Muñoz-Ortiz et al.

Systematic Reviews (2020) 9:201

https://doi.org/10.1186/s13643-020-01459-7

RESEARCH Open Access

Prevalence of hyperthyroidism,
hypothyroidism, and euthyroidism in
thyroid eye disease: a systematic review of
the literature
Juliana Muñoz-Ortiz1,2, Maria Camila Sierra-Cote2, Estefanía Zapata-Bravo2, Laura Valenzuela-Vallejo2,
Maria Alejandra Marin-Noriega2, Pilar Uribe-Reina1,2, Juan Pablo Terreros-Dorado2, Marcela Gómez-Suarez1,
Karla Arteaga-Rivera1 and Alejandra de-la-Torre2*

Abstract
Background: Thyroid eye disease is an autoimmune disorder of the orbital retrobulbar tissue commonly associated
with dysthyroid status. The most frequent condition is hyperthyroidism, although it is also present in hypothyroid
and euthyroid patients. The prevalence of thyroid conditions in patients with thyroid eye disease had been previously
evaluated; however, there is no consensus on a global prevalence. The study aims to estimate the prevalence of
hyperthyroidism, hypothyroidism, and euthyroidism in patients with TED, through a systematic review of literature.
Methods: We conducted a systematic review of the literature following the PRISMA guidelines, in MEDLINE, COCHRANE,
EMBASE, Science Direct, and LILACS databases. Inclusion criteria were primary studies of patients with a diagnosis of
thyroid eye disease made by an ophthalmologist or with diagnosis criteria, with measurement of thyroid function (TSH,
T3, and free T4), and diagnosis of the primary thyroid condition. A quality assessment was made through the Joanna
Briggs Institute Quality tools. Finally, we extracted relevant details about the design, the results, and the prevalence of
thyroid disorders in thyroid eye disease.
Results: The initial search revealed 916 studies, of which finally thirteen met inclusion criteria. Six studies were performed
in Europe (Germany, Wales, and Spain), five in Asia (Iran, South Korea, Japan, and Singapore), one in North America (USA),
and one in Africa (Ghana). The global prevalence, in patients of thyroid eye disease, was 10.36% for hypothyroidism, 7.9%
for euthyroidism, and 86.2% for hyperthyroidism.
Conclusions: Professionals should be aware that thyroid eye disease can be present in patients with a normal thyroid
function. The assessment for these patients is based on orbital images; serum TSH, T3, and free T4; antibody levels as
thyrotropin receptor antibodies; and thyroperoxidase levels. Additionally, we want to encourage research in this field in
other regions of the world such as Latin America.
Systematic review registration: PROSPERO ID CRD42020107167
Keywords: Dysthyroid ophthalmopathy, Hypothyroidism, Hyperthyroidism, Euthyroid, Prevalence

* Correspondence: alejadelatorre@yahoo.com
2
Research Group in Neurosciences NeURos, Escuela de Medicina y Ciencias
de la Salud, Universidad del Rosario, Carrera 24 # 63C 69, Bogotá, Colombia
Full list of author information is available at the end of the article

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Muñoz-Ortiz et al. Systematic Reviews (2020) 9:201 Page 2 of 12

