The Role of Immunological Challenges, Oxidative Stress, and Dietary Interventions in Managing Hashimoto’s Thyroiditis: A Narrative Review

Abstract

Hashimoto thyroiditis (HT) is an autoimmune thyroid disorder characterized by chronic inflammation and hypothyroidism. The current scientific understanding indicates that the development of HT is influenced by a combination of genetic and environmental factors. Nevertheless, oxidative stress (OS) and dysregulated immune processes play a substantial role in HT pathogenesis. Reactive oxygen species (ROS) play a critical role in thyroid hormone synthesis by facilitating iodide oxidation. Since thyroid hormones influence mitochondrial activity and regulate ROS production, the thyroid gland is particularly vulnerable to OS and disruptions in homeostasis. Research indicates that, in HT, the oxidative balance shifts toward a pro-oxidative state. Excessive levels of ROS disrupt cellular homeostasis and induce inflammation, leading to structural and functional damage of thyroid tissue. These processes play a substantial role in the pathogenesis and progression of HT. Among the various environmental factors that can be modulated, dietary nutrients are considered one of the most promising and underappreciated clinical tools in this process. The primary aim was to explore the potential role of dietary interventions in protecting thyroid function, supporting the immune response, and alleviating OS in individuals with HT. According to the literature data, proper nutrition in HT should include sufficient amounts of anti-inflammatory components. These emphasize the role of mono- and polyunsaturated fatty acids (such as omega-3, omega-6), polyphenols, whey protein, soy protein, and isoflavones. Moreover, a well-balanced and varied diet rich in antioxidants, including vitamins C and E, selenium, zinc, and polyphenols, may help reduce OS in HT, simultaneously modulating the immunological processes. Additionally, it is essential to ensure an adequate intake of micronutrients, including iodine, iron, selenium, and vitamins, especially vitamin D, to support thyroid homeostasis. Adopting a balanced and nutrient-rich diet, along with specific dietary patterns, may be beneficial in managing the symptoms and improving the overall well-being of individuals with HT.

HASHIMOTO THYROIDITIS: WHAT MODIFICATIONS ARE POSSIBLE?

Hashimoto thyroiditis (HT) is the most common autoimmune endocrine disease leading to hypothyroidism.^1,2 Epidemiological studies have demonstrated that women exhibit a 5-fold higher likelihood of developing HT compared with men, with incidence increasing with advancing age.¹ The prevalence of clinically overt hypothyroidism in HT is estimated at approximately 0.1%–2%, while the subclinical form affects 10%–15% of the population.³ This disease is characterized by intrathyroidal lymphocytic infiltration, resulting in chronic inflammation and increased oxidative stress (OS), destruction of thyroid cells, and fibrosis of the thyroid gland.⁴ This gradual destruction results in reduced production of thyroid hormones and an increase in synthesis of antibodies against thyroid peroxidase (TPO) and thyroglobulin (Tg). The enzyme TPO is involved in the synthesis of thyroid hormones by adding iodine to tyrosine residues of Tg, ultimately producing triiodothyronine (T3) or thyroxine (T4) hormones.⁵ The decrease in thyroid hormone production leads to typical symptoms of hypothyroidism, including weight gain, constipation, chronic fatigue, impaired concentration, mood disturbances, depression, and hair loss.⁶

The pathogenesis of HT is multifactorial and, in certain cases, arises from unidentified factors.³ According to the literature, genetic predispositions, along with environmental and immune system factors, play a substantial role in the development of HT. However, the mechanisms by which these factors interact remain unclear.^7,8 Genetic factors are estimated to account for approximately 70%–80% of the risk of developing HT, while environmental factors contribute to approximately 20%–30%. The main genetic factors implicated in HT include immunoregulatory genes, tissue compatibility genes (human leukocyte antigen [HLA] class II), Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22), cytotoxic T lymphocyte antigen 4 (CTLA4), and thyroid-specific genes (Tg or Thyroid Stimulating Hormone Receptor [TSHR]).⁹ These genes have also been identified as risk factors for other autoimmune diseases, such as celiac disease (CD), type 1 diabetes, and rheumatoid arthritis. Autoimmune diseases often co-occur because they share the same HLA haplotypes.^10,11

The literature indicates that environmental factors contributing to HT include dietary nutrients, medications, and infectious diseases.¹² Among these factors, dietary nutrients are considered to have the greatest modulating potential to decrease the risk of the development of HT and improve treatment outcomes. Apart from adequate levels of iodine, which is a fundamental micronutrient essential for proper thyroid function, other dietary components such as selenium, iron, vitamins (particularly vitamin D), zinc, melatonin, and omega-3 fatty acids have been found to play a role in thyroid homeostasis. Consuming antioxidant-rich foods (eg, polyphenols, whey protein, selenium, zinc, and vitamins D) may protect thyroid tissues against oxidative damage.¹³ Presently, the treatment for HT comprises levothyroxine substitution, aimed at managing the clinical symptoms of the disease. Unfortunately, there is currently no definitive treatment available to inhibit the autoimmune process responsible for the destruction of thyroid cells.¹⁴ However, studies have indicated that dietary components may have a positive effect on reducing the severity of hypothyroidism symptoms, reducing OS, and improving typical immunological response.¹⁵ A proper diet can potentially inhibit thyroid degeneration through its anti-inflammatory properties and by reducing the severity of chronic inflammation in the thyroid gland. However, based on the available evidence, no specific nutritional recommendations have been established to date. Therefore, many authors emphasize the validity of using a personalized dietary intervention for patients with HT.

This review aimed to advance the understanding of the relationship between nutrition and the pathogenesis of HT. The study evaluated the impact of dietary deficiencies and clarified the roles of proinflammatory and anti-inflammatory nutrients in the disease’s pathogenesis. While various nutritional factors associated with HT have been identified, the effects of dietary interventions on thyroid function, inflammation, and antioxidant status remain poorly defined. Consequently, the study focused on exploring dietary interventions as a potential therapeutic approach, identifying strategies that could alleviate symptoms and improve patient outcomes. This systematic understanding of nutritional factors provides a foundation for guiding future dietary recommendations for individuals with HT.

METHODS

We searched the relevant literature of the PubMed database, using the key terms “Hashimoto thyroiditis” in combination with “Diet,” “Oxidative stress,” “Iodine,” “Iron,” “Vitamin D3,” “Selenium,” “Monounsaturated and polyunsaturated fatty acids,” “Polyphenols,” “Anti-inflammatory proteins,” “Gluten,” “Gluten-free Diet,” and “Mediterranean diet.” The literature search was performed up to January 2025. The reviewed articles were evaluated and included in the present review according to the following criteria: English language and publication in peer-reviewed journals. Articles written in other languages apart from English were excluded. The search strategy is summarized in Figure 1.

Figure 1.

