Journal Pre-proof

COVID-INDUCED THYROID
AUTOIMMUNITY

Alessandro Brancatella, Nicola Viola, Ferruccio

Satini, Francesco Latrofa

PII: S1521-690X(23)00011-8
DOI: https://doi.org/10.1016/j.beem.2023.101742
Reference: YBEEM101742

To appear in: Best Practice & Research Clinical Endocrinology & Metabolism
Please cite this article as: Alessandro Brancatella, Nicola Viola, Ferruccio Satini
and Francesco Latrofa, COVID-INDUCED THYROID AUTOIMMUNITY,
Best Practice & Research Clinical Endocrinology & Metabolism, ()
doi:https://doi.org/10.1016/j.beem.2023.101742
This is a PDF file of an article that has undergone enhancements after acceptance,
such as the addition of a cover page and metadata, and formatting for readability,
but it is not yet the definitive version of record. This version will undergo
additional copyediting, typesetting and review before it is published in its final
form, but we are providing this version to give early visibility of the article.
Please note that, during the production process, errors may be discovered which
could affect the content, and all legal disclaimers that apply to the journal pertain.
© Published by Elsevier.
COVID-INDUCED THYROID AUTOIMMUNITY

Alessandro Brancatella, MD (PhD Student)

Nicola Viola, MD (PhD Student)
Ferruccio Satini, MD (Associate Professor)
Francesco Latrofa, MD (Associate Professor)

Endocrinology Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa,
Italy

f
oo
Corresponding Author:

pr
Francesco Latrofa, MD
Endocrinology Unit I, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa,
e-
Italy. Phone +39050995001; Fax +39050996551; e-mail: francesco.latrofa@unipi.it
Pr
ABSTRACT

Breakdown of self-tolerance to thyroid antigens (thyroperoxidase, thyroglobulin and the thyrotropin-

receptor) is the driver of thyroid autoimmunity. It has been suggested that infectious disease might trigger
al

autoimmune thyroid disease (AITD). Involvement of the thyroid has been reported during severe acute
n

respiratory syndrome virus 2 (SARS-CoV-2) infection, in the form of subacute thyroid in subjects with mild
ur

coronavirus disease 19 disease (COVID-19) and of painless, destructive thyroiditis in hospitalized patients
with severe infection. In addition, cases of AITD, both Graves‟ disease (GD) and Hashimoto‟s thyroiditis
Jo

(HT), have been reported in association with (SARS-CoV-2) infection. In this review, we focus on the
relationship between SARS-CoV-2 infection and occurrence of AITD. Nine cases of GD strictly related to
SARS-CoV-2 infection and only three cases of HT associated to COVID-19 infection have been reported.
No study has demonstrated a role of AITD as a risk factor for a poor prognosis of COVID-19 infection.

KEY WORDS: SARS-CoV-2; COVID-19; autoimmune thyroid disease; Graves‟ disease; Hashimoto‟s
thyroiditis

LIST OF ABBREVIATIONS
ACE 2: angiotensin-converting enzyme
AITD: autoimmune thyroid disease
APC: antigens presenting cells

1
GD: Graves‟ disease
GO: Graves‟ Orbitopathy
HT: Hashimoto‟s thyroiditis
MHC: major histocompatibility complex
MMI: methimazole
ORadj: adjusted odds ratio
SARS-CoV-2: severe acute respiratory syndrome coronavirus 2
Tg-Ab: thyroglobulin antibodies
TPO-Ab: thyroid peroxidase antibodies
TSH-R-Ab: thyrotropin receptor antibodies

f
oo
INTRODUCTION

pr
Autoimmune thyroid disease (AITD) is characterized by an autoimmune response to thyroid
antigens. It requires a specific genetic background and is triggered by the exposure to environmental factors
e-
(1). Hashimoto‟s thyroiditis (HT) and Graves‟ disease (GD) are the more common types of AITD: HT is
usually associated to serum autoantibodies to thyroid peroxidase (TPO-Ab) and to thyroglobulin (Tg-Ab)
Pr
and is characterized by thyroid damage that can lead to hypothyroidism, whereas hyperthyroidism of GD is
due to autoantibodies that stimulates the thyrotropin receptor (TSH-R-Ab) (1) (2). These disorders are
common worldwide, and their incidence is increasing. The prevalence of HT is 10-12% in the general
al

population, the highest of all autoimmune diseases, whereas that of GD is estimated to be 1-2.5% (2–4). As
in other autoimmune disorders, AITD is more common in females (3,4). The breakdown of self-tolerance to
n

thyroid antigens (TPO, Tg, and the TSH-R) is the main driver of thyroid autoimmunity (5). Immunogenicity
ur

of autoantigens is linked to some specific characteristics, namely genetic polymorphism, a higher numbers of
peptides available for binding to major histocompatibility complex (MHC) on antigens presenting cells
Jo

