The influence of viTAmin D AnD iRon on ThyRoiD funcTion AnD ThyRoiD autoimmunitY

Razmatranje autoimunosti kao uzroka bolesti počelo je kada i sama imunologija, 1901. godine. sa Erlihovim pojmom Horror autotoxicus. Tri godine kasnije opisano je hladno autoantitelo autohemolizin, zaslužno za paroksizmalnu hemoglobinuriju, ali bez da je oformljen ikakav trajan koncept autoimunosti kao uzročnika ove bolesti. Erlihova doktrina doduše nije pomogla u prihvatanju koncepta autoimunosti, kao ni okrenutost imunologije u tom periodu prema spoljnim uzročnicima umesto unutrašnjim. Između 1915. i 1945. godine imunologija se okrenula drugim poljima istraživanja, iako su rađene studije vezane za autoimunost, a 1945. godine dolazi do ekspanzije istraživanja autoimunosti. Pojam je opšteprihvaćen tek oko 1965. godine (1). Autoimune bolesti predstavljaju spektar bolesti uzrokovanih zapaljenjem, usled produkcije autoantitela i posledičnog citotoksičnog delovanja T limfocita. Podaci ukazuju na razlike u prevalenciji autoimunih bolesti između Evrope, Severne Amerike, Australije i Novog Zelanda (definisano kao zona 1) i Azije, Bliskog istoka, Kariba i Južne Amerike (zona 2) (2). U većini autoimunih bolesti žene čine >85% bolesnika. Samo u nekim autoimunim bolestima sa prezentacijom u detinjstvu, kao što je dijabetes melitus tip 1, rizik od obolevanja je podjednak za oba pola. Postoje tri pika za nastupanje autoimunih bolesti: između 8. i 10. godine (juvenilni reumatoidni artritis, DM tip 1), između 33. i 50. godine (mijastenija gravis, multipla skleroza, SLE, skleroderma, Grejvsova bolest) i između 52. i 63. godine (Hašimoto tireoiditis, adultni reumatoidni artritis) (3). Autoimune bolesti štitne žlezde su najprevalentnije organ-specifične bolesti i zahvataju 2–5% populacije (4), sa velikom varijabilnošću među polovima (5–15% žena, 1–5% muškaraca) (5). Najznačajnija dva entiteta u okviru autoimunih bolesti štitaste žlezde su Hašimoto tireoiditis i Grejvsova bolest. Ove bolesti su posledica gubitka imunološke tolerancije sopstvenih antigena. Dolazi do ćelijskog i humoralnog imunog odgovora protiv antigena štitne žlezde sa reaktivnom infiltracijom T i B limfocitima, proizvodnjom autoantitela i zatim razvijanja kliničkih manifestacija bolesti (6, 7). Ovo


The influence of viTAmin D AnD iRon on ThyRoiD funcTion AnD ThyRoiD autoimmunitY
Consideration of autoimmunity as a cause of disease began when immunology itself began in 1901 with Ehrlich's term Horror autotoxicus. Three years later, the cold autoantibody autohemolysin was described, responsible for paroxysmal hemoglobinuria, but without forming any lasting concept of autoimmunity as the cause of this disease. Ehrlich's doctrine admittedly did not help in accepting the concept of autoimmunity, nor did the focus of immunology in that period on external causes instead of internal ones. Between 1915 and 1945, immunology turned to other fields of research, although studies related to autoimmunity were carried out, and in 1945 there was an expansion of autoimmunity research. The term was generally accepted only around 1965 (1).
Autoimmune diseases represent a spectrum of diseases caused by inflammation, due to the production of autoantibodies and the consequent cytotoxic action of T lymphocytes. Data indicate differences in the prevalence of autoimmune diseases between Europe, North America, Australia and New Zealand (defined as zone 1) and Asia, the Middle East, the Caribbean and South America (zone 2) (2). In most autoimmune diseases, women make up >85% of patients. Only in some autoimmune diseases with childhood presentation, such as diabetes mellitus type 1, the risk of the disease is equal for both sexes. There are three peaks for the onset of autoimmune diseases: between the ages of 8 and 10 (juvenile rheumatoid arthritis, DM type 1), between the ages of 33 and 50 (myasthenia gravis, multiple sclerosis, SLE, scleroderma, Graves' disease) and between the ages of 52 and 63 (Hashimoto's thyroiditis, adult rheumatoid arthritis) (3).