Search Strategy

THE INTERPLAY OF INFLAMMATION, OXIDATIVE STRESS, AND DIETARY FACTORS

Hashimoto thyroiditis is characterized by intrathyroidal infiltration of lymphocytes, leading to chronic inflammation, destruction of thyroid cells, and atrophy. Both cellular and humoral immunity play a substantial role in HT pathogenesis, with regulatory T cells (Tregs) crucial in preventing autoimmunity. Lymphocytes that infiltrate the thyroid gland can affect thyroid cells directly, by cytotoxic damage or indirectly through cytokine production.¹⁶ Cytokines derived from the lymphocytic infiltration play a crucial role in thyroid cell injury, by stimulation of the thyroid cells to release proinflammatory mediators, leading to the autoimmune response and, in turn, increased inflammation.⁸ Proinflammatory and anti-inflammatory nutrients participate in modulating the immune response in various autoimmune diseases, including HT.^17,18 By targeting specific dietary components, it may be possible to modulate the immune response and attenuate the inflammatory processes associated with HT, ultimately improving patient outcomes and quality of life. Nevertheless, OS, considered as a main indicator of increasing HT symptoms, can modulate both immunological and autoimmune processes by influencing the activity of immune cells and altering inflammatory responses. This modulation may lead to biological component damage resulting in changes in cytokine production, immune cell proliferation, and the overall balance between proinflammatory and anti-inflammatory pathways. Consequently, OS plays a critical role in the pathogenesis of various autoimmune diseases, highlighting the importance of maintaining redox homeostasis for optimal immune function in HT.

Oxidative stress refers to an imbalance between the production of ROS and their elimination through antioxidant mechanisms.¹⁹ This imbalance leads to an accumulation of ROS, which can cause damage to cellular molecules, including proteins, lipids, cell membranes, and DNA, disrupting physiological cell processes.²⁰ These processes include signal transduction, gene expression, and receptor activation.^21,22 These antioxidant systems comprise a range of enzymes, including superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), and nonenzymatic antioxidants, such as vitamins C and E, glutathione, and various phytochemicals, which contribute to the overall defense against OS. The coordinated action of these cellular antioxidant mechanisms is crucial for maintaining cellular integrity and protecting against OS-induced damage.²³ Various endogenous molecules are classified as antioxidants, including glutathione, alpha-lipoic acid (thioctic acid), coenzyme Q, ferritin, uric acid, bilirubin, metallothionein, l-carnitine, and melatonin, which act as endogenous antioxidants and radical scavengers. Additionally, antioxidants include exogenous compounds, such as ascorbate (vitamin C) and tocopherol (vitamin E).²⁴

Under physiological conditions, ROS play essential roles in numerous metabolic processes. They are essential for thyroid hormone synthesis during iodide oxidation.²⁵ Hydrogen peroxide (H₂O₂) is particularly involved in the synthesis of thyroid hormones. In the presence of H₂O₂, iodide ions undergo oxidation catalyzed by TPO. Subsequently, these oxidized iodide ions are attached to tyrosine residues, leading to the formation of thyroid hormones T3 and T4. Furthermore, thyroid hormones affect the mitochondrial activity and modulate ROS production.²⁶ However, excessive accumulation of ROS triggers inflammation and damage to the thyroid gland, leading to the development of HT. Burek and Rose²⁷ investigated the role of OS in the pathogenesis of HT. They conducted an in vitro study using cultures of NOD.H2h4 mouse thyrocytes, exposing the cells to exogenous iodine while measuring the production of ROS using a chemiluminescence method. The study demonstrated that elevated ROS levels enhance the immunogenicity of Tg by upregulating expression of intercellular adhesion molecule-1 (ICAM-1), which may initiate and exacerbate the progression of HT. Research showed that OS is implicated in the pathogenesis of HT, with oxidative status shifting towards a pro-oxidant state in individuals with HT.^28,29 Ruggeri et al³⁰ carried out a study to investigate the changes in oxidative balance in euthyroid HT. They examined 134 participants: 71 patients with newly diagnosed HT and 63 healthy patients as a control group. They carried out specific serum tests, such as derived Reactive Oxygen Metabolites (d-ROMs) and Biological Antioxidant Potential (BAP) tests. Serum OS markers, such as serum advanced glycation end-products (AGEs) along with advanced oxidation protein products (AOPPs), were also measured. The results indicated that serum d-ROMs were elevated and BAP decreased in patients with HT compared with controls, clearly indicating that the OS balance in HT is shifted towards the oxidative side. Moreover, AGE levels were higher in patients with HT than in controls and inversely correlated with BAP levels, what points to a substantial involvement of AGEs in HT pathogenesis. Another study conducted by Ruggeri et al³¹ examined the influence of AGEs and clinical relevance of OS in HT pathogenesis. They measured the serum levels of AGEs and AOPPs and antioxidant paraoxonase (PON-1) activity as potential reliable markers of OS in the serum of 40 patients with HT and 38 healthy volunteers as a control group. The results suggest that AGEs were significant higher while PON-1 activity was significant lower in patients with HT compared with controls, clearly indicating a pro-oxidant imbalance in patients with HT. Increased serum levels of AGEs led to enhanced OS, along with lover PON-1 activity in HT. Accordingly, AGE levels and alterations in PON-1 may be useful markers for monitoring the levels of OS in HT.

Several authors have highlighted an inverse relationship between plant-based diets, such as the Mediterranean diet (MD) and the Dietary Approaches to Stop Hypertension (DASH) diet, and decreased OS, as well as proinflammatory biomarker levels.^32,33,34 Therefore, patients might benefit from consuming antioxidant-rich food, such as fruit, vegetables, and nuts, in order to improve their antioxidative response.^35,36 Another study conducted by Giannakou et al³⁷ among women with HT examined the influence of dietary habits and obesity influence on OS. The patients were classified into 2 groups: 102 patients receiving thyroxine replacement therapy and 114 patients not receiving such therapy. The researchers measured total oxidative capacity (TOS) levels in serum and recorded the frequency and the type of food consumption. The study found that high TOS levels were more prevalent in women undergoing thyroxine replacement therapy and among overweight or obese women compared with those with a normal body mass index (BMI). Additionally, low fruit and vegetable consumption was associated with increased prevalence of high TOS levels. The study demonstrated that these risk factors were independent and additive in their effect on TOS. Daily consumption of fruit and vegetables, as well as maintaining a normal BMI, play crucial roles in maintaining low levels of OS. Zirilli et al³⁸ conducted a study to investigate differences between 2 dietary approaches (omnivorous vs semi-vegetarian) in relation to some OS markers, such as SOD, GPx, thioredoxin reductase (TRxR), glutathione reductase (GR), AGEs, and AOPPs. They examined 200 patients at the endocrinology unit of Messina University Hospital. Each participant completed a dietary questionnaire. The results of this study suggest that antioxidant parameters were significant lower in participants with an omnivorous diet than in semi-vegetarians and that the AGE and AOPP markers were significant lower in semi-vegetarians. The authors suggested that dietary patterns impact some OS parameters.

AUTOIMMUNIZATION IN THE CONTEXT OF NUTRITIONAL DEFICIENCIES AND SURPLUSES

Nutritional deficits or surpluses can significant impact the development and progression of HT.^39,40 Therefore, understanding the role of nutritional factors and addressing nutritional deficiencies or imbalances becomes essential in managing HT effectively.