(APC), and a high level of glycosylation, which favors antigen binding to mannose receptors localized on
cell surface on APC (5,6). Because these characteristics are more marked in Tg, its immunogenicity is higher
compared to TPO and the TSH-R (6,7). The influence of genes and environment is different in HT and GD.
Their relevance of genetic factors can be quantified using the sibling risk ratio, which is the ratio of the risk
of developing AITD in siblings of patients with AITD compared to the prevalence of AITD in the general
population (8,9). This ratio is 17 for GD and 28.0 for HT (9). Since family members share environmental
and genetic factors, studies have focused on twins, leading to a more clear definition of the influence of
genetic background and environment on the risk of developing AITD (8). Some twin studies have
demonstrated that the genetic background contributes for more than 75% to the risk of developing GD and
HT (9). Thus, the contribution of environmental factors to the onset of AITD accounts for the remaining
20% (7). Iodine intake, cigarette smoking, stress and infections among other environmental factors have

2
been reported to be associated with the development of AITD (7,10,11). Some studies have shown that
infectious disease may trigger autoimmune disorders, including AITD (12).
Starting from December 2019, SARS-CoV-2 infection has spread worldwide, infecting millions of
people (13). Early during the pandemic, it was observed that the thyroid can be involved during the SARS-
CoV-2 infection, in the form of subacute thyroid in patients with mild COVID-19 infection and of painless,
destructive thyroiditis in hospitalized subjects with a severe infection (14–16). In addition, some cases of
AITD, both GD and HT, have been reported in association with SARS-CoV-2 infection. In this review, we
focus on the relationship between SARS-CoV-2 infection and occurrence of AITD.

f
oo
METHODS

pr
A search of the databases EMBASE, MEDLINE and PubMed, was conducted in accordance
e-
with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) in September
2022. All studies identified using search terms up from inception until September 2022 were considered for
Pr
inclusion to the study. Database was searched using the following terms „Coronavirus disease 19 and
thyroid‟ OR „COVID-19 and thyroid‟ OR „SARS-CoV-2 and thyroid‟ OR „thyroid autoimmunity and
COVID-19‟ OR „SARS-CoV-2 and thyroid autoimmunity‟ OR “COVID-19 and thyroid immunity” OR
al

“SARS-CoV-2 and thyroid immunity” OR “COVID-19 and thyroid antibodies” OR “SARS-CoV-2 and
thyroid antibodies” OR “COVID-19 and thyroid autoantibodies” OR “SARS-CoV-2 and thyroid
n

autoantibodies” OR “COVID-19 and Hashimoto‟s thyroiditis” OR “SARS-CoV-2 and Hashimoto‟s

ur

thyroiditis” OR “COVID-19 and Graves‟ disease” OR “SARS-CoV-2 and Graves‟ disease”. The following
studies were excluded: non-English language and studies reporting AITD in subjects who underwent
Jo

COVID-19 vaccination. Clinical trials, prospective, observational studies such as case reports were all
included whereas meta-analysis and systematic reviews were excluded. Study titles and abstracts were
screened before full-text review was completed in duplicate by two study investigators (AB, NV).
Discrepancies were addressed by FL. A total of 18 studies matched the criteria for inclusion into this review.

RESULTS

Graves’ disease and SARS-CoV-2 infection

Nine cases of GD strictly related to SARS-CoV-2 infection were reported (Table 1). In the first
report, two cases were described. In the first case, GD had been in remission for 30 years, and relapsed one
month after COVID-19 infection (17). The second patient had no history of thyroid disease and developed
GD two months after COVID-19 infection. Both cases were successfully treated with methimazole (MMI)

3
(17). In the second report, authors described two cases of patients who experienced GD concurrently with
the presentation of SARS-CoV-2 infection (18). The first patient, a 47-year-old female with a previous
history of GD, had a relapse of hyperthyroidism contextually with COVID-19 infection (18). Treatment
with MMI quickly stabilized her thyroid function, with no complications. The second patient was a 61-year-
old female with atrial fibrillation and GD since 2004. One month after COVID-19 infection, she was
admitted to the hospital for arrythmias. A severe form of hyperthyroidism was diagnosed and treatment with
MMI was started, with restoration of euthyroidism within three months (18). The fifth reported case occurred
in a 33-year-old female who developed GD eight weeks after COVID-19 infection. She presented with
biochemical hyperthyroidism associated with high thyroid uptake at scintigraphy and high TSH-R-Ab serum
levels. The patient was successfully managed with methimazole (MMI)

f
(19). A case of GD associated with Graves‟ orbitopathy (GO) that occurred in a 33-year-old woman

oo
has been also reported. Symptoms of COVID-19 appeared in March 2020. Two months later, she
complained with tachycardia, weight loss, heat intolerance and nervousness. Thyroid function tests showed

pr
hyperthyroidism with positive serum TSH-R-Ab. Ultrasound examination of the thyroid gland revealed a
diffuse hypoechoic pattern. A clinically mild and inactive GO was diagnosed. The patient was treated with
e-
MMI, and an improvement of symptoms and thyroid function was observed (20). In another report, the
authors described Graves' hyperthyroidism in a 48-year-old African American male who had been admitted
Pr
to the hospital for cough, fatigue, and palpitations. Euthyroidism was restored within a few weeks on MMI
treatment (21). Two other cases of GD ensued few weeks after the recovery from COVID-19 infection have
been reported in 2022 (22, 23). Clinical features of the patients reported in the last two publications were
al

similar to those reported above.