Background Description of the condition

Rationale TED is the most common autoimmune disease of the
Thyroid disease (TD) is a quite common condition orbit [8]. The disease appears two to six times more
worldwide. According to the American Thyroid Associ- frequent in young women, but severe cases occur
ation, only in the United States of America (USA) reported more frequently in men older than 50 years [8].
20 million Americans with some form of TD, and at least In TED´s physiopathology, the orbit becomes infiltrated
12% will develop a thyroid condition during their lifetime. by B and T cells, activating genes involved in inflammation
According to hormonal levels, the patients with TD can be and tissue remodeling [9]. Orbital fat and extraocular mus-
classified into three different groups: hypothyroidism, cles expand from accumulating hyaluronidase-digestible
euthyroidism, and hyperthyroidism [1]. material and adipogenesis [6]. These events are mediated
Euthyroidism is defined as normal thyroid hormone by interleukins 1β, 6, 8, and 16; tumor necrosis factor α
production and serum levels [2]. Hyperthyroidism is a (TNF-α); RANTES (regulated on activation, normal T cell
clinical condition in which thyroid hormones are synthe- expressed and secreted); and CD40 ligand. The action of
sized excessively. The reported prevalence is 0.8% in the these cytokines turns bone marrow-derived fibrocytes into
USA and 1.3% in Europe. It is seen more frequently in CD34+ fibroblasts that further differentiate into myofibro-
women and adulthood. The clinical manifestations usu- blasts or adipocytes [10].
ally involve several systems, for example, weight loss can The CD34+ fibroblasts express low levels of TSHr and
be evidenced despite no appetite disturbance, limb other thyroid antigen receptors and overexpress IGF-1
tremor, tachycardia, and tachypnea [3]. On the contrary, receptors [11–13]. Thyroid-stimulating immunoglobu-
hypothyroidism is the condition in which thyroid hor- lins activate the IGF-1 receptor complex, leading to the
mones are deficient. It has a higher prevalence that varies expression of inflammatory molecules and glycosamino-
between 0.3 and 3.7% in the USA and 0.2 and 5.3% glycan synthesis; this signaling can also be activated in
in Europe. It occurs more frequently in women over adipocytes [10].
65 years of age and it is commonly seen in patients Clinical manifestations of TED mainly include eyelid
with autoimmune diseases, such as type 1 diabetes retraction (90%), exophthalmos (62%), restricted extrao-
mellitus and celiac disease, among others. The clinical cular motility (43%), eye pain (30%), tearing (21%), diplo-
manifestations are usually weight gain, fatigue, and pia (17%), photophobia (16%), blurred vision (8%), and
cold intolerance [4]. optic nerve dysfunction (6%) [14]. Patients with euthyr-
Thyroid eye disease (TED) is an autoimmune disorder oid/hypothyroid TED developed significantly less severe
of the orbital retrobulbar tissue associated with dysthyr- ocular symptoms, less active, and more asymmetrical
oidism, mainly hyperthyroidism in Graves’ disease (GD), disease than hyperthyroid patients [15].
even though it is present in hypothyroid and euthyroid TED management starts with the control of environ-
patients [5]. mental factors to decrease the risk of disease progres-
The prevalence of dysthyroidism in patients with TED sion, such as smoking cessation. Local management of
has been previously evaluated; however, there is no con- TED includes ocular lubrication, conjunctival autograft,
sensus on a global prevalence, and the physiopathologi- or even orbital decompression in severe cases. The oral
cal effect of thyroid hormones on the onset and glucocorticoids are recommended to be administered as
progression of TED has not been fully understood. prophylaxis for mild active TED when treated with
The thyroid-stimulating hormone receptor (TSHr) and radioactive iodine in patients with GD. Intravenous glu-
insulin-like growth factor 1 (IGF-1) receptor on orbital cocorticoids are the first line of treatment for moderate-
fibroblasts are likely to be the most important auto- to-severe and active TED. Options for disease mainten-
immune targets in the disease. It has been hypothesized ance are many and include orbital radiotherapy, selen-
that clinical phenotypes such as euthyroid or hypothyroid ium, cyclosporine, azathioprine, mycophenolate mofetil,
TED, or the predominance of muscle or fat enlargement, tocilizumab, or rituximab [16]. Recently, a new pharma-
may be caused by the molecular signature of different ceutic molecule was approved for TED, teprotumumab.
anti-thyrotropin-receptor antibodies [6]. Also, previous This is a fully human monoclonal antibody that attenu-
studies had concluded that dysthyroidism (hyperthyroid- ates signaling initiated at the IGF-1 receptor complex
ism or hypothyroidism) is associated with more severe blocking pathologic immune responses [17].
presentations of TED, recommending the assessment of
thyroid function during antithyroid treatment and the Description of the thyroid function measurement and the
management of TED [7]. diagnosis of the primary thyroid condition
The study aims to estimate the prevalence of hyperthy- Thyroid function measurement is made from the level of
roidism, hypothyroidism, and euthyroidism in patients hormones produced by the thyroid gland and the hor-
with TED, through a systematic review of literature. mone that stimulates its production. The normal thyroid