Iodine

Iodine is a micronutrient essential for the optimal functioning of the thyroid gland. It plays a crucial role as a substrate in the synthesis of thyroid hormones. There is a U-shaped relationship between iodine intake and thyroid disorders, meaning that both too little and too much iodine intake may be associated with an increased risk of thyroid disease, either hypo- or hyperthyroidism.⁴¹ Insufficient iodine intake can lead to thyroid dysfunction, including goiter, thyroid nodules, and hypothyroidism associated with uptake of iodine.⁴² Conversely, excessive intake of iodine (Urinary Iodine Concentration [UIC] >300 μg/L) can adversely affect thyroid function, thus increasing the prevalence of thyroid autoimmunity and hyperthyroidism, mainly due to Graves’ disease.⁴³ Notably, increased iodine intake is strongly associated with thyroiditis among genetically susceptible individuals.⁴⁴

The primary sources of iodine include milk, fish, seafood, drinking water, and iodized salt. In countries that have implemented iodine prophylaxis programs, such as Poland, iodized salt is commonly used to ensure sufficient iodine intake.⁴⁵ Iodine fortification programs contributed to eradication of endemic goiter and significant decreased the frequency of thyroid nodules and incidence of more aggressive forms of thyroid cancer. It also significant reduced the prevalence of neonatal hypothyroidism as well as improved cognitive function development in infancy, showing the beneficial effect of iodine supplementation on human health.⁴⁶

Lombardi et al⁴⁷ (Table 1) conducted a study to examine the effects of voluntary iodine prophylaxis in a small rural community in Pescopagano, Italy. They evaluated the prevalence of thyroid disorders 15 years after a previous survey conducted before iodine prophylaxis. They examined 1148 participants in 2010 and 1411 participants in 1995. The results showed that correcting iodine deficiency resulted in a decreased prevalence of goiter, thyroid nodules, and nonautoimmune hyperthyroidism over a 15-year period, while the prevalence of Graves’ disease and overt hypothyroidism did not change significant.⁴⁷ Sang et al⁴⁸ (Table 1) conducted a double-blind, placebo-controlled, randomized trial involving 256 euthyroid adults. The participants were randomly assigned to 12 groups, each receiving varying doses of iodine supplementation ranging from 0 to 2000 μg per day. The results indicated that excessive iodine supplementation, leading to a total iodine intake of approximately 800 μg per day, was associated with the development of subclinical hypothyroidism among the participants. The authors observed that no defined upper limit exists for the recommended range of iodine intake. Therefore, it is essential to maintain optimal iodine intake within a relatively narrow range to prevent both iodine deficiency disorders and the adverse effects of excessive iodine consumption.⁴⁸

Table 1.

Influence of Iodine on Selected Parameters in Thyroid—Recent Clinical Studies

Study	Study population	Methods	Results
Aghini Lombardi et al47	1148 Participants in 2010 and 1411 participants in 1995	Evaluation of the prevalence of thyroid disorders 15 y after a previous survey conducted before iodine prophylaxis.	Correcting iodine deficiency resulted in a decreased prevalence of goiter, thyroid nodules, and nonautoimmune hyperthyroidism
Sang et al48	256 Euthyroid adults with no thyroid disease	Double-blind, placebo-controlled, randomized trial Participants were randomly assigned to 12 groups, each receiving varying doses of iodine supplementation ranging from 0 to 2000 μg/d. Serum concentrations of FT4, FT3, and TSH titers of TPOAb and TgAb were measured.	Excessive iodine supplementation, leading to a total iodine intake of approximately 800 μg/d, was associated with the development of subclinical hypothyroidism among the participants.
Poncin et al49	Six-week-old female Wistar rats	An in vivo study Rats were used as a model of goiter formation (caused by an iodine-deficient diet) and iodine-induced involution (caused, by a high-iodine diet or by supplementation of 20 g l-thyroxine for 3 d). The control group received a normal iodine-intake diet. 4-HNE was measured.	OS was enhanced in hyperplastic as well as in involuting glands. Markers of antioxidant defense were upregulated in both groups. Both excess and deficiency of iodine can lead to OS.

Abbreviations: FT3, free T3; FT4, free T4;  OS, oxidative stress; TgAb, antithyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TSH, thyrotropin releasing hormone.

Poncin et al⁴⁹ (Table 1) conducted an in vivo study to investigate the effect of iodine intake on OS. The study used 6-week-old female Wistar rats as a rat model of goiter formation (caused by an iodine-deficient diet) and iodine-induced involution (caused by a high-iodine diet or by supplementation of 20 g l-thyroxine for 3 days). The control group received a normal iodine-intake diet. 4-Hydroxynonenal (4-HNE) was measured as an OS marker. The results showed that OS was enhanced in hyperplastic as well as in involuting glands. Additionally, glutathione peroxidase and peroxiredoxin serum levels (markers of antioxidant defense) were also upregulated in both groups. The results of this study indicate that both excess and deficiency of iodine can lead to OS and that thyrocytes are well adapted to endogenously produced ROS in case of thyroid pathologies caused by either ID or its excess.

Iron

Thyroid hormones as well as typical iron concentrations play a crucial role in hematopoiesis, particularly in erythropoiesis. Research suggests that thyroid hormones directly influence the proliferative capacity of erythroid precursors, which may be important for understanding the mechanism underlying erythropoietic dysfunction in human thyroid diseases.^50,51 In patients with hypothyroidism, there is a decrease in the erythropoietic activity of the bone marrow, resulting in anemia.⁵² A decrease in the erythropoietic activity of bone marrow is believed to be the physiological adaptation of tissues to the reduced oxygen demand of cells, caused by decreased basic metabolism in hypothyroidism. Therefore, the relationship between thyroid hormones and iron levels is complex and bidirectional.⁵³ Yu et al⁵⁴ (Table 2) conducted a study to investigate the association between ID and hypothyroxinemia in nonpregnant women and women in early pregnancy. They examined 7953 pregnant women in the first trimester and 2000 nonpregnant women. Serum TSH, free T4 (FT4), thyroid peroxidase antibody (TPOAb), total body iron, serum ferritin, and serum transferrin receptor were measured. The results indicated that serum FT4 levels were significant lower in both pregnant and nonpregnant women with ID compared with those with adequate iron levels. This study concluded that ID is an independent risk factor for hypothyroxinemia in both pregnant and nonpregnant women.⁵⁴ Moreover, Ravanbod et al⁵⁷ (Table 2) conducted a randomized, double-blind, active-controlled trial involving 60 patients with subclinical hypothyroidism and iron-deficiency anemia. The patients were classified into 3 equal groups: the first group received treatment with iron salt (ferrous sulfate, 65 mg/d) and placebo for 3 months, the second group received levothyroxine (50 µg/d) and placebo, and the third group received both levothyroxine (50 µg/d) and iron salt (ferrous sulfate, 65 mg/d). Changes in hemoglobin, ferritin, and TSH levels were compared among the groups. This trial demonstrated a significant positive correlation between free thyroid hormone levels and hemoglobin, hematocrit, and erythrocyte counts in patients with hypothyroidism.^55,56

Table 2.

Influence of Iron on Selected Parameters in Patients With Thyroid Disfunction—Recent Clinical Studies

Study	Study population	Methods	Results
Yu et al54	7953 Pregnant women in the first trimester and 2000 nonpregnant women	All participants completed the questionnaires on demographic data, history of thyroid diseases, chronic diseases, smoking and drinking, parity, and medication use. Serum concentration of TSH, FT4, total body iron, ferritin, transferrin receptor, titers of TPOAb were measured	Serum FT4 levels were significant lower in both pregnant and nonpregnant women with ID compared with those with adequate iron level; ID is an independent risk factor for hypothyroxinemia.
Ravanbod et al57	60 Patients with subclinical hypothyroidism and iron-deficiency anemia	Randomized, double-blind, active-controlled trial Three equal groups: (1) group received treatment with iron salt (ferrous sulfate, 65 mg/day) and placebo for 3 mo, (2) second group received levothyroxine (50 µg/d) and placebo, (3) group received both levothyroxine (50 µg/d) and iron salt (ferrous sulfate, 65 mg/d) Serum concentrations of Hemoglobin (Hg), hematocrit, erythrocyte counts, ferritin, and TSH were measured	Substantial positive correlation between free thyroid hormone levels and Hg, hematocrit, and erythrocyte counts in patients with hypothyroidism
Bremner et al56	1179 Participants from the 1994 Busselton Health Study, including a subset of 1011 euthyroid individuals and 168 participants: 32 with low TSH, 93 with high TSH (including 4 with overt hypothyroidism), 2 with low FT4, 20 with high FT4, and 21 were taking medication that affected thyroid function or tests.	The study used data from the 1994 Busselton Health Study, which is based on data from people who participated in the 1981 and the 1994 surveys, in which each assessment included a detailed health questionnaire, physical examination, and collection of a venous blood samples. Serum concentrations of TSH, FT3, FT4, iron, transferrin, and ferritin were measured.	Serum iron concentrations were lower in participants with subclinical hypothyroidism compared with euthyroid participants.
Soppi et al59	25 Euthyroid women with HT, who still experienced symptoms of hypothyroidism	The participants received an oral iron supplementation for 6–12 mos. Serum concentrations of ferritin were measured.	Symptoms of hypothyroidism resolved in two-thirds of the patients whose ferritin levels reached >100 µg/L after 6–12 mo of oral iron supplementation. Iron supplementation can influence effectiveness of the hypothyroidism treatment.