n

Hashimoto’s thyroiditis and SARS-CoV-2 infection

ur

Only three cases of HT can be described as clearly following COVID-19 infection, because AITD
had not been reported beforehand (Table 2). In the first report, a 38-year-old female developed
Jo

hypothyroidism, confirmed by high TSH serum levels and very low serum levels of free thyroxine (FT4), six
weeks after COVID-19 infection. Clinical evaluation showed that the AITD was the cause of
hypothyroidism (19). In the second case, a 45-year-old male experienced subclinical hypothyroidism
associated with positive TPO-Ab, one week after he recovered from a COVID-19 infection (24). In the third
case, a 33-year-old female developed autoimmune hypothyroidism, 20 days after COVID-19 disease (25).
All three cases were treated with levothyroxine, attaining remission of symptoms and normalization of
thyroid function within a few months. In addition, two reports described patients with a well-known history
of HT and normal thyroid function that experienced a change in thyroid function status after COVID-19
infection. In the first case, a 42-year-old female developed overt hypothyroidism three months after COVID-
19 disease (26). In the second, a 29-year-old female experienced a post-partum thyroiditis with mild
thyrotoxicosis one month after she recovered from COVID-19 infection (27). Finally, another report

4
described a patient admitted to the hospital because of COVID-19 pneumonia and concomitant myxedema.
Unfortunately, no data about thyroid function prior to COVID-19 infection was available (28).

Course of SARS-CoV-2 infection in patients with AITD

Many studies have evaluated the risk factors associated with a poor prognosis of COVID-19
infection. In no study a previous thyroid dysfunction has emerged as a risk factor (29) (30). Nevertheless,
most of them were not designed to accurately investigate the previous thyroid history of subjects
experiencing SARS-CoV-2 infection. To our knowledge, only one population study has investigated if a
preexistent thyroid disorder (established based on the use of thyroid specific drugs, namely levothyroxine or
anti-thyroid drugs) was associated with a higher risk of contracting SARS-CoV-2 infection or with a poor

f
prognosis of COVID-19 disease (31). Comparing SARS-CoV-2-positive patients to matched SARS-CoV-2-

oo
negative patients, the likelihood of taking levothyroxine was similar: 2.9% (809 out of 28,078) in the first
and 2.9% (7,994 out of 280,007) in the latter group. Similarly, the likelihood of taking antithyroid drugs was

pr
similar in both groups: 91 (0.3%) SARS-CoV-2-positive and 936 (0.3%) SARS-CoV-2-negative patients.
Thus, patients taking medications for hypothyroidism or hyperthyroidism did not have an increased risk of
e-
contracting SARS-CoV-2 infection. In addition, the risk of a poor prognosis of the infection was evaluated in
16,502 individuals with COVID-19, 572 (3.5%) of whom were using levothyroxine and 75 (0.5%)
Pr
antithyroid drugs. Although at the “crude analysis” the use of levothyroxine was associated with an
increased risk of death (Relative risk, 2.39 [95% CI 1.80–3.19]), hospitalization (2.15 [1.84–2.50]), intensive
care unit admission (1.88 [1.23–2.87]), mechanical ventilation (1.75 [1.06–2.87]), and dialysis (3.24 [1.63–
al

6.44]) (31), these associations, except for hospitalization, were not confirmed at the propensity score
weighting analysis. These results are in agreement with a previous retrospective study, which included 3703
n

COVID-19 positive patients evaluated in New York (32). Of these, 251 patients (6.8%) had a pre-existing
ur

hypothyroidism and received thyroid hormone therapy. Hypothyroidism was neither associated with an
increased risk of hospitalization [Adjusted Odds Ratio (ORadj): 1.23 (95% CI: 0.88- 1.70), mechanical
Jo

ventilation [ORadj: 1.17 (95% CI: 0.81-1.69)] nor death [ORadj: 1.07 (95% CI: 0.75-1.54)] (32). Conversely, a
telephone survey investigating a small group of patients, reported a higher risk of contracting SARS-CoV-2
in subjects with AITD, compared to the general population (33).

