154
Gogakos, A. 192
Hegedüs, L. 225
Kahaly, G.J. 278
Kapellen, T. 270
Karges, B. 118
Kassem, S. 154
Kiess, W. VII, 118, 270
Knobel, M. 56
Krassas, G.E. VII, 192
Lazarus, J.H. 25
Medeiros-Neto, G. 56
Pfäffle, R. 270
Rasmussen, Å.K. 80
Rivkees, S.A. VII, 169
Spiliotis, B.E. 44
Tsatsoulis, A. 1
Tsoumalis, G. 1
Weetman, A.P. 104
Wiersinga, W.M. 210
Author Index

288
Albumin, thyroid hormone transport 82
Amiodarone, iodine content 73
Autoimmune polyglandular syndrome
(APS)
APECED 270
types 270
Autoimmune thyroid disease, see also
Hashimoto’s thyroiditis
autoimmune thyroiditis
diagnosis 74
iodine intake studies 74, 75
clinical presentation 107, 108
diabetes type 1 association 112, 113,
271–273
pathogenesis 111, 112
pathophysiology 107
predisposition 104, 105, 108–111
self-tolerance failure 105–107
Turner syndrome association 110, 111,
273–275
B cell, function in pregnancy 28
Bone morphogenetic protein-4, pituitary
development role 5
BRAF gene, papillary thyroid carcinoma
mutations 212, 213
Cassava, goitrogens 69
Computed tomography (CT)
advantages and limitations 254
congenital thyroid defects 255, 256
diffuse thyroid disease 256
indications 255
normal thyroid f indings 255
positron emission tomography
combination for thyroid imaging
236–238
thyroid nodules 256, 258
Congenital hypothyroidism (CH)
clinical outcomes 123, 124
diagnosis 124, 125
epidemiology 118
gene mutations 118–121
neonatal screening
hypothyroxinemia 130, 131
isolated hyperthyrotropinemia 131
methods 129, 130
overview 122, 123, 128, 129
transient hypothyroidism 132
radionuclide imaging 229–231
treatment 125
ultrasonography 242, 243
Cretinism, iodine def iciency 63–65
CTLA-4 gene, autoimmune thyroid disease
predisposition alleles 110
Deiodinases
D3 knockout mouse 40
gene polymorphisms 90, 91
gestational changes 22, 49
neonatal levels 50
tissue distribution in pregnancy 29
types and functions 88
Diabetes type 1, autoimmune thyroid
disease association 112, 113,
271–273
Subject Index

Subject Index 289
Ectopic thyroid
radionuclide imaging 231, 232
ultrasonography 243, 244
Eya1 gene, thyroid gland development role
18
Fetal thyroid function (FTF)
hypothalamic-pituitary-thyroid axis
47–49
maternal-fetal unit and fetal thyroid gland
function 45–47
overview 44, 45
thyroid hormone action 49, 50
Fibroblast growth factor (FGF)
Fgfr2 gene and thyroid gland
development role 19, 20
pituitary development role 5
Follicular thyroid carcinoma, see Thyroid
cancer
Foxe1 gene
knockout effects 16, 17
thyroid gland development role 11, 12, 16
GATA-2 zinc finger protein, pituitary
development role 7
GNAS1 gene, mutation and neonatal
thyrotoxicosis 40
Goiter
autoimmune thyroid disease 107
goitrogens 69
iodine deficiency 58, 59, 136
iodine excess 71, 72
radionuclide imaging of congenital goiter
232
ultrasonography 240, 242, 245
Graves’ disease, see also Hyperthyroidism
magnetic resonance imaging findings
262
pregnancy management
fetal monitoring 35
Graves’ orbitopathy 35
postpartum management 36
preconception 31, 32
previously treated patients 32
propylthiouracil 24
radioiodine effects in early gestation 33
surgery 35, 36
thyroid-associated ophthalmopathy, see
Graves’ ophthalmopathy
treatment in children
overview 169, 170, 186
propylthiouracil and methimazole
cancer risks 183, 184
complications 182, 183
dosing 182
history of use 180, 181
mechanism of action 181
outcomes 182, 183
radioiodine therapy
cancer risks 176–179
complications 174, 176
historical perspective 171
iodine-131 172, 173
long-term cure rates 173
offspring effects 179
outcomes 173, 174
remission rates 170, 171
thyroidectomy 179, 180
young children 184, 185
Graves’ ophthalmopathy
activity and severity 194
immunopathogenesis 192–194
juvenile disease
diagnosis 199, 200
incidence 195, 196
insulin-like growth factor-I role
203
octreotide scintigraphy 202, 203
smoke exposure risks 200, 201
survey of European physicians
197–200
symptomatology 196, 197
treatment
corticosteroids 201, 202
octreotide 202–205
prospects 205, 206
SOM 230 205
pregnancy 35
Hashimoto’s thyroiditis
computed tomography 256
features 134–136
radionuclide imaging 232, 233
ultrasonography 245, 246