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Muñoz-Ortiz et al. Systematic Reviews (2020) 9:201 Page 3 of 12

function is called euthyroidism, described by the Ameri- reported but was possible to calculate it, the study was
can Thyroid Association as a normal range between 0.4 also included. Articles were excluded from the analysis if
and 4.0 mU/L for thyroid-stimulating hormone (TSH) the diagnosis of the thyroid function status were second-
[18]. On the other hand, hyperthyroidism presents ele- ary to thyroid disease treatment or if the study design
vated free thyroxine (T4) and triiodothyronine (T3) and was a review, letter to the editor, case report, case series,
decreased TSH serum levels (0.0–0.4 mU/L) [3]. Besides, or systematic reviews.
hypothyroidism is diagnosed with elevated serum con-
centration of TSH (above 4.0 mU/L) and decreased free Information sources
T4 levels [18]. We used a combination of exploded controlled vocabu-
lary (MeSH, Emtree, DeCS) and free-text terms (consid-
How the thyroid function measurement and the diagnosis ering spelling variants, plurals, synonyms, acronyms, and
of the primary thyroid condition might work abbreviations) with field labels, truncation, proximity op-
By measuring the TSH, T3, and free T4 levels in TED erators, and Boolean operators.
patients, the thyroid function can be objectively evalu- The literature search was conducted in the following
ated and classified. The prevalence report of these condi- electronic databases up to July 29 of 2019: MEDLINE,
tions will allow the calculation of weighted prevalence. COCHRANE, EMBASE, ScienceDirect, and LILACS. No
limits regarding language and period of publication were
Why it is important to do this review used (Additional file 1). The search was updated on
The prevalence of TED in hyperthyroidism is very well April 21 of 2020.
described because of its high prevalence. However, the
low prevalence calculation in hypothyroid and euthyroid Study selection
patients with the ophthalmological condition means that The electronic search was made by two reviewers (JMO
in clinical practice, these patients are initially ruled out and MCSC). Duplicates were eliminated through an
for the TED study. Diagnosis could be in a late stage Excel function. We performed an independent review of
with a delay in treatment initiation and complications article titles and abstracts extracting data according to
development. the predefined eligibility criteria. In case of disagree-
ment, a third reviewer (ADLT) made the inclusion deci-
Objective sion (Fig. 1).
The study aims to estimate the prevalence of hyperthy-
roidism, hypothyroidism, and euthyroidism in patients Data collection process
with TED, through a systematic review of literature. A data collection form was designed in Excel. Three re-
viewers (MCSC, EZB, and LVV) independently extracted
Methods relevant details about the design and the results of each
Protocol and registration study which included author, study period, location,
The present review was performed according to the Pre- study design, number of patients with TED, and the
ferred Reporting Items for Systematic Reviews and prevalence of primary hyperthyroidism, hypothyroidism,
meta-analysis (PRISMA) guidelines [19]. The protocol and euthyroidism.
registration can be found under the PROSPERO ID
CRD42020107167. Risk of bias
We followed the chapter of systematic reviews of preva-
Study design lence and incidence of the Johanna Briggs Institute (JBI)
The study design is a systematic review of literature to conduct this systematic review and classified the
evaluating the prevalence of primary hyperthyroidism, articles using the respective tool for each study design [20,
hypothyroidism, and euthyroidism in patients with TED 21]. An expert methodologist (MGS) established cutting
diagnosis. points for the minimum score acceptable for study inclu-
sion: 72% for cohort studies, 75% for cross-sectionals, and
Eligibility criteria 80% for case-control, or if any of it met all our major in-
We included all published articles if (a) the abstract was clusion criteria [21] (Additional file 2).
available; (b) it contained original data; (c) the TED was
diagnosed by an ophthalmologist or diagnosis criteria Results
were settled; (d) the thyroid disorders were measured General description
with blood levels of TSH, free T4, and T3 [3, 18]; and Our search strategy extracted 916 published articles (199
(e) if it reported the prevalence of primary thyroid func- from MEDLINE, 570 from Embase, 127 from Science-
tion variation on TED patients. If the prevalence was not Direct, 14 from Cochrane and 6 from LILACS).