DISCUSSION

Starting from December 2019, SARS-CoV-2 has emerged as a pandemic respiratory virus causing a
severe interstitial pneumonia (COVID-19) (13,34). After three years of pandemic, about 630 million people
have been infected with SARS-CoV-2 and six million have died from COVID-19 worldwide. The
importance of an early diagnosis and of a prompt isolation of the infected cases became a global challenge to
contain the infection (35). The development of nasopharyngeal swabs and of immunological tests for the
detection of SARS-CoV-2 and their widespread use has enabled the tracing of millions of COVID-19 cases

5
around the world (35). This huge amount of data allows clinicians investigating the correlation of this
infection with other diseases. Indeed, since the first months of the pandemic, it was clear that SARS-CoV-2
virus can cause extra-pulmonary manifestations, namely myocarditis, pericarditis, nephritis, Guillain-Barre
syndrome and others (36,37). In May 2020, we first reported thyroid involvement by SARS-CoV-2 infection
in a young woman experiencing subacute thyroiditis (SAT) a few weeks after the recovery from COVID-19
infection (14). Subsequently, other SAT cases related to SARS-CoV-2 infection were reported by our and
other groups (38–40). SAT is a disease of viral or post-viral origin and other respiratory viruses have
previously emerged as causative agents (41). Further studies have shown that SAT induced by SARS-CoV-2
is similar to those caused by other viruses, except for a higher risk of evolution to permanent hypothyroidism
(15). Almost simultaneously to SAT reports, a painless destructive thyroiditis was described in hospitalized

f
patients with severe forms of COVID-19 (16). It is still debated if this thyrotoxicosis is a specific

oo
manifestation of severe COVID-19 or, it is vice versa related to other factors (e.g., medications, iodine
contrast agent and others). The likelihoods of a direct thyroid damage caused by the virus is supported by

pr
some studies showing that the cellular receptor of SARS-COV-2 (angiotensin-converting enzyme [ACE 2])
is highly expressed on thyroid tissue (42).
e-
Some reports have highlighted the possible role of SARS-CoV-2 infection as a trigger factor for the
onset of AITD (17-28). Indeed, some cases of GD and HT ensued in patients with a recent COVID-19
Pr
infection has been described in the three years of pandemic (17-28). The possibility that infectious diseases
may trigger an AITD is suggested by molecular and epidemiological studies. Indeed, the presence of type II
MHC molecules was demonstrated on the surface of the thyrocytes of patients with HT but not in normal
al

subjects (12). Expression of these molecules may be induced by interferon- and indirectly by viruses,
favoring the presentation of autoantigens by thyroid cells to T cells, with the consequent activation of T cells
n

and autoimmune response. (43). Other studies have evaluated the link between AITD and some common
ur

infectious disease. No association was found between the infection of Helicobacter Pylori and HT whereas
data on the role of Yersinia Enterocolitica in the pathogenesis of AITD were conflicting (44). The
Jo

prevalence of antibodies to Yersinia Enterocolitica outer membrane proteins was higher in the healthy
female relatives of patients with AITD compared to controls (45). Nevertheless, during the follow-up, the
rate of development of thyroid antibodies (and of hypothyroidism) was similar in subjects with positive
antibodies to Yersinia Enterocolitica and in those who were negative (46). Similar results were shown
following the relatives of patients with GD (47). Overall, these results suggest that Yersinia Enterocolitica
does not play a role in the pathogenesis of AITD. As far as the correlation between viral infections and
AITD, one issue that has been investigated is the possible association between AITD and chronic hepatitis C
(HCV) of the liver. Some researchers reported a higher frequency of hypothyroidism and thyroid
autoantibodies in untreated HCV patients, but these results were not supported by other studies (48,49).
Thus, no study has demonstrated a strict correlation between viral infection and AITD.
The association between COVID-19 and AITD is currently speculative, given the absence of large
prospective studies investigating this issue. More than 600 million people have been infected by SARS-CoV-

6
2 worldwide and the number is constantly growing. If SARS-CoV-2 infection is a specific risk factor for the
development of AITD, an increase in the incidence of HT and GD would have been reported in the last few
years. According to the available literature, a rise in the frequency of cases of GD and HT has not been
observed. However some patients could have developed positive Tg-Ab and TPO-Ab with no evidence of
hypothyroidism and related symptoms (50). Indeed, many studies have shown that about 10-12% of patients
with HT do not present sign and symptoms of hypothyroidism for their entire lifetime. In addition, evolution
to hypothyroidism is usually slow, with an estimated rate of progression to overt hypothyroidism of 4% per
year (51). Thus, we cannot exclude that, in the future a rise in AITD prevalence or a higher percent of
progression to hypothyroidism in AITD patients following COVID-19 pandemic, will be observed, although
this hypothesis now seems unlikely.