Abbreviations: FT3, free T3; FT4, free T4; HT, Hashimoto thyroiditis; ID, iron deficiency; OS, oxidative stress; TPOAb, thyroid peroxidase antibody; TSH, thyrotropin releasing hormone.

Bremner et al⁵⁶ (Table 2) conducted a study involving 1179 participants from the 1994 Busselton Health Study, including a subset of 1011 euthyroid individuals. They analyzed serum iron parameters as well as levels of TSH, free triiodothyronine (FT3), and FT4. The study found that serum iron concentrations were lower in participants with subclinical hypothyroidism compared with euthyroid participants. Therefore, when ID and subclinical hypothyroidism coexist, combined treatment with thyroxine is more effective than iron supplementation alone in managing anemia.^56,57,58 Another study conducted by Soppi et al⁵⁹ (Table 2) involved 25 euthyroid women who still experienced symptoms of hypothyroidism, highlighting the underestimated role of iron in patients with HT. At the onset of the study, none of the participants were found to have anemia; however, all women had serum ferritin levels less than 60 µg/L. The participants were treated with oral iron supplementation for 6–12 months. After this period, symptoms of hypothyroidism resolved in two-thirds of the patients whose ferritin levels reached more than 100 µg/L. The results suggest that iron supplementation can influence effectiveness of the hypothyroidism treatment.

Vitamin D₃

Vitamin D occurs in 2 main forms—cholecalciferol (vitamin D₃) and ergocalciferol (vitamin D₂), which are precursors of hormones that play an important role in the regulation of calcium and phosphate metabolism.^60,61 The natural sources of vitamin D in food include fatty fish (salmon, cod liver oil, sardines) and dairy products.⁶² Additionally, vitamin D may play an important role in modulating the immune system as an immunoregulatory agent.⁶³ Hu et al⁶⁴ found that vitamin D deficiency affected cellular immunity, especially T-mediated immunity, and may potentially affect intrathyroidal infiltration of lymphocytes in thyroid glands. This study suggests that 1.25(OH)₂D plays a protective role against state of inflammation and may reduce the severity of chronic inflammation in the thyroid gland in HT.

Furthermore, the vitamin D receptor (VDR) has been identified in nearly all immune system cells, and certain genetic variations in the receptor have been linked to a higher susceptibility to autoimmune diseases.^65,66 Feng et al⁶⁷ conducted a meta-analysis to evaluate the association between VDR gene polymorphisms and the risk of autoimmune thyroiditis (AIT). The authors concluded that the BsmI (rs1544410) or TaqI (rs731236) polymorphisms are significant associated with autoimmune thyroid disease, whereas the ApaI (rs7975232) or FokI (rs2228570) polymorphisms are not. Recent studies have confirmed a link between vitamin D deficiency and HT.^68,69 Decreased vitamin D levels were found to be associated with the presence of antithyroid antibodies,⁷⁰ abnormal thyroid function, increased thyroid volume, elevated TSH levels, and adverse pregnancy outcomes in women with HT.^71,72 Kivity et al⁷³ conducted a study which demonstrated an increased prevalence of vitamin D deficiency among individuals diagnosed with HT when compared with a control group. Furthermore, they observed an inverse relationship between vitamin D levels and the concentration of antithyroid antibodies (Table 3). Another study performed by Chahardoli et al⁷⁴ (Table 3), involving patients with HT, investigated the effects of vitamin D supplementation. The participants received a weekly dose of 50 000 units of vitamin D, which resulted in a substantial decrease in the levels of Thyroglobulin antibody (TgAb) and TSH in the vitamin D group. However, there were no substantial changes observed in the serum levels of T3 and T4. These findings suggest that screening for vitamin D deficiency and subsequent supplementation may be warranted in patients with HT, although further research is needed to fully understand the implications.⁷⁵

Table 3.

Influence of Vitamin D on Selected Parameters in Patients With Hashimoto Thyroiditis—Recent Clinical Studies

Study	Study population	Methods	Results
Kivity et al73	92 Patients, (50 with HT, 42 without HT)	Serum blood samples were collected from patients. Serum concentration of 25(OH)D, titers of TPOAb, and TgAb were measured	The prevalence of vitamin D deficiency was higher in patients with HT. An inverse relationship between vitamin D levels and the concentration of antithyroid antibodies
Chahardoli et al74	42 Women with HT	Study group who received 50 000 IU vitamin D, weekly for 3 mo, vs a control group Serum concentration of 25(OH)D, iron, T4, T3, TSH, titers of TPOAb, and TgAb were measured.	Vitamin D supplementation resulted in a substantial decrease in the levels of TgAb and TSH.

Abbreviations: HT, Hashimoto thyroiditis; TgAb, antithyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TSH, thyrotropin releasing hormone; 25(OH)D, 25-hydroxyvitamin D.

Selenium

Selenium is a vital trace element that, similar to iodine, plays a crucial role in various endocrine processes, particularly those involved in the synthesis, activation, and metabolism of thyroid hormones.⁷⁶ The significance of selenium for thyroid function is underscored by the fact that the thyroid gland serves as the primary reservoir of selenium in the body. Iodothyronine deiodinases are selenoproteins that contribute to the homeostasis of thyroid hormones. Three different types of iodothyronine deiodinases (D1, D2, and D3) were identified.^77,78 They are present in tissues throughout the body, where they catalyze the production of T3 from T4 and the degradation of T3 to diiodothyronine (T2) by the respective deiodination of the outer and inner rings.⁷⁸ D1 deiodinase and D2 deiodinase are mainly responsible for the synthesis of T3 by T4 deiodination.⁷⁹ D3 deiodinase plays a major role in the degradation of T3 to T2 in case of excess T3.⁷⁸ Deiodinases require selenium as a cofactor for optimal functioning. Consequently, selenium deficiency disrupts thyroid hormone metabolism by inhibiting the activity of D1, D2, and D3 deiodinases. Hence, a diet abundant in selenium supports the synthesis and metabolism of thyroid hormones, while also safeguarding the thyroid gland against excessive iodine exposure.⁸⁰