Subject Index 290
Hepatic nuclear factor 3␤, thyroid gland
development role 20
Heteromeric amino acid transporter (HAT),
thyroid hormone transport 84
Hhex transcription factor, thyroid gland
development role 11, 12, 17, 18
Hoxa3 gene
knockout effects 18, 19
thyroid gland development role 18
Human leukocyte antigen (HLA),
autoimmune thyroid disease
predisposition alleles 109, 110
Hyperthyroidism, see also Graves’
disease
pregnancy
child development effects 37, 38
diagnosis 30
effects on mother and child 30, 31
etiology 29, 30
Graves’ disease management
fetal monitoring 35
Graves’ orbitopathy 35
postpartum management 36
preconception 31, 32
previously treated patients 32
propylthiouracil 24
radioiodine effects in early gestation
33
surgery 35, 36
neonatal thyrotoxicosis, see Neonatal
thyrotoxicosis
prevalence 25
radionuclide imaging 233, 234
Hypothalamic-pituitary-thyroid axis
ontogenesis 2, 3, 47–49
placenta role in maturation 21–23
Hypothalamus, nuclei 3, 4
Hypothyroidism, see also Autoimmune
thyroid disease; Congenital
hypothyroidism
childhood and adolescence
clinical presentation 133, 134
diagnosis 134
etiology 132
treatment 134
pregnancy
child development effects 37, 38
diagnosis 37
etiology 36, 37
management 37
prevalence 25, 36
transient hypothyroidism in newborn
iodine excess 72, 73
laboratory findings 132
Iodine
deficiency
adaptation mechanisms 58, 59
brain damage mechanisms in perinatal
period 63–66
children and adolescents 66, 67
goiter 58, 59, 136
goitrogens 69
neonates and infants 61–63
nutrient deficiency exacerbation 68
overview of disorders 58, 59
prenatal effects 60, 61, 284
prevention 137, 138
risk factors 69
excess
adaptation mechanisms 69, 70
health consequences 70–73
geographic distribution 56, 57
metabolism in pregnancy 25, 26
more than adequate intake studies 73–75
placenta provision 22, 23
recommended intake 57, 58, 136
sources 56
supplementation studies 278–280, 284,
285
Iron
deficiency 281, 282
supplementation studies 282, 283
Lhx-3 transcription factor, pituitary
development role 6
Lipiodol, iodine deficiency management
137
Lipoproteins, thyroid hormone transport
82
Magnetic resonance imaging (MRI)
advantages and limitations 258, 260
congenital thyroid defects 260, 261

Subject Index 291
diffuse thyroid disease 261
indications 260
normal thyroid findings 260
thyroid nodules 262
Methimazole (MMI), Graves’ disease
management in children
cancer risks 183, 184
complications 182, 183
dosing 182
history of use 180, 181
mechanism of action 181
outcomes 182, 183
Millet, goitrogens 69
Mitochondria, thyroid hormone effects
96
Monocarboxylate transporter-8 (MCT8),
thyroid hormone transport 84–87
Neonatal screening, see Congenital
hypothyroidism
Neonatal thyrotoxicosis
epidemiology 39
etiology 39, 40
treatment 39
NIS, see Sodium/iodide symporter
Nkx2 genes
Nkx2–1, see Titf-1 gene
thyroid gland development role 20
Nonthyroidal illness (NTI), features
92, 97
Octreotide, Graves’ ophthalmopathy
management in children 202–205
scintigraphy 202, 203
Organic anion transporters, thyroid
hormone transport 84
Papillary thyroid carcinoma, see Thyroid
cancer
Pax-6 gene, pituitary development role 6
Pax-8 gene
knockout effects 15, 16
thyroid gene expression regulation
20, 21
thyroid gland development role
11, 12
Pendred’s syndrome
clinical features 154, 155, 157, 158
deafness pathophysiology 162–164
etiology 154
pendrin mutations 158, 159
prospects for study 165, 166
Pendrin
mutation, see Pendred’s syndrome
renal function 165
thyroid function 21, 159–162
Pit-1 transcription factor, pituitary
development role 7
Pituitary
anterior pituitary anatomy 4
history of study 1, 2
organogenesis and transcription factors
5–7
Pitx genes, pituitary development role 6
Placenta
hypothalamic-pituitary-thyroid axis
maturation role 21–23
thyroid hormone transport 29, 46, 47
Positron emission tomography (PET),
computed tomography combination for
thyroid imaging 236–238
Pregnancy, see also Fetal thyroid function
immune system changes 27, 28
iodine metabolism 25, 26
thyroid autoantibodies and pregnancy
failure 29
thyroid disease, see Hyperthyroidism;
Hypothyroidism; Thyroid nodules
thyroid hormone changes 26
Prop-1 gene
congenital hypothyroidism gene
mutations 119
pituitary development role 6
Propylthiouracil (PTU)
Graves’ disease management
children
cancer risks 183, 184
complications 182, 183
dosing 182
history of use 180, 181
mechanism of action 181
outcomes 182, 183
pregnancy 24
mechanism of action 89, 90