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Muñoz-Ortiz et al. Systematic Reviews (2020) 9:201 Page 4 of 12

Fig. 1 PRISMA flowchart

After screening, 73 articles were assessed for eligibility articles for different reasons (all the patients had hyper-
and only 60 met the selection criteria and were evalu- thyroidism, did not present ophthalmopathy, or it was
ated through the JBI quality tool; 38 full-text articles not possible to determine the prevalence) 14 articles
were assessed for eligibility. Finally, after discarding 25 met all the inclusion criteria, but two articles had the

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Muñoz-Ortiz et al. Systematic Reviews (2020) 9:201 Page 5 of 12

same sample because they were made in the same popu- Thyroid states
lation. To avoid overrepresentation of this cross- Hyperthyroidism
sectional study, we included only the data of one of The thirteen studies reported the presence of primary
them [22, 23] (Fig. 1) (Additional file 3). hyperthyroidism in patients with TED. Some of the stud-
ies reported GD [25, 28, 30, 31] as the primary cause of
Characteristics hyperthyroidism. The range of prevalence was between
Our final inclusion strategy yielded 13 published articles, 6 (65.7–99.1%), with a total calculated prevalence of
were conducted in Europe (Germany, Wales, and Spain), 5 86.2%. Countries like Wales (93,6%), USA (90%), and
in Asia (Iran, Korea, Japan, and Singapore), one in North Iran (92,4%) had a higher prevalence, in contrast to an-
America (USA), and one in Africa (Ghana). All the studies other study in Wales with 65.7% and Spain that had the
were published between 1996 and 2018. Two of the studies lowest prevalence (66.7%) (Fig. 2).
had a small sample size of TED patients (18 and 47) and the
rest had a bigger population (between 103 and 1020). All pa-
tients had a diagnosis of TED and thyroid function had been Hypothyroidism
measured with TSH, free T4 levels, and T3 (if needed) or Ten studies (eight cross-sectional and two cohorts) re-
had it initially as an inclusion criteria (Tables 1 and 2). ported the presence of primary hypothyroidism patients
presenting TED, with a range of prevalence between 0.2
General description of the included studies and 33.3% and a total calculated prevalence of 10.36%,
Cohort studies where Spain showed the higher prevalence and
Of the 13 studies, two were cohort studies [15, 27]. The Singapore the lowest. Some of them with the diagnosis
first one, performed by Eckstein et al., reported on a retro- of Hashimoto hypothyroidism [25]. All patients with sec-
spective study from a TED database 182 consecutive pa- ondary hypothyroidism (after treatment for any dysthyr-
tients treated at the University Hospital of Essen, oidism with thyroidectomy, ion ablation, or radiation)
Germany [15]. The second one was made between 1996 were excluded (Fig. 3).
and 1999 in Asia, the sample was of 1020 patients with
TED diagnosis, and 1001 were excluded in their analysis Euthyroidism
study because they had the previous history of thyrotoxi- Nine of the 13 studies had TED patients with euthyroid-
cosis or hyperthyroidism (we included these patients into ism. The prevalence ranges from 0.9% in Iran and 15.4%
the hyperthyroid group of our study). Ten had subclinical in Germany. With a total calculated prevalence of 7.9%,
thyrotoxicosis (these patients were added to the hyperthy- the studies were located in Ghana, USA, Germany,
roid group in our study), and the other nine patients were Korea, Iran, Singapore, Japan, and Wales. The TED sam-
in hypothyroid or euthyroid status [27]. ple size ranges from 103 to 1020 patients (Fig. 4).