The main sources of selenium are meat and meat products (31%), shellfish and fish (20%), rice and pasta (12%), and bread and cereals (11%). The highest concentration of selenium (1 mg/kg) is found in Brazil nuts.⁸¹ Nevertheless, the potential toxicity of selenium occurs both below and above the recommended intake range, so both low and high levels of selenium can be associated with increased disease risk, while an optimal or moderate level within the recommended range is associated with the lowest risk. Data in the literature have revealed that the necessary concentration of selenium in the blood is estimated at 60–140 µg/L.⁸² Ruggeri et al⁸³ conducted a study to evaluate the effect of selenium on oxidative damage in human thyrocytes and thyroid fibroblasts in vitro. They exposed primary cultures to H₂O₂ in the presence or absence of selenomethionine or selenite. Cell viability, caspase-3 activity, B-cell lymphoma 2 (BCL-2)/Bcl-2 Associated X protein (BAX) gene expression, DNA fragmentation, malondialdehyde (MDA) levels, and GPx activity were measured. The results suggest that thyrocytes and thyroid fibroblasts exposed to H₂O₂ and preincubated with both selenomethionine and selenite displayed a crucial dose-dependent increase in cell viability compared with cells incubated with H₂O₂ alone. Treatment with selenomethionine and selenite remarkably reduced caspase-3 activity and BAX mRNA levels and increased BCL-2 mRNA levels and GPx activity in a dose-dependent manner. The authors concluded that, in human thyrocytes and fibroblasts in vitro, selenium exerts protective effects against H₂O₂ in a dose-dependent manner. Wu et al⁷⁶ (Table 4) conducted a cross-sectional observational study involving 6152 residents from 2 counties in Shaanxi Province, China. Each participant completed a demographic and dietary questionnaire, and blood samples were collected. The study concluded that higher serum selenium levels were inversely associated with a lower likelihood of developing HT, subclinical hypothyroidism, hypothyroidism, and thyroid enlargement, as indicated by the odds ratio measurements. Turker et al⁸⁵ (Table 4) conducted a study to investigate the long-term (9 months) effects of varying doses (200 mg/d or 100 mg/d) of l-selenomethionine on HT. They analyzed 88 patients with HT who were divided into 2 groups: 1 group received placebo, while the other group received 200 mg l-selenomethionine per day orally for 3 months. After this period, part of the l-selenomethionine group continued with the 200 mg/day dose, while, in others, the dose was reduced to 100 mg per day. All of the patients were also receiving l-thyroxine to maintain serum TSH levels below 2 mIU/L. The study found that selenium supplementation in combination with levothyroxine significant reduced TPOAb levels in patients with HT compared with those in the placebo group. These findings suggest that selenium supplementation could be an effective adjunct treatment for HT and may contribute to better metabolic control.^76,84 In another clinical trial conducted by Krysiak and Okopien⁸⁶ it was observed that supplementation with both levothyroxine and selenium led to a decrease in serum C-reactive protein (CRP) levels and a reduction in the release of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) by monocytes in patients with HT. The most substantial reductions in cytokine levels and plasma CRP were observed when both medications were administered concurrently. More interestingly, Chakrabarti et al⁸⁷ (Table 4) conducted a study to investigate the effect of OS in patients with HT, by using serum MDA concentration as a marker of OS. They analyzed 60 patients who were divided into 2 groups. One group received l-thyroxine and a placebo, while the other group was administered l-thyroxine in combination with selenium (100 µg/2× d) as antioxidant supplementation. Serum MDA level was assessed at the beginning and after 6 months of treatment (ie, at the end of the study). The results showed that MDA levels were reduced in both groups after treatment. Moreover, the group treated with l-thyroxine and selenium exhibited a greater decline in MDA levels. Therefore hypothyroidism is related to increased OS, which could be reduced with l-thyroxine treatment, but the additional role of selenium as a form of additional antioxidant intervention needs more research. Nevertheless, a study conducted by Tian et al⁸⁸ (Table 4) confirmed that treatment with selenium as antioxidant supplementation may decrease TPOAb via reducing OS. In that study, 40 patients with AIT were classified into 2 groups. One group was treated for 3 months with selenium supplementation; the second group received a placebo over a 3-month period. A third group comprised 20 healthy volunteers. Total antioxidant capacity (TAC), SOD, MDA, TSH, TgAb, and TPOAb were measured before and after 3 months of selenium treatments. The results of this research demonstrated that MDA levels were higher, while SOD activity and TAC were lower, in patients with AIT compared with the control group. Additionally, a substantial decrease in MDA levels and an increase in TAC were observed after 3 months of selenium treatment. The authors’ results suggest that selenium treatment may decrease TPOAb synthesis via enforcing a defense against OS in patients with AIT. Therefore, excessive ROS levels are implicated in autoimmune diseases such as HT.⁸⁹

Table 4.

Influence of Selenium on Selected Parameters in Patients With Thyroid Disfunction—Recent Clinical Studies

Study	Study population	Methods	Results
Wu et al84	6152 Residents from 2 counties in Shaanxi Province, China	Cross-sectional observational study The participants completed a demographic and dietary questionnaire, and blood samples were collected. Serum concentrations of TSH, FT3, FT4, and selenium and titers of TPOAb were measured	Higher serum selenium levels were associated with lower likelihood of HT, subclinical hypothyroidism, hypothyroidism, and thyroid enlargement development as reflected by odds ratio measurements.
Turker et al85	88 Patients with HT	One group received placebo, a second group received 200 mg l-selenomethionine per day orally for 3 mo; after this period, part of the l-selenomethionine group continued with the 200-mg/d dose, while others reduced the dose to 100 mg/d. All the patients were also receiving l-thyroxine to maintain serum TSH levels below 2 mIU/L. Serum concentrations of TSH, FT3, and FT4, and titers of TPOAb	Selenium supplementation in combination with levothyroxine significant reduced TPOAb levels in patients with AIT compared with those in the placebo group.
Chakrabarti et al87	60 Patients with hypothyroiditis	One group received l-thyroxine and a placebo; the other group was administered l-thyroxine in combination with selenium (100 µg/twice a day). Serum MDA levels were measured at the beginning and after 6 mo of treatment.	The group treated with l-thyroxine and selenium exhibited a greater decline in MDA levels; hypothyroidism is related to increased OS.
Tian et al88	40 Patients with AIT, 20 healthy volunteers	40 Patients with AIT were divided in 2 groups. One group was treated for 3 mo with selenium supplementation; a second group received a placebo over a 3-mo period. The control group was 20 healthy volunteers. Serum concentrations of TSH, MDA, TAC, and SOD and titers of TPOAb, and TgAb before and after 3 mo of selenium treatments.	Treatment with selenium as antioxidant supplementation may decrease TPOAb via reducing OS. MDA levels were higher, while SOD activity and TAC were lower, in patients with AIT compared with the control group. The was a substantial decrease in MDA levels and an increase in TAC was observed after 3 mo of selenium treatment.

Abbreviations: AIT, autoimmune thyroiditis; FT3, free T3; FT4, free T4; HT, Hashimoto thyroiditis; MDA, malondialdehyde; OS, oxidative stress; SOD, superoxide dismutase; TAC, total antioxidant capacity; TgAb, antithyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TSH, thyrotropin releasing hormone.

