Genetic and Environmental Factors in

the Pathophysiology of Hashimoto’s

Thyroiditis
Maria Lucia Sur1,2, MD, PhD, Remus Gaga1,2, MD, Călin Lazăr1,2, MD, PhD,
Cecilia Lazea1,2, MD, PhD  

1
Department of Pediatrics, Iuliu Hațieganu University of Medicine and Pharmacy, Victor Babeș 8, Cluj-Napoca,
2
Romania, Clinical Emergency Hospital for Children, Moților 68, Cluj-Napoca, Romania

Corresponding author: Remus Gaga, MD, Department of Pediatrics, Iuliu Hațieganu University of Medicine and
Pharmacy, Victor Babeș 8, Cluj-Napoca, Romania, Clinical Emergency Hospital for Children, Moților 68, Cluj-Napoca,
Romania, E-mail: remusgaga@gmail.com

Circulating autoantibodies against thyroglobulin and thyroid

Abstract peroxidase (TPO) have been found in almost all patients with

F
inding multiple familial patients with Hashimoto autoimmune hypothyroidism. Thyroid-stimulating hormone
thyroiditis in our clinic a search in the literature
receptor antibodies (TSH-R Ab) that block the receptor rather
confirms that genetic factors, in addition to
than stimulating it as in Graves’ disease are also present in
environmental factors, seem involved in the etiology of
some cases of HT (3).
this disease.
The exact mechanisms underlying the autoimmune thyroiditis
Ref: Ped. Endocrinol. Rev. 2020;17(4):343-348 are not fully known but the hypothesis relies in both genetic
doi: 10.17458/per.vol17.2020.gsl.geneticenvironmentalhashimoto and environmental involvement.
Key words: Hashimoto’s thyroiditis, autoimmune
The aim of this review is to analyze the genetic and
thyroiditis, hypothyroidism, environmental factors, genetic
environmental factors involved in the pathophysiology of HT.
susceptibility.

Methods
Introduction Electronic bases: PubMed, Clinical Key, Medline, UpToDate
and Cochrane Database of Systematic Reviews were search for
Chronic autoimmune thyroiditis or Hashimoto’s thyroiditis relevant articles and data on the subject using the key words:
(HT) is an inflammatory disease characterized by diffuse
autoimmune thyroiditis, Hashimoto’s thyroiditis, chronic
lymphocytic infiltration, fibrosis, and parenchymal atrophy.
lymphocytic thyroiditis, hypothyroidism, environmental factors
Being the most common cause of primary hypothyroidism
and genetic susceptibility.
in iodine sufficient areas, HT remains a common problem
especially in women. There are also multiple cases in children The main papers analyzed were clinical and epidemiological
and adolescents (1,2). studies, reviews, reference books and clinical practice