Cross-sectional studies
Ten articles were cross-sectional studies and published be- Discussion
tween 1996 and 2018. One of the studies was conducted in Context
the USA, and the rest in Wales, Germany, Spain, Iran, Japan, TD is a widely common endocrine pathology. According
and Ghana. The population’s range within the studies was to the American Thyroid Association, nearly 12% of the
between 18 and 610 patients; the ten articles had individuals USA population develop any thyroid condition during
with TED and primary hyperthyroidism, with a calculated their life, and closely 20 million Americans have some
prevalence of 85.7% in the ranges of 65.7–95.7%. In eight ar- form of TD. Thyroid disbalances can cause certain serious
ticles, primary hypothyroidism was present in TED individ- consequences, such as cardiovascular diseases, osteopor-
uals, with a calculated prevalence of 12.18% between 2.6 and osis, complications during pregnancy, and infertility [1].
33.3% and euthyroid patients with TED was present in six One important manifestation of TD is TED. This condi-
articles without a history of dysthyroidism, with a calculated tion can significantly decrease the quality of life of those
prevalence of 6.7% with a range between 0.9 and 13.6%. Data who suffer it due to its signs and symptoms [34].
from a referral endocrinology clinic (Tehran University Insti- The importance of this study lies in providing informa-
tute of Endocrinology) were overrepresented and two studies tion about the level of thyroid hormones in patients with
pertained to the same population. TED, to correctly differentiate Graves’ ophthalmopathy
(GO) and TED. This confusion occurs since most patients
Case-control studies with TED have biochemical evidence of hyperthyroidism
The case-control study published by Jang et al. deter- with the most common cause being GD; however, TED
mined the clinical and biochemical characteristics of 163 may occur in patients with hypothyroidism (mainly
Korean patients with TED between 2008 and 2010 [26]. Hashimoto’s thyroiditis) or euthyroidism [35].

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 Table 1 Selection criteria
Author Study design Endocrinological Ophthalmological diagnosis Exclusion of secondary to thyroid Observations
diagnosis of thyroid status of TED disease treatment thyroid hormone
status at TED onset
Ackuaku-Dogbe et al. [24] Cross-sectional Thyroid function tests and By ophthalmologist Authors measured the thyroid status NA
physical examination at the time the first treatment of the
disease was established
Expósito et al. [25] Cross-sectional Thyroid function tests According to information Information of basal hormonal status This study only includes
register in clinical records was extracted from the data of the glucocorticoid-treated patients for an
cause of the disease (GD or active moderate-severe TED status and
Hashimoto thyroiditis) does not explain through which cri-
teria the patients were diagnosed with
Muñoz-Ortiz et al. Systematic Reviews

TED
Bartley et al. [14] Cross-sectional Thyroid function tests By ophthalmologist and Authors measured the thyroid status The patients classified as primary
imaging tests diagnosis index registered on the hypothyroidism and Hashimoto
medical records thyroiditis (all patients were in
hypothyroid status) were merged into
the hypothyroid group to calculate
(2020) 9:201

the prevalence
Eckstein et al. [15] Cohort study Thyroid function tests According to information Investigators measured the thyroid NA
register in clinical records status before or within 6 months after
the onset of TED
Jang et al. [26] Case-Control Thyroid function tests By ophthalmologist and CT The diagnosis of euthyroidism was Hypothyroid patients were not
scans based on normal serum hormone included in the study
levels and no clinical history of
hyperthyroidism. Hyperthyroidism was
established using hormonal criteria
and if the patient had a history of
antithyroid therapy, in this last group
only patients that remained
hyperthyroid were included.
Kashkouli et al. [23] Cross-sectional Thyroid function tests, By a specialized The classification of thyroid hormone A limitation of this study is the
thyroid gland-scan, and ophthalmological clinic status was made according to the underestimation of euthyroid patients.
sonography primary thyroid diagnosis register on This study included patients from the
the clinical records thyroid disorder and not from the
ophthalmological diagnosis, euthyroid
patients were excluded from the
beginning and therefore were not
evaluated by ophthalmology
Khoo et al. [27] Cohort study Thyroid function tests By experienced The study did not mention possible The total number of patients with TED
endocrinologists and for causes of secondary hormonal status identified at the Thyroid Clinic was
equivocal cases further on the patients (following thyroid calculated according to the patients

