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Etiology of Simple Goiter

Article  in  Thyroid: official journal of the American Thyroid Association · April 2009

DOI: 10.1089/thy.2009.0047 · Source: PubMed

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THYROID
Volume 19, Number 3, 2009
ª Mary Ann Liebert, Inc.
DOI: 10.1089=thy.2009.0047
Etiology of Simple Goiter
Laszlo Hegedüs,1 Thomas H. Brix,1 and Ralf Paschke2
S imple goiter (SG), that is an enlarged nontoxic thyroid
gland which is not the result of an inflammatory or neo-
plastic process, although on the wane, remains a nearly global
problem (1,2). Until increasingly employed iodization pro-
grams significantly reduces its prevalence, the etiology as well
as the therapy of benign nontoxic goiter should remain in focus.
It is well accepted that sporadic or endemic SG (2,3), along
with the other common thyroid diseases co-existing with
goiter including Graves’ disease (4), toxic multinodular goiter,
and Hashimoto’s thyroiditis (5), is a complex disease. These
are all common and multifactorial with the clinical phenotype
representing the net effect of many contributing genetic and
environmental factors. It has been difficult to disentangle en-
vironmental influences from genetic susceptibility, progress
has been slow in revealing candidate genes, and little is known
of the roles of gene–environment and gene–gene interaction.
A role for genetic factors in the etiology of SG has long been
recognized. Familial aggregation is illustrated by the 5–10
times greater prevalence of SG among the probands of first
degree female relatives as compared with the background
population (2,3). Subsequently, twin studies (3), demonstrat-
ing a significantly higher concordance rate in monozygotic
(53%, 95% CI 23–83%) than in dizygotic twins (18%, 95% CI 5–
35%), have clarified that the familial aggregation is the result
of shared genes and not of shared environment. Our study in
a nonendemic goiter area (3) estimated that heritability or
additive genetic factors accounted for 82% (95% CI, 67–92%) of
cases, while specific individual environmental factors likely
accounted for 18% (95% CI, 8–33%) of goiter development in
females. The influence of heritability decreases with the pres-
ence of major environmental factors such as iodine deficiency
(2). As a consequence, susceptibility genes are more easily
discerned in nonendemic goiter areas. The pronounced influ-
ence of heritability on thyroid size (6) and thyroid nodularity
(7), with or without concomitant clinical goiter, strengthens
the concept that there is a considerable genetic influence on the
development of SG.
A detailed account of the genetic influences on the devel-
opment of SG is beyond the scope of this editorial. Mutations
and polymorphisms in the genes for thyroid peroxidase
(TPO), thyroglobulin (Tg), sodium iodide symporter (NIS),
and thyrotropin receptor (TSHR), however, all have a role (8–
10). SG is polygenic, moreover, with no single gene being
either necessary or sufficient for disease development. The
limited studies to date suggest that the genetic background
1
Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark.
2
Third Medical Department, University of Leipzig, Leipzig, Germany.
209
EDITORIALS AND COMMENTARY
varies from family to family. Furthermore, our understanding
of the interaction between heredity and environment is very
limited. There is a clear lack of longitudinal studies in indi-
viduals with genetically based susceptibility to determine
how and when environmental triggers such as iodine defi-
ciency or cigarette smoking influence the occurrence of SG.
When studying this issue it is important to realize that SG is
not one single phenotype.
The pronounced sex difference in prevalence of thyroid
disease, often 5–10 times more common in females, is puz-
zling. Theoretically, a skewed X chromosome inactivation
(XCI) pattern—which is probably genetically determined—
and resultant tissue chimerism could offer a novel explanation
for the female preponderance of thyroid disorders, including
that of SG (11). The X chromosome harbors genetic markers
linked to SG (12) and a skewed XCI (i.e., predominant inac-
tivation of the normal X chromosome) could result in ex-
pression of X-linked diseases. When recently tested, this
hypothesis was rejected (13). Intake of oral contraceptives,
another potential explanation for the sex-related difference in
prevalence of SG, is actually associated with a decreased
thyroid size (14).
Whereas environmental influences can be modified while
genetic background cannot, much of the current focus on the
etiology and treatment of SG has been on identifying and
correcting environmental influences. Large-scale studies have
demonstrated the importance of surprisingly small variations
in iodine intake not only for the prevalence of overt goiter but
also for the regulation of thyroid size in nongoitrous indi-
viduals (15). Interestingly, a relatively small increase in iodine