343 Pediatric Endocrinology Reviews (PER) n Volume 17 n No 4 n August 2020

 Genetic and Environmental Factors in
Hashimoto’s Thyroiditis

guidelines. Reference lists of the reviewed articles were also demonstrated only in 20% to 30% cases of AITD. Relatives of
scanned for additional information. AITD patients carry a high risk of contracting the disease
themselves. The 5-year risk quantified by the “Thyroid Events
Discussion Amsterdam-score” and based on serum thyroid-stimulating
hormone (TSH), thyroid peroxidase antibodies (TPO-Ab) and
family history was increased in patients with HT (8).
Definition
Chronic autoimmune thyroiditis or Hashimoto’s thyroiditis
Clinical Aspects
(HT) is an inflammatory disease characterized by thyroid Most of the HT cases appear as subclinical or even euthyroid in
lymphocytic infiltration often leading to an underactive the beginning. The risk of progression from subclinical to overt
thyroid gland, HT being the most common cause of hypothyroidism is related to the magnitude of TSH elevation
hypothyroidism in iodine-sufficient areas of the world.  and the presence of TPO-Ab. (3) Studies from the last 10 years
Clinically the disease can present as gradual thyroid failure, were included in our review, all of them indicating that overt
with or without goiter formation due to autoimmune-mediated hypothyroidism is a rare clinical presentation in HT (9-13). This
apoptosis of the thyroid epithelial cells. is explained by the pathophysiology of the disease but also by
the modern means of diagnosis (table 1).
The typical markers of the disease, found in almost all cases
are the antibodies against one or more thyroid antigens, Epidemiological data have also revealed that type 1 diabetes
diffuse lymphocytic infiltration of the thyroid (predominantly (T1D) and AITD frequently occur together in the same family
thyroid-specific B and T cells) and follicular destruction, which and sometimes in the same individual, suggesting a strong
is the characteristic sign of thyroiditis (1). shared genetic susceptibility. They are both characterized by
T-cell infiltration and production of autoantibodies directed at
Epidemiology the target organs (14).
The epidemiology of HT is related to the epidemiology of other
HT and AITD are also frequently associated with other
autoimmune diseases affecting other endocrine organs such as
autoimmune and endocrine syndromes. AITD is a part of
the pancreatic islet beta cells, adrenal and pituitary glands.
Polyglandular Autoimmune Syndrome (PAS) Type II along with
However, HT is by far the commonest autoimmune endocrine
Addison Disease and sometimes T1D. In PAS IIIB, AITD can be
disease (4).
associated with pernicious anemia and in PAS IIIC with vitiligo
Even though HT affects primarily middle-aged women it can and/or alopecia and/or other organ-specific autoimmune
also occur in men and women of any age and in children, being diseases.
regarded lately as the most common cause of pediatric thyroid
It has become relevant to both the clinician and the patient to
disease (5).
be aware of the possibility of multiple glandular autoimmune
An autoimmunity review by Cooper et al. in 2003 estimated diseases (15). This is suggested by our clinics’ experience as
that the prevalence of autoimmune hypothyroidism in children well, many of our pediatric patients being diagnosed with HT
aged 10-19 was 532.1/100 000 and 83% of the cases were and T1D, celiac disease or autoimmune hepatitis.
females (4).
Genetic Susceptibility
Etiology
Advances in genetic methods enabled significant progress
Autoimmune thyroid diseases (AITD) result from the complex
in the identification of complex diseases by using new
interplay of exogenous and endogenous factors.
genetic techniques. There have been described 4 phases in
The cause of Hashimoto's thyroiditis is thought to be a identification of complex autoimmune diseases like AITD:
combination between genetic susceptibility and environmental Phase 1 - candidate gene analyses; Phase 2 - whole-genome
factors. The familial association with Graves' disease (GD) and linkage studies; Phase 3 - genome-wide association studies
the fact that GD and HT may sometimes evolve into each other (GWAS); Phase 4 - whole-genome sequencing (16).
proves that the two disorders are closely related (6,7).
In AITD the major thyroid antigens are involved in thyroid
Many patients from our clinic were cases with familial autoimmunity. TSH-R mRNA has also been detected in other
aggregation of Hashimoto’s thyroiditis. Whether this is tissues and although its role in many of these tissues is unclear,
happening because of the genetic factors or because of the data suggest that TSH can modulate bone cell and adipocyte
environment remains a significant question in understanding HT. function. The retroocular expression of the TSH-R has been
Genetic factors have been associated with susceptibility implicated in thyroid eye disease (Graves’ orbitopathy) and
in 70% to 80% whether environmental factors have been pretibial myxedema (thyroid dermopathy) (17).

Pediatric Endocrinology Reviews (PER) n Volume 17 n No 4 n August 2020 344

 Genetic and Environmental Factors in
Hashimoto’s Thyroiditis

Table 1. Clinical Presentation of Hashimoto’s thyroiditis in children

Treatment and evaluation in each study:

1. Treatment was initiated shortly after diagnosis in all 42 hypothyroid patients and 44/48 compensated hypothyroid patients, and within 16
months in 19/24 euthyroid patients (9).
2. Twelve of the 28 patients who were initially euthyroid and did not receive therapy developed subclinical or overt hypothyroidism during
the first 18 months of the follow-up period and were started on thyroid medication. A significant decrease was observed in the anti-Tg
levels of patients receiving levothyroxine from the beginning (10).
3. The most common reasons for referral in the study were investigation of growth (not necessarily abnormal growth), thyroid enlargement
and a family history of thyroid disease. Treatment with levothyroxine was shortly initiated after diagnosis (11).
4. Most children with HT were euthyroid and remained euthyroid during follow-up. Data showed that levothyroxine treatment may have
beneficial effects on the thyroid antibody titers (13).