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evaluations were carried out disease treatment) that were initially included in the
by ophthalmology study (1020). 1001 were excluded
colleagues because they had previous history of
thyrotoxicosis or hyperthyroidism (we
included these patients into the
hyperthyroid group), 10 had
subclinical thyrotoxicosis (these
Page 6 of 12
 Table 1 Selection criteria (Continued)
Author Study design Endocrinological Ophthalmological diagnosis Exclusion of secondary to thyroid Observations
diagnosis of thyroid status of TED disease treatment thyroid hormone
status at TED onset
patients were added to the
hyperthyroid group), and the other 9
patients were in hypothyroid or
euthyroid status
McKeag et al. [28] Cross-sectional Thyroid function tests By ophthalmologist and The criteria of the study included only
imaging tests patients with Graves’ thyrotoxicosis
before or at the time of diagnosis of
TED and only patients with primary
Muñoz-Ortiz et al. Systematic Reviews

hypothyroidism are named in the

study.
Medghalchi et al. [29] Cross-sectional Thyroid function tests By ophthalmologist, imaging The study did not mention possible
tests and visual field analysis causes of secondary hormonal status
on the patients (following thyroid
disease treatment)
(2020) 9:201

Mukasa et al. [30] Cross-sectional Thyroid function tests By a specialized All the patients included were It is not clear if the prevalence of
ophthalmological clinic untreated and were assessed for GO hypothyroidism was cero in this group
within 3 months of their initial visit to or if at the beginning of the study
the hospital these patients were excluded
Ponto et al. [31] Cross-sectional By a specialized By independent The primary hormone levels were A limitation of this study is the
autoimmune (endocrine) ophthalmologist or a measured according to the underestimation of euthyroid patients.
clinic specialized thyroid–eye clinic autoimmune-associated thyroid This study initially included patients
disease with autoimmune thyroid disease (GD
and Hashimoto’s thyroiditis), euthyroid
patients were not included in the
initial selection criteria and were
gathered with hypothyroid patients
Ponto et al. [32] Cross-sectional Thyroid function tests By an ophthalmologist The primary thyroid status was NA
measured 6 months before or after
TED diagnosis
Cozma et al. [33] Cross-sectional By a specialized thyroid– By a specialized thyroid-eye Patients with normal thyroid function NA
eye clinic, thyroid clinic tests, no history of disease or
function tests treatment, no clinical signs or
symptoms of thyroid disease were
included

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Page 7 of 12
Muñoz-Ortiz et al. Systematic Reviews (2020) 9:201 Page 8 of 12

Table 2 Characteristics of included studies

Author Study period Country Number of patients Prevalence (%) Prevalence (%) Prevalence (%)
with TED hyperthyroidism in TED hypothyroidism in TED euthyroidism in TED
Ackuaku-Dogbe et al. [24] 2014–2016 Ghana 117 104 (88.9) 5 (4.3) 8 (6.8)
Expósito et al. [25] 2007–2011 Spain 18 12 (66.7) 6 (33.3) –
Bartley et al. [14] 1976–1990 USA 120 108 (90) 5 (4.2) 7 (5.8)
Eckstein et al. [15] 2000 Germany 182 143 (78.6) 11 (6) 28 (15.4)
Jang et al. [26] 2008–2010 South Korea 163 139 (85.3) – 24 (14.7)
Kashkouli et al. [22] 2003–2006 Iran 303 280 (92.4) 23 (7.5) –
Khoo et al. [27] 1996–1999 Singapore 1020 1011 (99.1) 2 (0.2) 7 (0.7)
McKeag et al. [28] 2006–2007 Wales 47 44 (93.6) 3 (6.4) –
Medghalchi et al. [29] 2012–2014 Iran 103 83 (80.5) 19 (18.4) 1 (0.9)
Mukasa et al. [30] 2010–2010 Japan 238 210 (88.2) – 28 (11.8)
Ponto et al. [31] 1999–2012 Germany 610 584 (95.7) – –
Ponto et al. [32] 2005–2012 Germany 461 441 (95.6) 12 (2.6) 8 (1.7)
Cozma et al. [33] 1997–2005 Wales 140 92 (65.7) 29 (20.7) 19 (13.6)