THE FUTURE OF NUTRITIONAL INTERVENTIONS: BALANCING PROINFLAMMATORY AND ANTI-INFLAMMATORY NUTRIENTS

Monounsaturated and Polyunsaturated Fatty Acids: Omega-3 and Omega-6

Polyunsaturated fatty acids (PUFAs) are divided into omega-3 fatty acids and omega-6 fatty acids. Both types of fatty acids are precursors of signal molecules with opposite effects. Arachidonic acid is a dominant omega-6 fatty acid. It is converted to eicosanoids, such as prostaglandins, leukotrienes, and other lipoxygenase or cyclooxygenase products. These products are important regulators of inflammatory cellular function. As mediators of the inflammatory reaction, they affect, among others, smooth muscle contractions and vascular permeability; contribute to the development of pain, fever, and edema; and have a chemotactic effect on leukocytes.⁹⁰ Omega-3 fatty acids belong to the PUFA family and are known for their anti-inflammatory properties. They are mainly found in walnuts, rapeseed oil, soybean oil, and oily fish.⁹¹ Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are substrates that compete with each other for the delta-6 enzymes involved in the synthesis of arachidonic acid. The synthesis of proinflammatory eicosanoids decreases when there is a reduction in arachidonic acid production within cells.⁹² The anti-inflammatory effect of omega-3 acids also consists in the fact that they are precursors of the synthesis of resolvins, protectins, and maresins, which belong to the specialized pro-resolving mediators (SPMs).⁹³ The resolvins, protectins, and maresins are specialized pro-resolving mediators derived from omega-3 fatty acids, including EPA- and DHA-derived pathways. Resolvins D series (derived from DHA) act by the ALX/FPR2 and resolvin D receptor 1 (DRV1), also known as GPR32, and also modulate nuclear factor kappa–light chain enhancer of activated B cells (NF-κB). Moreover, they reduce the production of proinflammatory cytokines. The resolvins E series (derived from EPA) act through 2 receptors—the E-series receptor (ERV), also called chemokine-like receptor 1 (CMKLR1), and chemerin receptor 23 (ChemR23)—not only on the immune system but also on dendrites and epithelial tissue and they modulate immune cell action and downregulate the production of inflammatory cytokines. Protectins (derived by DHA and docosapentaenoic acid [DPA]) act through the receptor GPR37 by regulating the action of neutrophils and macrophages, downregulating TNF-α, and upregulating interferon-γ (IFN-γ). Maresins act by inhibiting the action of Toll-like receptor 4 (TLR4), which results in downregulation of NF-κB and the simultaneous activation of the RAR-related orphan receptor alpha (RORα) and upregulation of 12-lipoxygenase (12-LOX) synthesis.⁹⁴

Benveng et al⁹⁵ showed an association between decreased serum thyroid autoantibody levels and the consumption of oily fish, which is rich in omega-3 fatty acids. They conducted a study among pregnant women and postpartum women and concluded that frequent consumption of omega-3–rich oily fish was associated with a more favorable profile of serum thyroid antibodies. They divided 236 thyroid disease–free, White pregnant women into 4 groups: A (n = 48; who consumed swordfish), B (n = 52; who consumed oily fish), C (n = 68; who consumed swordfish + other fish, not necessarily oily fish), and D (n = 68; who consumed fish other than swordfish and oily fish). Serum TgAb and TPOAb were measured during pregnancy (first and second trimesters) and postpartum (day 4), and participants completed a food-frequency questionnaire. The results indicated that a higher frequency of oily fish consumption was associated with lower thyroid antibody concentrations.

Polyphenols

Polyphenols are bioactive compounds found in various plant-based sources, such as vegetables, fruits, and spices (eg, curry), as well as beverages such as green and black tea, coffee, red wine, and cocoa.⁹⁶ Polyphenols can be categorized into 4 main groups—flavonoids, stilbenes, lignans, and phenolic acids⁹⁷—and are observed to have many antioxidant and anti-inflammatory properties. The anti-inflammatory activity of polyphenols is attributed to their inhibitory influence on the pathways of NF-κB, mitogen-activated protein kinase (MAPK), and phosphatidylinositide 3-kinases/protein kinase B (PI3K/AkT) and ability to inhibit the activity of enzymes such as cyclooxygenase and phospholipase A2, thus impacting the production of arachidonic acid. Furthermore, polyphenols play a crucial role in protecting the body from OS by the regulation and management of ROS by promoting the synthesis of nitric oxide (NO), and upregulating the activity of SOD, catalase, and GPx.⁹⁸ The antioxidant properties are due to their typical molecular structure (their multiple hydroxyl groups on aromatic rings allow them to donate electrons/hydrogens to neutralize free radicals), which guarantees an antioxidant action for all classes, as there is delocalization of the free radical itself, with consequent antioxidant activity. In addition, polyphenols show an epigenetic action in modulating microRNA expression. Polyphenols are mostly present in Mediterranean foods; therefore, an MD should be considered as key to better health status.⁹⁹

The following phenolic compounds are identified in ginger: mainly gingerols, shogaols, and paradols, which are responsible for the various bioactive properties of ginger.¹⁰⁰ Ginger root is used to relieve and treat common issues, such as headache, common cold, nausea, and vomiting. In recent years, ginger has been found to have biological properties such as anti-inflammatory and antioxidant properties that can be attributed to its polyphenols.¹⁰¹ Justo et al¹⁰² carried out a study to evaluate anti-inflammatory effects of ginger and rosemary extracts, as sources of polyphenolic compounds on macrophages and tumor cell lines. Ginger and rosemary extracts were obtained by supercritical fluid extraction. Cell viability, production of inflammatory mediators, and NO release were measured in vitro on a J774 cell line and murine macrophage primary culture after being exposed or not to these extracts. The trial showed that the ginger and rosemary extracts inhibited the production of proinflammatory cytokines and the release of NO by murine macrophages and J774 cells. Kar et al¹⁰³ conducted a study to investigate the phytochemical profile of polyphenols and to evaluate the effect of Ficus religiosa leaf extract on thyroid activity in rats with hypothyroidism induced by 6-propylthiouracil. The study used adult female Wistar rats, which were administered 3 doses of F religiosa leaf extract (50, 100, and 200 mg/kg). The dose of 100 mg/kg was found to be the most effective, resulting in increased thyroid hormones and decreased levels of TSH. Zhang et al¹⁰⁴ conducted a study to investigate a potential role of Yanghe decoction, a well-known formula consisting of Rehmannia, deer horn gum, cinnamon, rue, Ephedra, ginger charcoal, and licorice, in the treatment of HT by metabolomics. The study used 9 mice, which were divided into 3 equal groups: model group (group M), the group treated with Yanghe decoction (group T), and a control group (group C). Group T was administered Yanghe decoction, while group C and group M were used as a model of HT. The metabolome of plasma samples from each group of mice was determined using mass spectrometry and the serum levels of IL-35 and IL-6 as inflammatory factors were measured. The study showed that the metabolites along with metabolic network can be altered by Yanghe decoction treatment of HT and that Yanghe decoction can effectively reduce the serum levels of inflammatory factors in HT.