Other genes like HLA-DR3 and in some other cases HLA- The Role of T Cells in the Pathophysiology of
DR4 were shown to be susceptible for GD and HT. Cytotoxic
Hashimoto’s Thyroiditis
T-lymphocyte-associated protein 4 (CTLA-4) gene which is a
member of the immunoglobulin family is also associated with One of the most important steps in the pathogenesis is
HT. Its mechanism is to encode a protein which transmits an believed to be the activation of the autoreactive CD4+ T
inhibitory signal to T cells. Mutations in this gene have been cells: T helper (Th) cells specific for thyroid autoantigens.
associated with T1D, GD, HT, celiac disease, systemic lupus Th cells type 1 (Th1) activate cytotoxic T lymphocytes (CD8+
erythematosus (SLE) and other autoimmune diseases (18). lymphocytes) and macrophages which directly destroy thyroid
follicular cells.
Nanba et al. reported that IFN-gamma and IL-4 gene
polymorphisms, which result in higher IFN-gamma and lower Th1 and Th2 T helper cell subsets affect patterns of injury and
IL-4 production have a bigger rate in patients with severe HT outcomes in AITD. Immune responses resulting in elevated Th1
than in those with mild HT (19). or Th2 suggest different inflammatory pathways and disease
It is now clear that new analytic approaches will reveal many outcomes (23). The mechanisms in which T cells subtypes are
other genes which make small etiologic contributions visible formed are described below (figure 1).
in the diversity of clinical presentations. For example, a Numerous studies confirm that Th1 cells were increased in
combination of new genetic markers has been studied and patients with severe HT(p<0.05) and Th2 cells were increased
the results show an association with an increased risk of in patients with milder forms (p<0.001). Therefore the Th1/
progression from TPO-Ab positivity to hypothyroidism. The Th2 ratio is considered an important predictive factor (19).
MAGI3 gene has been studied as a marker of this kind, being
Another subset of Th cells with a role in development and
able to predict which TPO-Ab positive patients are particularly
progress of chronic inflammation and tissue damage in HT
at risk of developing clinical thyroid dysfunction (14,20).
are Th17 cells. A higher proportion of Th17 cells, as well as
The importance of genetic factors in the cause of autoimmune higher levels of cytokines produced by these cells were found
hypothyroidism is indicated by the frequent presence of in peripheral blood and thyroid tissue in HT patients compared
thyroid autoantibodies and other autoimmune disorders in with healthy controls.
family members. Scientific data has been demonstrated in
It is also observed that T regulatory (Treg) cells accumulate
twin studies which show a high concordance rate (0.55) in
in the thyroid tissue of HT patients. They have shown an
monozygotic twins. An example of this kind is the famous
immunosuppressive role in the pathogenesis of HT, contributing
Danish study in which the concordance rate in monozygotic
twins was found to be 30 to 60 percent (21). The sibling to the autoimmune destruction of the thyroid tissue (24).
recurrence risk was proven to be more than 20 (22).

345 Pediatric Endocrinology Reviews (PER) n Volume 17 n No 4 n August 2020

 Genetic and Environmental Factors in
Hashimoto’s Thyroiditis

Figure 1. The role of CD4+ T Cells in the pathophysiology of Hashimoto’s thyroiditis

CD4 T cells have a wider range of effector functions than CD8 T cells and can differentiate into many different subtypes, such as: Th1 – role in
cell-mediated immunity, inflammation and host defense; Th2 – role in autoimmunity and allergies; Th17 – role in inflammation and wound healing.
Each subtype is produced by the influence of specific cytokines and growth factors.

Environmental Factors Mild iodine deficiency is associated with a decrease in the

prevalence of HT and hypothyroidism, while excessive iodine
Several environmental factors have also been associated with a
intake is linked with a higher prevalence. As an example, in
high incidence of HT.
China, AITD was found in 0.3 percent of those with deficient
The thyroid gland is rich in selenium, containing more quantity iodine intake and 1.3 percent of those with excessive iodine
per gram tissue than any other organ in our bodies. Low intake (27). In the same way, high iodine-containing drugs,
selenium levels have been associated with a decrease in the such as amiodarone often precipitate autoimmune thyroiditis.
immune function and a high prevalence for viral infections. In some cases it has been demonstrated that excessive iodine
Consequently, selenium intake was considered to help the intake in mothers can cause hypothyroidism in infants (28).
immune system by lowering the levels of TPO antibodies. The balance between oxidants and antioxidants is critical
Although this was tested in multiple studies the results were for the optimal functioning of the thyroid gland (29). High
not significantly different from the ones identified in the oxidative stress is involved in the pathogenesis of thyroid
placebo groups. One of the last studies of this type was cancer as well. This explains the progress from HT to thyroid
conducted by De Farias et al in 2015 (25). Further studies are cancers described in the literature (30).
needed to prove a relationship between low selenium intake
Environmental factors and lifestyle are widely known for
and HT. influencing the balance between oxidants and antioxidants.
Low vitamin D levels have been identified as risk factors for Exposure to exogenous sources of oxidants such as cigarette
various autoimmune diseases (T1D, rheumatoid arthritis, and smoke, ozone, ionizing radiation and heavy metal ions as
multiple sclerosis). There have been many cross-sectional well as unhealthy diet and reduced physical activity causes
studies evaluating an association between vitamin D blood oxidative stress production (31).
levels and AITD but the results were not accurate. The only However, environmental factors need further studies to
prospective study in this area did not confirm these data, confirm that they can influence the pathogenesis of HT on
showing that vitamin D deficiency is not related to early stages their own, not just as a trigger in a genetically predisposed
of thyroid autoimmunity (26). host (32).