Methodology assessment Even though we found a lot of information to answer

Many studies had been carried out studying TED. In our our question, we had to exclude most of the papers and
literature search, we found much information regarding studies we found, due to their lack of methodological
this topic, including etiology, pathophysiology, diagnosis quality. As explained in the methodology section, we
and evaluation, and treatment. A common premise, found used the Joanna Briggs guidelines to assess the methodo-
in most of the studies, was the importance of an early logical quality of each article we read. Only 63.33% of
diagnosis for a timely therapeutic approach and thus the studies were included after quality evaluation. Be-
minimize the negative consequences for the patient. Be- sides providing information about thyroid states in TED,
sides, this disease appears to affect more women of repro- we make a special call to the scientific community to
ductive age [8] and children and adolescents in a similar take into account adequate scientific methodology using
proportion or even slightly higher than adults [36]. the standardized tools for each study design.

Fig. 2 Geographical distribution of prevalence of hyperthyroidism (Singapore, Germany, Wales, Iran, USA, Ghana, Japan, South Korea, and Spain)

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Muñoz-Ortiz et al. Systematic Reviews (2020) 9:201 Page 9 of 12

Fig. 3 Geographical distribution of prevalence of hypothyroidism (Spain, Wales, Iran, Germany, Ghana, USA, and Singapore)

In our literature search, we identified different studies TED patients only associated with GD, underestimating
that allowed the measurement of the prevalence of thyroid the prevalence of hypothyroidism and euthyroidism.
disorders in TED. We hypothesized that possible causes
were the range of the sample size on each study, their geo- Clinical aspects
graphical location, or their epigenetic factors influencing Hyperthyroidism is a thyroid disorder that has been
the results. Similarly, we found that 16 studies included known as the most prevalent associated with TED. In

Fig. 4 Geographical distribution of euthyroid prevalence (Germany, South Korea, Wales, Japan, Ghana, USA, Iran, and Singapore)

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Muñoz-Ortiz et al. Systematic Reviews (2020) 9:201 Page 10 of 12