f
On the other hand, studies aiming at identifying the risk factors associated with a worse prognosis of

oo
COVID-19 infection have excluded the role of a concomitant thyroid dysfunction (30) (29). This conclusion
is based on the few studies that have investigated the link between a previous thyroid disorder and prognosis

pr
of COVID-19. It is worth noting that these studies classified patients according to the use, or not, of
levothyroxine or anti-thyroid drugs (31,32). An evaluation on the possible role of AITD by itself, in absence
e-
of thyroid dysfunction, i.e., euthyroid patients with positive TPO-Ab or Tg-Ab, is lacking.
Finally, starting from the end of 2020, vaccines against SARS-COV-2 have been developed. mRNA
Pr
vaccines have been used for the first time against an infectious disease (52). Nowadays, five billion people
have been vaccinated worldwide. These vaccines have changed the natural history of COVID-19, reducing
dramatically the mortality for COVID-19 and partially the risk of infection (53,54). Safety profile of mRNA
al

vaccines is excellent, with a very few adverse events reported to date (53). Except for the common adverse
events associated with any type of vaccination, namely fever, fatigue and lymph node enlargements, mRNA
n

vaccines have been associated with a small but significant increase in the risk of self-limited myocarditis and
ur

pericarditis, especially in young males (55). No specific endocrinological alert has been reported to date.
Nevertheless, some cases of destructive thyroiditis have been described after COVID-19 vaccination (56). In
Jo

addition, a few isolated case publications and studies have reported that SARS-CoV-2 vaccination may
trigger AITD (57).
Different pathogenetic mechanisms have been proposed to explain these reactions. First, an
immunological trigger may favor the onset of an autoimmune reaction in a subject predisposed because of
his/her genetic background. Infectious disease and vaccination are well known immunological triggers.
Interestingly enough, it has been suggested that the immune response against SARS-CoV-2 antigens (both
natural or following the vaccination) could induce an autoimmune reaction by molecular mimicry (58,59).
Another pathogenetic hypothesis involved the “antigens spreading”, that may follow thyroid destruction
induced by the virus or by the cytokine storm. Nevertheless, as observed in other settings of destructive
thyroiditis, namely subacute thyroiditis or post-radioactive iodine treatment, the release of thyroid antigens
can favor the “de novo” appearance of thyroid antibodies but usually is not sufficient to break immune
tolerance and trigger AITD (60,61).

7
CONCLUSION

Few data support the association between COVID-19 and AITD. Further studies are required to
establish if SARS-CoV-2 infection is a trigger for AITD. A concomitant thyroid dysfunction does not seem
to be associated with a higher risk of contracting SARS-CoV-2 and a poor prognosis of COVID-19, while
data on the role of AITD per se are lacking. Different pathogenic mechanisms, including antigen spreading
and molecular mimicry, could explain the possible link between SARS-CoV-2 infection and AITD.

f
oo
pr
PRACTICE POINTS e-
 Thyroid diseases, namely subacute thyroiditis and autoimmune thyroid disease have been reported to
occur after COVID-19 infection.
Pr

 Subacute thyroiditis is usually characterized by clinical stigmata, whereas autoimmune thyroid

disease, especially Hashimoto‟s thyroiditis, may go unrecognized if not carefully searched for.
 There is currently no evidence of a rising incidence of autoimmune thyroid disease in the “COVID
al

era”.
n
ur

RESEARCH AGENDA
Jo

 Studies to compare the incidence of autoimmune thyroid disease after COVID-19 pandemic to that
observed in previous years to establish a link between SARS-CoV-2 infection and AITD.
 Studies to clarify the pathogenic mechanisms underlying the possible correlation between SARS-
CoV-2 infection and the onset of autoimmune thyroid disease.

LEGENDS

8
 f
oo
Figure 1: PRISMA CHART
Table 1:
pr
CASES OF GRAVES‟ DISEASE RELATED TO SEVERE ACUTE RESPIRATORY
e-
SYNDROME CORONAVIRUS 2 (SARS-CoV-2) INFECTION
Author, Year Sex, Previous Time interval from Evidence Treatment
Pr

Age history of GD SARS-CoV-2 infection of GO

(years)
Mateu-Salat et F, 60
Yes Concomitant No Methimazole
al., 2020 F, 53
No 2 months No Methimazole
al

Jimenez Blanco F, 45
Yes 2 months No Methimazole
et al., 2021 F, 61
Yes Concomitant No Methimazole
n

Feghali et al., F, 33
No 2 months No Methimazole
2021
ur

Lanzolla et al., F, 33 No 2 months Yes Methimazole

2021
Jo

Ghareebian at al., M, 48 No Concomitant No Methimazole

2022
Urbanovych et F, 22 No 3 weeks No Methimazole
al., 2022
Sousa et al., 2022 M, 28 No 3 weeks No Methimazole
F = female; M = male; GD = Graves‟ disease; GO = Graves‟ Orbitopathy