Pediatric Endocrinology Reviews (PER) n Volume 17 n No 4 n August 2020 346

 Genetic and Environmental Factors in
Hashimoto’s Thyroiditis

Conclusions 11. Skarpa V, Kousta E, Tertipi A, Anyfandakis K, Vakaki M, Dolianiti

M, Fotinou A, Papathanasiou A. Epidemiological characteristics of
children with autoimmune thyroid disease. Hormones 2011;10(3):207–
214
Genetic factors play a great role in the development of HT.
12. Wasniewska M, Corrias A, Salerno M, Mussa A, Capalbo D, Messina
This results in family aggregation of the disease. MF, Aversa T, Bombaci S, De Luca F, Valenzise M. Horm Res Paediatr
2012;78(4):232-236
One of the most important steps in the pathogenesis is the
13. Lee HS, Hwang JS. The natural course of Hashimoto’s thyroiditis in
activation of the autoreactive CD4+ T cells. children and adolescents. J Pediatr Endocrinol Metab 2014;27(9–
Environmental factors can trigger the disease in genetically 10):807–812
14. Jr DA, Imperatore G, Dabelea D, Marcovina S, Helen M. Thyroiditis
susceptible patients. Further studies will be needed to and Type 1 Diabetes 2016;32–39
conclude that they have an independent influence on the 15. Bliddal S, Nielsen CH, Feldt-Rasmussen U. Recent advances in
disease. understanding autoimmune thyroid disease: The tallest tree in the
forest of polyautoimmunity. F1000Research 2017;6(0):1–12
Although there are reports that suggest a higher incidence in 16. Tomer Y. Genetic susceptibility to autoimmune thyroid disease: past,
HT nowadays, it is important to note that the disease was not present, and future. Thyroid 2010;20(7):715–725
diagnosed until relative recently and the awareness of it is 17. Abe E, Marians RC, Yu W, Wu X, Ando T, Li Y, Iqbal J, Eldeiry L,
increasing. Rajendren G, Blair HC, Davies TF, Zaidi M. TSH Is a Negative Regulator
of Skeletal Remodeling. Cell 2003;115:151–162
18. Allenspach E, Torgerson TR. Autoimmunity and Primary
Disclosure Immunodeficiency Disorders. J Clin Immunol 2016;36:57–67
19. Nanba T, Watanabe M, Inoue N, Iwatani Y. Increases of the Th1/Th2
cell ratio in severe Hashimoto’s disease and in the proportion of Th17
All authors contributed equally to this work. cells in intractable Graves’ disease. Thyroid 2009;19(5):495–501
20. Medici M, Porcu E, Pistis G, Teumer A, Brown SJ, Jensen RA.
There were no financial or personal relationships that might Identification of Novel Genetic Loci Associated with Thyroid
bias the content of this work. Peroxidase Antibodies and Clinical Thyroid Disease. PLoS Genet
2014;10(2)
21. Brix TH, Kyvik KO, Hegedüs L. A population-based study of chronic
References autoimmune hypothyroidism in Danish twins. J Clin Endocrinol Metab
2000;85(2):536–539
1. Kliegman R, Geme J St. Nelson Textbook of Pediatrics. 21st ed. 22. Villanueva R, Greenberg DA, Davies TF, Tomer Y. Sibling recurrence
Elsevier 2019 risk in autoimmune thyroid disease. Thyroid 2003;13(8):761–764
2. Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lancet 23. Li Q, Wang B, Mu K, Zhang JA. The pathogenesis of thyroid
2017;390(10101):1550–1562 autoimmune diseases: New T lymphocytes – Cytokines circuits beyond
3. Brent GA, Weetman AP. 13 – Hypothyroidism and Thyroiditis. In: the Th1−Th2 paradigm. J Cell Physiol 2019;234(3):2204–2216
Williams Textbook of Endocrinology [Internet]. Fourteenth. Elsevier 24. Vukovic R, Zeljkovic A, Bufan B, Spasojevic-Kalimanovska V,
2020;pp. 404–432 e6 Available from: http://dx.doi.org/10.1016/ Milenkovic T, Vekic J. Hashimoto Thyroiditis and Dyslipidemia in