our study, the estimated prevalence was 86.2%. The most IL1RNVNTR polymorphisms, and they also help as a
frequent cause of hyperthyroidism is GD. Patients prognostic indicator [48].
present with heat intolerance, sweating, weight loss, goi- All forms of HT are characterized pathologically by
ter, emotional lability, insomnia, hyperkinetic behavior, lymphocyte B and T cell infiltration of the thyroid gland,
fatigue, weakness, tachycardia, and tremors [37]. as well as follicular helper T cells, increased in the thy-
Even though TED and GD share multiple similarities, roid peripheral blood. Furthermore, there is a clear cor-
they are two separate conditions. Although both involve relation with antigen-specific T suppressor failure such
the immune system, especially TRAbs, the target organ as decreased sensitivity of CD4+ T cells to the inhibitory
is different, in TED is the eye and orbit, while in GD is effect of TGFβ [46]. Antibodies found in HT not only
the thyroid gland. make part of the pathogenesis of the disease but also
In GD, autoreactive T cells against the TSHr escape help to establish a diagnosis and predict the develop-
both central and peripheral selection [38]. B cells de- ment of hypothyroidism [46, 47].
velop into antibody-producing plasma cells in a process Whereas thyroid-stimulating antibodies (TSAb) have a
requiring second signals interacting with T cells, thus clear functional role activating TSHr in GD, it is also
resulting in the production of cytokines such as interleu- known the existence of blocking activity by the thyroid-
kins 1β, 6, and 12; interferon-γ; tumor necrosis factor α; blocking antibodies (TBAb). The balance between TSAb/
CD40 ligand; and others. It promotes antibody secretion TBAb determines disease presentation and fluctuating
and T cell support of class switching [39]. After T cells thyroid hormone levels between hyper or hypothyroidism
have infiltrated the thyroid gland, thyroid epithelial cells in patients with thyroid autoimmune diseases [46].
express MHC class II molecules because of interferon-γ Furthermore, few studies had demonstrated a strong
action. Thus, they have the potential to present thyroid association between functional TSAb and TED in pa-
antigens to T cells, perpetuating the inflammatory tients with autoimmune HT. TSAb was highly prevalent
process [10]. Activated autoantibodies of the IgG1 sub- in those with clinically overt and associated TED com-
class, primarily generated by intrathyroidal B cells, are pared to HT patients without eye pathologies. Also,
directed against the thyrotropin receptor. These anti- TSAb may be relevant to the pathophysiology of orbital
bodies stimulate thyroid hormone production that is un- involvement in HT [49].
controlled by the hypothalamic-pituitary axis [40]. The onset of the TED manifestation can be different
Genetic determinants conferring susceptibility to GD between the hyperthyroid, hypothyroid, and euthyroid
have been identified. These include genes encoding patients. Studies have demonstrated a lower involvement
thyroglobulin, thyrotropin receptor, HLA-DRβ-Arg74, of the orbital-soft-tissue in patients with hypothyroid and
the protein tyrosine phosphatase nonreceptor type 22 euthyroid state [15]. Moreover, Jang et al. concluded that
(PTPN22), and proteins involved in T cell signaling [41– euthyroid patients have higher asymmetrical involvement
43]. Epigenetic factors such as dietary iodine, exposure (79.2%) than hyperthyroid patients (27.3%) [26].
to tobacco smoke, infections, emotional stress, and
alemtuzumab therapy are also associated with GD [44]. Limitations
In an investigation made by Yin et al., genetic associ- The diagnosis method of TED was variable between the
ation studies were performed in a highly characterized studies, and the information they provided about the se-
GO population and compared with patients with GD lection criteria was based on an assessment made by an
but no clinically apparent GO. They found that the allele ophthalmologist or disease specialized center, as shown
and genotype frequencies were not statistically different in Table 1. Hence, we recognize that a limitation of our
between GO and non-GO patients, concluding that GO study is the lack of standardization in TED diagnosis
does not have a distinct genetic susceptibility to their among the included studies.
eye disease [45]. Further studies should evaluate the in- A small number of included works geographically dis-
fluence of immunologic, genetic, and epigenetic factors persed and highly variable “n” can be limitations of our
in GO and TED in hypothyroid and euthyroid patients. work. Nevertheless, it was the result after the quality and
Hashimoto thyroiditis (HT) is part of a spectrum of data assessment of all the found articles.
thyroid autoimmune diseases, ranging from typically
self-limiting focal forms [46] to other several clinico- Conclusion
pathologic entities like hashitoxicosis. Most HT forms We recommend to ophthalmologists to be aware of
ultimately evolve into hypothyroidism (with systemic TED clinical signs and suspect it even if the patients
clinical manifestations of a slow metabolism), although, have a normal thyroid function. The assessment for
in the initial presentation, patients can be hyperthyroid these patients should be based on orbital images, serum
or even euthyroid [47]. Moreover, HT is associated with T3, free T4, TSH, TRAbs, and interdisciplinary manage-
disturbance in genes like the TSHr and with ment with the endocrinologist.

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Muñoz-Ortiz et al. Systematic Reviews (2020) 9:201 Page 11 of 12

There are many studies made in Asia, Germany, USA, Ciencias de la Salud, Universidad del Rosario, Carrera 24 # 63C 69, Bogotá,
and Wales, among other countries, but there is a lack of Colombia.

information about this disease in Latin American popu- Received: 8 June 2020 Accepted: 14 August 2020
lation. This is why we encourage researchers to obtain
data from Latin American countries. Also, we strongly
recommend performing primary studies following high-
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