intake, for just a few years, leads to a measurable and signif-
icant decrease in thyroid volume (15), suggesting that modi-
fying iodine intake may rapidly lead to a decrease in incidence
of SG and subsequently in overt nodular toxic goiter. Studies
of this kind, such as performed in Denmark (16), will un-
doubtedly provide further evidence of the interaction be-
tween genetic susceptibility and environmental triggers.
Another modifiable goitrogen is cigarette smoking. There
is abundant evidence of its importance, from both case–
control studies and studies in discordant twin pairs (17,18).
Large-scale studies have demonstrated an interaction be-
tween low iodine intake and thiocyanate generating cigarette
smoking, offering an explanation for the effect and providing
a means to eliminate one or more factors in the genesis of
goiter (19).
210
In the present issue of Thyroid, Foroulis et al. (20) review
primary intrathoracic goiter (PITG). These goiters receive
their blood supply from mediastinal vessels and are not
linked to the cervical thyroid except for a thin band of con-
nective tissue. Thus, PITG is distinct from the far more com-
mon secondary intrathoracic goiters, which are an extension
of the cervical thyroid into the mediastinum. The formation of
PITG is related to the fact that ectopic thyroid tissue can be
found in any location along the path of migration of the thy-
roid, from the foramen cecum to the mediastinum. Ectopic
thyroid tissue is most often found as a mass in the dorsum of
the tongue (lingual thyroid), and less often in the mediasti-
num (21). Even rarer localizations, however, such as in the
submucosa of the duodenum and adjacent to the gallbladder
have been reported (22,23). The subdiaphragmatic localiza-
tion is best explained by recent findings in the zebra fish,
which demonstrate that ectopic vascular cells are sufficient to
misdirect thyroid tissue (24).
Congenital hypothyroidism is often associated with thyroid
dysgenesis (agenesis, ectopic localization, or hypoplasia) (25).
Fifty percent of such individuals have ectopic thyroid tissue,
but also frequently have other congenital malformations, with
cardiac anomalies being the most prevalent (25). While mice
homozygous for Foxe 1 mutations show a sublingual thyroid
(21), until now no specific mutation has been associated with
ectopic thyroid tissue in man. Congenital hypothyroidism is
also often associated with goiter in case of TPO, NIS, Tg,
Pendred syndrome (PDS), or TSHR mutations (10). Goiter
without hypothyroidism may also be associated with muta-
tions in the same genes, except TPO (10). Thus, although ge-
netic predisposition is evident and mutations have been
described in individuals with congenital or acquired hypo-
thyroidism and congenital or acquired goiter, a specific gene
defect remains to be identified (8,10). We suggest that the same
environmental and genetic factors are involved in cases in
which there is enlargement of both the normally located thy-
roid and the ectopic thyroid (9,10). In contrast, in cases where a
large ectopic goiter occurs in the patient with the normal thy-
roid not being involved by goiter (26), it is likely that the eti-
ology of the goiter in the ectopic thyroid tissue is the same as or
closely related to the reason that the ectopic goiter developed
in the first place. Thus the formation of the goiter in the aber-
rantly located thyroid would not be environmental but pos-
sibly due to a developmental defect involving ectopic vessel
formation as one explanation. These cases of a normal thyroid
in association with ectopic goiter, though rare, are important
for what they might teach us regarding goitrogenesis.
Though much remains to be learned about the etiology of
goiter in its normal in situ location, this is even more the case
for enlargement of ectopic thyroid tissue. In these patients
the diagnosis of malignancy within the ectopic thyroid tissue
is even more difficult. There are also management issues to
be considered. For example, the question of whether these
patients are candidates for nonsurgical therapy—e.g., with
radioiodine, with or without recombinant human TSH sti-
mulation (2,27)—could, in its own right, form the basis of a
separate editorial.
Acknowledgments
Laszlo Hegedüs and Thomas H. Brix are supported by
grants from The Agnes and Knut Mørks Foundation and The
EDITORIAL
Novo Nordisk Foundation. Ralf Paschke is supported by
grants from the Deutsche Forschungsgemeinschaft (DFG).
Disclosure Statement
Laszlo Hegedüs, Thomas H. Brix, and Ralf Paschke state
that they have no conflicts of interest.
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Address reprint requests to:
Laszlo Hegedüs, M.D., D.M.Sc.
Department of Endocrinology and Metabolism
Odense University Hospital
University of Southern Denmark
Kløvervænget 6 DK-5000 Odense C
Denmark
E-mail: laszlo.hegedus@ouh.regionsyddanmark.dk
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