B978-0-323-55596-8.00013-9 Childhood: A Review. Front Endocrinol (Lausanne) 2019;10:1–11
4. Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. 25. De Farias CR, Cardoso BR, De Oliveira GMB, De Mello Guazzelli
Autoimmun Rev 2003;2(3):119–125 IC, Catarino RM, Chammas MC. A randomized-controlled, double-
5. Nikolina Z, Mirjana K. Hashimoto Thyroiditis in Childhood – Review of blind study of the impact of selenium supplementation on thyroid
the Epidemiology, Genetic Susceptibility and Clinical Aspects of the autoimmunity and inflammation with focus on the GPx1 genotypes.
Disease. Maced J Med Sci3. 2012;5(3):336–3453 J Endocrinol Invest (Internet) 2015;38(10):1065–1074 Available from:
6. Kraiem Z, Baron E, Kahana L, Sadeh O, Sheinfeld M. Changes in http://dx.doi.org/10.1007/s40618-015-0285-8
stimulating and blocking TSH receptor antibodies in a patient 26. Effraimidis G, Badenhoop K, Tijssen JGP, Wiersinga WM. Vitamin
undergoing three cycles of transition from hypo to hyper‐thyroidism D deficiency is not associated with early stages of thyroid
and back to hypothyroidism. Clin Endocrinol (Oxf) 1992;36(2):211–214 autoimmunity. Eur J Endocrinol 2012;167(1):43–48
7. Solaimanzadeh I, Hossain MR, Shiferaw-Deribe Z, Sandhu 27. Walsh JP, Ward LC, Burke V, Bhagat CI, Shiels L, Henley D, Gillett
H. Alternating Thyroid Status Between Thyrotoxicosis and MJ, Gilbert R, Tanner M, Stuckey BGA. Small changes in thyroxine
Hypothyroidism in a Patient With Varying Antithyroid Antibodies. dosage do not produce measurable changes in hypothyroid symptoms,
AACE Clin Case Reports 2019;5(2):e112–e118 well-being, or quality of life: Results of a double-blind, randomized
8. Wiersinga WM. Clinical relevance of environmental factors in the clinical trial. J Clin Endocrinol Metab 2006;91(7):2624–2630
pathogenesis of autoimmune thyroid disease. Endocrinol Metab 28. Emder PJ, Jack MM. Iodine-induced neonatal hypothyroidism
2016;31(2):213–222 secondary to maternal seaweed consumption: A common practice in
9. De Vries L, Bulvik S, Phillip M. Chronic autoimmune thyroiditis in some Asian cultures to promote breast milk supply. J Paediatr Child
children and adolescents: At presentation and during long-term Health 2011;47(10):750–752
follow-up. Arch Dis Child 2009;94(1):33–37 29. Rostami R, Aghasi MR, Mohammadi A, Nourooz-Zadeh J. Enhanced
10. Özen S, Berk Ö, Şimşek DG, Darcan Ş. Clinical course of Hashimoto’s oxidative stress in Hashimoto’s thyroiditis: Inter-relationships to biomarkers
thyroiditis and effects of levothyroxine therapy on the clinical course of thyroid function. Clin Biochem (Internet) 2013;46(4–5):308–312
of the disease in children and adolescents. JCRPE J Clin Res Pediatr 30. Penta L, Cofini M, Lanciotti L, Leonardi A, Principi N, Esposito
Endocrinol 2011;3(4):192–197 S. Hashimoto’s disease and thyroid cancer in children: Are they
associated? Vol. 9, Frontiers in Endocrinology. Frontiers Media SA 2018

347 Pediatric Endocrinology Reviews (PER) n Volume 17 n No 4 n August 2020

 Genetic and Environmental Factors in
Hashimoto’s Thyroiditis

31. Aseervatham GSB, Sivasudha T, Jeyadevi R, Arul Ananth D.

Environmental factors and unhealthy lifestyle influence oxidative
stress in humans--an overview. Environ Sci Pollut Res Int
2013;20(7):4356–4369 32
32. Ban Y, Tomer Y. Genetic susceptibility in thyroid autoimmunity. Pediatr
Endocrinol Rev 2005;3(1):20-32

Pediatric Endocrinology Reviews (PER) n Volume 17 n No 4 n August 2020 348