Subject Index 292
Radioiodine
Graves’ disease management in children
cancer risks 176–179
complications 174, 176
historical perspective 171
iodine-131 172, 173
long-term cure rates 173
offspring effects 179
outcomes 173, 174
scintigraphy, see Radionuclide
imaging
thyroid cancer management in children
215–217
uptake factors 227
Radionuclide imaging
congenital defects
congenital goiter 232
ectopic thyroid 231, 232
hypothyroidism 229–231
overview 228, 229
Hashimoto’s thyroiditis 232, 233
hyperthyroidism 233, 234
indications 226–228
normal findings 228
radioiodine isotopes 225, 226
thyroid nodules 234, 235
RET gene, papillary thyroid carcinoma
mutations 212, 213
Rpx gene, pituitary development role 6
Salt, iodized 137
Selenium
deficiency 68, 91
intoxication 92
supplementation studies 280, 281
Smoking, Graves’ ophthalmopathy risks
200, 201
Sodium iodide symporter (NIS)
congenital hypothyroidism gene
mutations 121
thyroid cancer expression 212
thyroid hormone synthesis role 10
SOM 230, Graves’ ophthalmopathy
management in children 205
T helper balance, pregnancy 27
Thyroglobulin (TG)
biosynthesis 9, 10
congenital hypothyroidism gene
mutations 121
gestational changes 21, 22
Thyroid cancer
clinical presentation in children 213, 214
epidemiology in children 210, 211
management in children
follow-up 217, 218
radioiodine therapy 215–217
thyroidectomy 214, 215
nodules, see Thyroid nodules
pathology of differentiated thyroid
carcinoma 211–213
prognosis 218–220
ultrasonography 251–254
Thyroidectomy
Graves’ disease management in children
179, 180
thyroid cancer management in children
214, 215
Thyroid eye disease, see Graves’
ophthalmopathy
Thyroid gland
autoantibodies and pregnancy failure 29
functional anatomy 8–11
imaging, see Computed tomography;
Magnetic resonance imaging; Positron
emission tomography; Radionuclide
imaging; Ultrasonography
neonatal and infant function 51–53
ontogenesis 7, 8
transcription factors in development
early development 11–18
late development 18–20
thyroid-specific gene transcription 20,
21
Thyroid hormone
critical illness levels 92
deiodination, see Deiodinases
extranuclear actions 95, 96
fetal actions 49, 50
gestational changes 22, 44, 45
mitochondrial effects 96
neonatal levels
full-term infants 50
pre-term infants 50, 51

Subject Index 293
pregnancy changes 26
receptors
congenital hypothyroidism gene
mutations 121
DNA binding 142, 143
genomic actions 93, 95
ligands 95–98
mutants 95, 147–151
structure 143, 147–151
types 93, 143
resistance
clinical features 144–146
diagnosis 146, 147
management 147
molecular biology 147–151
transport
albumin 82
blood 80–82
lipoproteins 82
membrane transporters
heteromeric amino acid transporter
84
monocarboxylate transporter-8
84–87
organic anion transporters 84
thyroxine-binding globulin 81, 82
transthyretin 82
Thyroid nodules
computed tomography 256, 258
magnetic resonance imaging findings
262
pregnancy
diagnosis 38
prevalence 38
treatment 38, 39
radionuclide imaging 234, 235
ultrasonography 248, 249, 251
Thyroid peroxidase (TPO)
congenital hypothyroidism gene
mutations 121
thyroid hormone synthesis role 10
Thyroid-stimulating hormone (TSH)
congenital hypothyroidism gene
mutations
hormone 118
receptor 119
function 2
gestational changes 22, 28, 47, 48
neonatal levels
full-term infants 50, 52
pre-term infants 50, 51
neonatal screening 122, 123, 128, 129
receptor signaling 11
structure 4, 5
thyroid follicular cell stimulation 10
Thyrotropin, see Thyroid-stimulating
hormone
Thyrotropin-releasing hormone (TRH)
gestational changes 49
regulation of secretion 4
Thyroxine-binding globulin (TBG)
genetic diseases 82
gestational changes 21, 48
neonatal levels 50, 51
serum concentration 81
steroid hormone effects 81
Titf-1 gene
knockout effects 14, 15
thyroid gland development role 11, 12
Transthyretin (TTR), thyroid hormone
transport 82
Triiodothyroacetic acid (TRIAC), thyroid
hormone resistance management 147
Tshr gene, thyroid gland development role
18
Ttf genes, thyroid gene expression
regulation 20, 21
Turner syndrome, autoimmune thyroid
disease predisposition 110, 111,
273–275
Ultrasonography (US)
congenital thyroid defects
congenital goiter 245
ectopic thyroid 243, 244
hypothyroidism 242, 243
Williams’ syndrome 244, 245
diffuse thyroid disease 245–248
Hashimoto’s thyroiditis 245, 246
indications 238, 239
normal thyroid findings 239, 240,
242
patient positioning for thyroid imaging
238

Subject Index 294
thyroid cancer 251–254
thyroid nodules 248, 249, 251
Vitamin A
deficiency 283
supplementation studies 283
thyroid function 68
Williams’ syndrome, ultrasonography
244, 245
Zinc
deficiency 283, 284
thyroid function 68, 283, 284
Ultrasonography (US) (continued)