Anti-inflammatory Proteins

Whey and soy protein have antioxidant and anti-inflammatory properties. Thus, both animal and plant protein sources may represent effective nutritional strategies to counteract inflammation and related harmful effects. Whey protein is a type of protein derived from cow milk, constituting approximately 20% of the total protein content in milk, while the remaining 80% is composed of casein.¹⁰⁵ Whey protein demonstrates various bioactive functions, including prebiotic effects, anti-inflammatory properties, antioxidant activity, support for tissue repair, maintenance of gut integrity, pathogen eradication, and toxin elimination.¹⁰⁶ Consequently, data in the literature suggest that whey protein may help prevent OS by enhancing the availability of reduced glutathione (GSH) and boosting the activity of endogenous antioxidant enzymes such as catalase and SOD.¹⁰⁷ The anti-inflammatory capacity of whey protein was demonstrated in the study conducted by Grey et al¹⁰⁸ involving patients with cystic fibrosis. Twenty-one patients were randomly assigned to receive either whey protein isolate (Immunocal^® [Immunotec Inc., Montreal, QC, Canada]; 10 g twice a day) or casein placebo for 12 weeks. Peripheral lymphocyte GSH was used as a marker of lung GSH levels. After supplementation with whey protein, a 46.6% increase in GSH levels in lymphocytes was observed compared with baseline, while the casein group did not show a substantial change. Another in vitro study performed by Xu et al¹⁰⁷ showed the antioxidant effect of whey protein by decreasing H₂O₂ toxicity by increasing the GSH level in the myoblasts. In the cell viability experiment, C₂C₁₂ myoblasts were cultured for 24 hours with or without whey protein (whey protein content was 80.05 g/100 g), after preincubation in growth medium for 24 hours. H₂O₂ was then added to the culture and incubated for 30 minutes. An initial incubation of whey protein with murine C₂C₁₂ myoblasts prevented a decrease in cell viability after their subsequent treatment with H₂O₂. Endogenous antioxidant defense, such as glutathione, catalase, and SOD activity, was also enhanced by the antioxidant effect of whey protein. These findings suggest that whey protein enhances antioxidant properties and provides protection against acute OS through multiple pathways. Therefore, whey protein supplementation may be useful in maintaining optimal GSH levels and redox balance, counteracting inflammation in patients with chronic thyroiditis. Further research should investigate such a perspective. A study conducted by Akkurt et al¹⁰⁹ in 24 rats that received different doses of isole hydrolyzed whey protein (IHWP) and rats fed only standard feed showed that daily use of IHWP may increase the synthesis of thyroid hormones due to its high amino acid content. The rats were randomly assigned to 3 groups. Two groups were fed standard feed + daily IHWP (containing 0.3 g/kg and 0.5 g/kg IHWP, respectively) and the control group was fed standard feed for 12 weeks. Blood samples were collected from all rats before and after IHWP administration. The results of this research demonstrated that thyroid hormones T4 and T3 were significant higher and TSH level was lower in groups fed IHWP compared with the control group.

Over the past 2 decades soy products have become increasingly popular in Western countries, partly due to their association with improved health and reduced all-cause mortality.¹¹⁰ Soy protein constitutes approximately 35%–40% of the dry weight of soybeans. Soy products offer a nutritional profile comparable in quality to animal proteins, while being lower in saturated fat and devoid of cholesterol. Additionally, soybeans contain biologically active compounds known as isoflavones, which are closely associated with soy proteins. Isoflavones, specifically the major soy phytoestrogens found in soy products, have been extensively studied. Both soy protein and isoflavone-enriched soy protein exhibit the potential to alleviate chronic inflammation by modulating the NF-κB signaling pathway and cytokine production.¹¹¹ Another study conducted by Burris et al¹¹² used 5-week-old female apolipoprotein E (apoE-/-) knockout mice to investigate the acute and chronic inflammatory response to different diets. The mice were fed either a casein diet or an isoflavone-free soy protein diet for 1 or 5 weeks. The expression of NF-κB–dependent inflammatory mediators, including TNF-α, Monocyte Chemoattractant Protein-1 (MCP-1), and Vascular Cell Adhesion Molecule-1 (VCAM-1), was measured in the aorta and liver. This research demonstrated that a diet rich in soy proteins effectively suppresses the NF-κB–dependent expression of inflammatory mediators. These findings highlight the potential of soy protein due to its isoflavone content as a distinctive anti-inflammatory agent, offering promise for the prevention and treatment of chronic inflammatory diseases.

The concurrent rise in gluten consumption and the prevalence of autoimmune diseases has prompted the hypothesis that gluten may be associated not only with an increased risk of CD but also with other autoimmune conditions, such as HT.¹¹³ Gluten is the main wheat protein, accounting for approximately 80% of all wheat protein. Gluten peptides can also be found in related cereals, such as barley, rye, and oats. Gliadin, a component of gluten, shares a similar protein structure with thyroid tissue.^114,115 Gluten consumption is believed to trigger an immune response in the body, resulting in the production of antibodies against gliadin. These antibodies, due to their resemblance in structure between gliadin and thyroid tissue, may mistakenly target and attack the thyroid tissue.¹¹⁶

Krysiak et al¹¹⁷ conducted a study that showed that women with HT, who were incidentally found to have positive anti-tissue transglutaminase antibodies, experienced a decrease in the titers of anti-thyroid antibodies, including TPOAb and TgAb, after adhering to a gluten-free diet (GFD). Additionally, an increase in blood concentration of vitamin D₃ was also observed (Table 5).^117,118 This study confirmed that a GFD might provide clinical benefits to patients with autoimmune thyroid disease, by reducing the level of thyroid antibodies and the severity of the autoimmune process. Ihnatowicz et al¹¹⁸ conducted another review to analyze the available knowledge regarding the effect of gluten or a GFD on thyroid autoimmunity in HT, with or without CD. Through a review of relevant literature and analysis of the PubMed and Google Scholar databases, the authors concluded that exclusion of gluten might increase the risk of HT development due to potential nutritional deficiencies associated with the lower quality of gluten-free products. Furthermore, the study indicated that gluten intake from crops grown on selenium-depleted soil may elevate the risk of HT development. Nevertheless, only a few studies have reported that a GFD would be useful for patients with HT, even without coexisting CD. Based on the available literature, there is currently insufficient evidence to recommend a GFD for patients with HT.

Table 5.

Influence of Gluten on Selected Parameters in Patients With HT—Recent Clinical Studies

Study	Methods	Results
Krysiak et al117	The study involved 34 women with AIT. Participants were assigned to 2 groups. The first group (group A, n = 16) complied with the GFD for 6 mo; the secound group (group B, n = 18) remained without any dietary treatment. Serum titers of TPOAb and TgAb and serum levels of TSH, FT4, FT3, and 25-hydroxyvitamin D were measured at the beginning of the study and 6 mo later.	Women with HT, who were incidentally found to have positive anti-tissue transglutaminase antibodies, experienced a decrease in the titers of TPOAb and TgAb, after adhering to a GFD. Additionally, an increase in blood concentration of vitamin D3 was also observed.
Ihnatowicz et al118	Review of relevant literature and analysis of the PubMed and Google Scholar	Gluten exclusion might increase the risk of HT development due to potential nutritional deficiencies associated with the lower quality of gluten-free products. The researchers, based on the available literature, do not recommend a GFD for patients with HT.

Abbreviations: AIT, autoimmune thyroiditis; FT3, free T3; FT4, free T4; GFD, gluten-free diet; HT, Hashimoto thyroiditis; TgAb, antithyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TSH, thyrotropin releasing hormone.

MEDITERRANEAN DIET AS A POTENTIAL PROTECTIVE MODEL

Environmental factors play a crucial role in the development of HT.^7,8 Accordingly, diet and dietary habits seem to contribute to HT development and thyroid autoimmunity modulation. For that reason, the diet and nutritional patterns have become the subject of many studies. Ruggeri et al¹¹⁹ carried out a study to explore the existing knowledge on the relationship between dietary patterns and thyroid autoimmunization and to examine the role of the MD as a potential protective model. Through a review of relevant literature and analysis of the PubMed, ISI Web of Science, and Scopus databases, the authors concluded that the MD has a potentially protective effect against thyroid autoimmunity and that low consumption of animal foods has a protective effect on thyroid autoimmunity. Kaličanin et al¹²⁰ (Table 6) carried out a study to find food groups that differ in consumption frequency between patients with HT and euthyroid patients. They analyzed 491 patients with HT and 433 controls who completed a food-frequency questionnaire. The findings showed increased consumption of animal fat and processed meat in patients with HT compared with controls, who consumed significant more red meat, whole grains, plant oil, and nonalcoholic drinks.¹²⁰

Table 6.