Table 2: CASES OF HASHIMOTO‟S THYROIDITIS RELATED TO SEVERE ACUTE RESPIRATORY

SYNDROME CORONAVIRUS 2 (SARS-CoV-2) INFECTION
Author, Sex, Previous history Time interval from Serum Treatment
Year Age of AITD SARS-CoV-2 infection TSH at
(years) diagnosis -
IU/L
Feghali et F, 38 No 6 weeks 136 Levothyroxine
al., 2021
9
Tee et al., M, 45 No 7 days 6.5 Levothyroxine
2021
Knack et al., F, 33 No 20 days 8 Levothyroxine
2021
Allam et al., F, 42 Yes 80 days 25.5 Levothyroxine
2021
Mizuno et F, 29 Yes 36 days 0.02 No therapy
al., 2021
Dixit et al., F, 69 Not known Concomitant 61.3 Levothyroxine
2021
F = female; M = male; AITD = autoimmune thyroid disease; TSH = thyrotropin

REFERENCES

f
oo
1. Ajjan RA, Weetman AP. The Pathogenesis of Hashimoto‟s Thyroiditis: Further Developments in our
Understanding. Horm Metab Res = Horm und Stoffwechselforsch = Horm Metab. 2015
Sep;47(10):702–10.
2.
from: http://www.nejm.org/doi/10.1056/NEJMra1510030
pr
Smith TJ, Hegedüs L. Graves‟ Disease. N Engl J Med [Internet]. 2016;375(16):1552–65. Available
e-
3. Bülow Pedersen I, Laurberg P, Knudsen N, Jørgensen T, Perrild H, Ovesen L, et al. A population
study of the association between thyroid autoantibodies in serum and abnormalities in thyroid
Pr

function and structure. Clin Endocrinol (Oxf). 2005 Jun;62(6):713–20.

4. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum
TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health
al

and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002 Feb;87(2):489–99.
n

5. **Weetman AP. Autoimmune thyroid disease: propagation and progression. Eur J Endocrinol. 2003
Jan;148(1):1–9.
ur

6. McLachlan SM, Rapoport B. Breaking tolerance to thyroid antigens: changing concepts in thyroid
autoimmunity. Endocr Rev. 2014 Feb;35(1):59–105.
Jo

7. Wiersinga WM. Clinical Relevance of Environmental Factors in the Pathogenesis of Autoimmune

Thyroid Disease. Endocrinol Metab (Seoul, Korea). 2016 Jun;31(2):213–22.
8. Brix TH, Christensen K, Holm N V, Harvald B, Hegedüs L. A population-based study of Graves‟
disease in Danish twins. Clin Endocrinol (Oxf). 1998 Apr;48(4):397–400.
9. Brix TH, Kyvik KO, Hegedüs L. What is the evidence of genetic factors in the etiology of Graves‟
disease? A brief review. Thyroid. 1998 Aug;8(8):727–34.
10. Bulow Pedersen I, Knudsen N, Carle A, Schomburg L, Kohrle J, Jorgensen T, et al. Serum selenium
is low in newly diagnosed Graves‟ disease: a population-based study. Clin Endocrinol (Oxf). 2013
Oct;79(4):584–90.
11. Wiersinga WM. Smoking and thyroid. Clin Endocrinol (Oxf). 2013 Aug;79(2):145–51.
12. Prummel MF, Laurberg P. Interferon-alpha and autoimmune thyroid disease. Thyroid. 2003
Jun;13(6):547–51.
10
13. *Guan W-J, Ni Z-Y, Hu Y, Liang W-H, Ou C-Q, He J-X, et al. Clinical Characteristics of
Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb 382(18):1708-1720;
14. **Brancatella A, Ricci D, Viola N, Sgrò D, Santini F, Latrofa F. Subacute Thyroiditis After Sars-
COV-2 Infection. J Clin Endocrinol Metab. 2020 Jul;105(7).
15. Brancatella A, Viola N, Rutigliano G, Sgrò D, Santini F, Latrofa F. Subacute Thyroiditis During the
SARS-CoV-2 Pandemic. J Endocr Soc. 2021 Oct;5(10):bvab130.
16. *Muller I, Cannavaro D, Dazzi D, Covelli D, Mantovani G, Muscatello A, et al. SARS-CoV-2-related
atypical thyroiditis. The lancet. Diabetes & endocrinology. Sep 2020;8(9):739-741
.
17. **Jiménez-Blanco S, Pla-Peris B, Marazuela M. COVID-19: a cause of recurrent Graves‟

f
hyperthyroidism? Vol. 44, Journal of endocrinological investigation. 2021. p. 387–8.

oo
19. **Feghali K, Atallah J, Norman C. Manifestations of thyroid disease post COVID-19 illness: Report
of Hashimoto thyroiditis, Graves‟ disease, and subacute thyroiditis. Vol. 22, Journal of clinical and

pr
translational endocrinology case reports. 2021. p. 100094.
20. Lanzolla G, Marcocci C, Marinò M. Graves‟ disease and Graves‟ orbitopathy following COVID-19.
e-
Vol. 44, Journal of endocrinological investigation. 2021. p. 2011–2.
21. Ghareebian H, Mariash C. COVID-19-Induced Graves‟ Disease. Vol. 14, Cureus. 2022. p. e22260.
Pr
22. Urbanovych AM, Laniush F, Borovets M, Kozlovska K. Coronavirus as a Trigger Of Graves‟
Disease. Acta Endocrinol (Bucharest, Rom 2005). 2021;17(3):413–5.
23. Sousa B, Pestana Santos C, Gonçalves Ferreira A, Judas T. Graves‟ Disease Caused by SARS-CoV-2
al

Infection. Eur J case reports Intern Med. 2022;9(7):3470.

24. **Tee LY, Harjanto S, Rosario BH. COVID-19 complicated by Hashimoto‟s thyroiditis. Vol. 62,
n

Singapore medical journal. 2021. p. 265.

ur

25. Knack RS, Hanada T, Knack RS, Mayr K. Hashimoto‟s thyroiditis following SARS-CoV-2 infection.
BMJ Case Rep. 2021 Aug;14(8).
Jo

26. *Allam MM, El-Zawawy HT, Ahmed SM, Aly Abdelhamid M. Thyroid disease and covid-19
infection: Case series. Vol. 9, Clinical case reports. 2021. p. e04225.
27. *Mizuno S, Inaba H, Kobayashi K-I, Kubo K, Ito S, Hirobata T, et al. A case of postpartum
thyroiditis following SARS-CoV-2 infection. Endocr J. 2021 Mar;68(3):371–4.
28. Dixit NM, Truong KP, Rabadia S V, Li D, Srivastava PK, Mosaferi T, et al. Sudden Cardiac Arrest in
a Patient With Myxedema Coma and COVID-19. Vol. 4, Journal of the Endocrine Society. Aug
2020. 28;4(10).
29. Takeyama M, Yachi S, Nishimoto Y, Tsujino I, Nakamura J, Yamamoto N, et al. Mortality-
Associated Risk Factors in Hospitalized COVID-19 Patients in Japan: Findings of the CLOT-
COVID Study. J Epidemiol. 2022 Nov;
30. Dessie ZG, Zewotir T. Mortality-related risk factors of COVID-19: a systematic review and meta-
analysis of 42 studies and 423,117 patients. BMC Infect Dis. 2021 Aug;21(1):855.

11
31. *Brix TH, Hegedüs L, Hallas J, Lund LC. Risk and course of SARS-CoV-2 infection in patients
treated for hypothyroidism and hyperthyroidism. Vol. 9, The lancet. Diabetes & endocrinology.
2021. p. 197–9.
32. *van Gerwen M, Alsen M, Little C, Barlow J, Naymagon L, Tremblay D, et al. Outcomes of Patients
With Hypothyroidism and COVID-19: A Retrospective Cohort Study. Front Endocrinol (Lausanne).
2020;11:565.
33. Fallahi P, Ferrari SM, Elia G, Paparo SR, Patrizio A, Balestri E, et al. Thyroid autoimmunity and
SARS-CoV-2 infection: Report of a large Italian series. Autoimmun Rev. 2022 Aug;21(11):103183.
34. Remuzzi A, Remuzzi G. COVID-19 and Italy: what next? Lancet (London, England). 2020 Mar;
35. Luo Z, Ang MJY, Chan SY, Yi Z, Goh YY, Yan S, et al. Combating the Coronavirus Pandemic:

f
Early Detection, Medical Treatment, and a Concerted Effort by the Global Community. Res

oo
(Washington, DC). 2020;2020:6925296.
36. Dhakal BP, Sweitzer NK, Indik JH, Acharya D, William P. SARS-CoV-2 Infection and

pr
Cardiovascular Disease: COVID-19 Heart. Heart Lung Circ. 2020 Jun 29(7):973-987;
37. Toscano G, Palmerini F, Ravaglia S, Ruiz L, Invernizzi P, Cuzzoni MG, et al. Guillain-Barré
e-
Syndrome Associated with SARS-CoV-2. Vol. 382, The New England journal of medicine. 2020. p.
2574–6.
Pr
38. Brancatella A, Ricci D, Cappellani D, Viola N, Sgrò D, Santini F, et al. Is subacute thyroiditis an
underestimated manifestation of SARS-CoV-2 infection? Insights from a case series. J Clin
Endocrinol Metab. Oct 2020 Oct 1;105(10);
al

39. Ippolito S, Dentali F, Tanda ML. SARS-CoV-2: a potential trigger for subacute thyroiditis? Insights
from a case report. Journal of endocrinological investigation.Aug. 2020. 43(8):1171-1172.
n
ur