Influence of the Mediterranean Diet on Selected Parameters in Patients With Thyroid Function—Recent Clinical Studies

Study population	Methods	Results	Study
491 Patients with HT and 433 controls	Every participant completed a food-frequency questionnaire	Patients with HT consumed more animal fat and processed meat, compared with controls, who consumed significant more red meat, whole grains, plant oil, and nonalcoholic drinks.	Kaličanin et al120
324 Euthyroid overweight/obese participants (228 women and 96 men) from Apulia (southern Italy)	Cross-sectional study The participants completed a Prevention with Mediterranean Diet questionnaire, and TSH, FT4, and FT3 in serum were measured	A strict adherence to an MD was independently associated with slightly reduced serum FT3 and FT4 levels (still within the reference range).	Zupo et al121
2346 Adult male patients	Cross-sectional study Data on thyroid function (levels of FT4, FT3, TT4, TT3, Tg, TgAb, TPOAb, and TSH) and dietary status from NHANES were examined and the DII was calculated.	A positive association between DII and total T4 serum levels, with no influence on FT3, FT4, or TSH serum levels.	Liu et al122
200 Patients (173 females and 27 males; 81 patients were diagnosed with HT, while 119 participants constituted the control group) were enrolled, who were not under any pharmacological treatment	Among every participant, serum TSH, FT3, anti-thyroid antibodies, and circulating OS markers, (AGEs) were measured. Each patient completed a questionnaire on dietary habits, assessing the intake frequencies of food groups and adherence to the MD.	A positive correlation between meat consumption and an elevated risk of developing thyroid autoimmunity, while adherence to the MD was associated with thyroid protective effects. A substantial association between OS parameters and the consumption of animal foods.	Ruggeri et al13
45 Euthyroid patients with HT	Patients were randomly assigned to different dietary regimens: MD (n = 15), GFD (n = 15) and FD (n = 15). Serum levels of TSH, FT4, TgAb, TPOAb, and OS markers (AGEs, GPx, TRxR, TEAA) were measured at the beginning and after 3 mo.	The MD has protective effect against OS, while a GFD does not significant affects markers of OS and thyroid function.	Lagana et al123

Abbreviations: AGE, advanced glycation end-product; DII, Dietary Inflammatory Index; FD, free diet; FT3, free T3; FT4, free T4; GFD, gluten-free diet; GPx, glutathione peroxidase; HT, Hashimoto thyroiditis; MD, Mediterranean diet; NHANES, National Health and Nutrition Examination Survey; OS, oxidative stress; TEAA, total plasma antioxidant activity; Tg, thyroglobulin; TgAb, antithyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TRxR, thioredoxin reductase; TSH, thyrotropin releasing hormone.

Another study examined the influence of dietary patterns on thyroid function. Zupo et al¹²¹ (Table 6) conducted a cross-sectional study to explore the effect of adherence to the MD on thyroid function. They examined 324 euthyroid overweight/obese participants (228 women and 96 men) from Apulia (southern Italy). The participants completed a Prevention with Mediterranean Diet (PREDIMED) questionnaire, and TSH, FT4, and FT3 in serum were measured. The authors concluded that strict adherence to an MD was independently associated with slightly reduced serum FT3 and FT4 levels (but still within the reference range). Another cross-sectional study conducted by Liu et al¹²² (Table 6) examined the relationship between the dietary inflammatory potential and thyroid function. They examined data from the National Health and Nutrition Examination Survey (NHANES) in 2346 adult male patients. Data were obtained from the years 2007–2008 because this period included complete information on thyroid function (levels of FT4, FT3, total triiodothyronine [TT3], total thyroxine [TT4], Tg, TgAb, TPOAb, and TSH) and dietary status necessary to calculate the Dietary Inflammatory Index (DII). The results indicated a positive association between DII and total T4 serum levels; accordingly, participants adhering to a more proinflammatory diet appeared to have higher total T4 levels. Ruggeri et al¹³ (Table 6) carried out a study to investigate dietary habits and their relationship with redox homeostasis in patients with thyroid autoimmunity. In this study, 200 untreated patients were enrolled, including 173 females and 27 males. The study group comprised 81 patients diagnosed with Hashimoto’s thyroiditis (HT), while 119 individuals constituted the control group. In each participant, serum thyroid stimulating hormone TSH, FT3, anti-thyroid antibodies, and circulating OS markers, such as AGEs, were measured. Each patient completed a questionnaire on dietary habits, assessing the intake frequencies of food groups and adherence to the MD. The results indicated a positive correlation between meat consumption and an elevated risk of developing thyroid autoimmunity, while adherence to the MD was associated with thyroid-protective effects. Moreover, the study demonstrated a substantial association between OS parameters and the consumption of animal foods. The results suggest that low consumption of animal foods has a protective effect on thyroid autoimmunity and that dietary patterns positively influence redox balance and potentially mitigate disorders related to OS imbalance. Laganà et al¹²³ (Table 6) carried out a study to examine the association between adherence to an MD or GFD with redox homeostasis in HT. They examined 45 euthyroid patients with HT who were randomly assigned to different dietary regimens: MD (n = 15), GFD (n = 15) and free (without restriction) diet (n = 15). Serum levels of TSH, FT4, TgAb, and TPOAb and OS markers such as AGEs, GPx, TRxR, and total plasma antioxidant activity (TEAA) were measured at the beginning of the study and after 3 months. The authors concluded that the MD has protective effect against OS, while a GFD does not significant affect markers of OS and thyroid function. The MD exerts anti-inflammatory and antioxidant effects, due to the content of monounsaturated fatty acids (particulary oleic acid), fibers, vitamins, and minerals (selenium, iron, iodine), which are the key components for a proper function of thyroid.¹¹⁹ For that reason, the MD should be considered as a potential protective model and should be recommended for patients with HT.

CONCLUSION

Numerous studies have demonstrated the efficacy of personalized dietary interventions as a valuable adjunct to standard l-thyroxine therapy in the clinical management of HT. A well-structured nutritional approach can complement medical treatment by targeting inflammation and modulating OS levels, which are crucial in this disease pathogenesis. The nutritional intervention for individuals with HT should focus on maintaining optimal nutritional status and preventing deficiencies. Essential micronutrients, such as iodine, iron, selenium, and vitamin D, are particularly important for thyroid function and immune regulation. Additionally, anti-inflammatory dietary components such as omega-3 and omega-6 fatty acids, polyphenols, whey protein, soy protein, and isoflavones may offer beneficial effects in managing the disease. These nutrients and compounds can reduce inflammation and improve antioxidant capacity, contributing to better overall thyroid health and symptom management. The MD exerts anti-inflammatory and antioxidant effects and should be considered as a potential protective model and recommended to patients with HT (Figure 2).

Figure 2.

Role of Dietary Components in Thyroid Dysfunction

Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FT3, free T3; FT4, free T4; ROS, reactive oxygen species.

Author Contributions

J.M.-J.: conceptualization, methodology, data curation, visualization, writing—original draft preparation. A.B.: methodology, data curation, writing—review and editing. A.A.: conceptualization, formal analysis, supervision, writing—review and editing. A.J.K.: formal analysis. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded by internal financing of the Medical University of Bialystok (B.SUB.23.530).

Conflicts of Interest

None declared.

Data availability

No new data were generated or analyzed in this study. Data sharing is not applicable to this article.