40. Viola N, Brancatella A, Sgrò D, Santini F, Latrofa F. Clinical, biochemical features and functional
outcome of patients with SARS-CoV-2-related subacute thyroiditis: a review. Endocrine. 2022
Jo

Nov;1–7.
41. Desailloud R, Hober D. Viruses and thyroiditis: an update. Virol J. 2009 Jan;6:5.
42. Lazartigues E, Qadir MMF, Mauvais-Jarvis F. Endocrine significance of SARS-CoV-2‟s reliance on
ACE2. Endocrinology. Sept. 2020;1;161(9
43. Weetman AP. Autoimmune thyroid disease. Chapter 18. In: Jameson LJ, et al., editors.
Endocrinology: adult and pediatric. 7th ed. Philadelphia: Elsevier/Saunders; 2016. p. 1423–36.
44. Shmuely H, Shimon I, Gitter LA. Helicobacter pylori infection in women with Hashimoto thyroiditis:
A case-control study. Medicine (Baltimore). 2016 Jul;95(29):e4074.
45. Wenzel BE, Strieder TM, Gáspár E, Wiersinga WM. Chronic infection with Yersinia enterocolitica in
patients with clinical or latent hyperthyroidism. Adv Exp Med Biol. 2003;529:463–6.
46. Effraimidis G, Tijssen JGP, Strieder TGA, Wiersinga WM. No causal relationship between Yersinia
enterocolitica infection and autoimmune thyroid disease: evidence from a prospective study. Clin

12
 Exp Immunol. 2011 Jul;165(1):38–43.
47. Brix TH, Hansen PS, Hegedüs L, Wenzel BE. Too early to dismiss Yersinia enterocolitica infection
in the aetiology of Graves‟ disease: evidence from a twin case-control study. Clin Endocrinol (Oxf).
2008 Sep;69(3):491–6.
48. Antonelli A, Ferri C, Fallahi P, Ferrari SM, Ghinoi A, Rotondi M, et al. Thyroid disorders in chronic
hepatitis C virus infection. Thyroid. 2006 Jun;16(6):563–72.
49. Metcalfe RA, Ball G, Kudesia G, Weetman AP. Failure to find an association between hepatitis C
virus and thyroid autoimmunity. Thyroid. 1997 Jun;7(3):421–4.
50. Caturegli P, De Remigis A, Rose NR. Hashimoto thyroiditis: Clinical and diagnostic criteria.
Autoimmunity Reviews. May 2014. 13(4-5):391-7

f
51. Promberger R, Hermann M, Ott J. Hashimoto‟s thyroiditis in patients with normal thyroid-stimulating

oo
hormone levels. Expert Rev Endocrinol Metab. 2012 Mar;7(2):175–9.
52. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev

pr
Drug Discov. 2018 Apr;17(4):261–79.
53. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and Efficacy of
e-
the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec;383(27):2603–15.
54. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and Safety of the
Pr
mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021 Feb;384(5):403–16.
55. Rout A, Suri S, Vorla M, Kalra DK. Myocarditis associated with COVID-19 and its vaccines - a
systematic review. Prog Cardiovasc Dis. 2022 Oct;
al

56. Jeeyavudeen MS, Patrick AW, Gibb FW, Dover AR. COVID-19 vaccine-associated subacute
thyroiditis: an unusual suspect for de Quervain‟s thyroiditis. BMJ Case Rep. 2021 Nov;14(11).
n

57. Ruggeri RM, Giovanellla L, Campennì A. SARS-CoV-2 vaccine may trigger thyroid autoimmunity:
ur

real-life experience and review of the literature. J Endocrinol Invest. 2022 Dec;45(12):2283–9.
58. Churilov LP, Normatov MG, Utekhin VJ. Molecular Mimicry between SARS-CoV-2 and Human
Jo

Endocrinocytes: A Prerequisite of Post-COVID-19 Endocrine Autoimmunity? Pathophysiol Off J

Int Soc Pathophysiol. 2022 Aug;29(3):486–94.
59. Mehta A, Andrew Awuah W, Yarlagadda R, Kalmanovich J, Huang H, Kundu M, et al. Investigating
thyroid dysfunction in the context of COVID-19 infection. Ann Med Surg. 2022 Oct;104806.
60. Latrofa F, Ricci D, Bottai S, Brozzi F, Chiovato L, Piaggi P, et al. Effect of Thyroglobulin
Autoantibodies on the Metabolic Clearance of Serum Thyroglobulin. Thyroid. 2018 Mar;28(3):288–
94.
61. Latrofa F, Ricci D, Montanelli L, Altea MA, Pucci A, Pinchera A, et al. Thyroglobulin autoantibodies
of patients with subacute thyroiditis are restricted to a major B cell epitope. J Endocrinol Invest. 2012
Sep;35(8):712–4.

13