Autoimmune diseases of the thyroid gland are the most prevalent organ-specific diseases and affect 2-5% of the population (4), with great variability between the sexes (5-15% of women, 1-5% of men) (5). The two most significant entities within auto immune thyroid diseases are Hashimoto's thyroiditis and Graves' disease. These diseases are the result of loss of immune tolerance of own antigens. There is a cellular 1 Medigroup Bulevar, Healh Centre and humoral immune response against thyroid gland antigens with reactive infiltration of T and B lymphocytes, production of autoantibodies and then the development of clinical manifestations of the disease (6,7). These are diseases of multifactorial etiology, with a complex interaction between environmental factors and genetic predisposition (8).
Genetics play a significant role in the pathogenesis of autoimmune thyroid diseases. Some of the genes responsible for these autoimmune diseases are common to Hashimoto's and Graves' disease, while genes specific to one of these 2 diseases have also been identified (9). The association between HLA genes and these diseases is well known. This explains some similarities in the pathological findings between Hashimoto's thyroiditis and Graves' disease, because in both diseases the presentation is dependent on certain HLA-B and HLA-DR, which suggests that hereditary risk factors are important in the pathogenesis of these diseases (10,11). In addition to HLA genes, other genes responsible for the immune system are also responsible for the development of all autoimmune diseases, as well as autoimmune diseases of the thyroid gland, which speaks in favor of genetic susceptibility to autoimmune diseases. Polymorphisms in certain CTLA-4 alleles are associated with a predisposition to Hashimoto's thyroiditis and Graves' disease (12)(13)(14)(15)(16). In a study conducted on 379 patients in Great Britain, 42% of patients in the test group had the G allele of the CLA-4 gene, while 32% in the control group had that allele (16). This genetic abnormality was associated with stimulation of thyroid antibody production and clinical presentation of autoimmune thyroiditis in interaction with other loci also responsible for genetic predisposition to this disease (6,13,16,17). CD40 is found only on follicular cells of the thyroid gland and on B lymphocytes. The polymorphism of this gene is associated with a 20-30% increase in translation of the mRNA transcript of CD40 in patients with autoimmune thyroid diseases (18). Polymorphism of the PTPN22 gene, which encodes a negative regulator of T lymphocyte activation, has been linked to both autoimmune diseases of the thyroid gland and autoimmune diseases in general (9). Abnormalities in the FOXP3 gene, which is responsible for the differentiation of T lymphocytes into Treg cells, have been linked to the juvenile form of Graves' disease (19). Changes in the CD25 gene are also associated with Graves' disease (20).
Although the link between genetic susceptibility and environmental factors thyroiditis is clear, the mechanism by which genetic variability interacts with environmental factors in autoimmune diseases is still not fully understood. Recent data point to the role of epigenetic mechanisms. Epigenetic modulation of gene expression can be manifested by changes in DNA methylation, histone modification (acetylation, deacetylation, methylation), as well as RNA interference via microRNA molecules. More recently, it has been shown that IFN-α induces alteration in the thyroglobulin gene through epigenetic changes in histones (21). Given that IFN-α is secreted locally during viral infections, this could explain the mechanism by which infections could trigger the development of autoimmune thyroid diseases (22). Another epigenetic phenomenon described in the pathogenesis of autoimmune diseases of the thyroid gland is the inactivation of the X chromosome. The degree of inactivation of the X chromosome is a significant factor in the increased tendency of women to these autoimmune diseases, according to the study by Yin et al. (23).
Numerous environmental factors are associated with the occurrence of autoimmune thyroid diseases such as low birth weight, iodine excess, selenium deficiency, stress, smoking, allergies, radiation exposure, drugs, viral or bacterial infections, as well as fetal microchimerism (24). Smoking is one of the more important environmental factors related to this disease, if not the most important factor (25). Cigarette smoke contains cyanide, which is metabolized to thiocyanate, which can disrupt iodine concentrations in the thyroid gland (26). There is evidence to sug gest that the involvement of infections in the pathogenesis of these diseases is very significant. However, even non-pathogenic microorganisms, normal inhabitants of the human microflora, induce a pro-inflammatory or regulatory immune response in the host (27). There are data that B. Burgdoferi and Y. Enterocolitica are frequent triggers of thyroid autoimmunity. Molecular mimicry is hypothesized to be the way in which these two microorganisms elicit an autoimmune response (28,29). Some other microorganisms that are assumed to play the role of triggers in autoimmune diseases of the thyroid gland are H. Pylori, Coxsackie virus, hepatitis C virus and retroviruses (29).
Although iodine is necessary for the functioning of the thyroid gland, it is also one of the most important causes of thyroid dysfunction. A mild iodine deficiency is associated with a reduced prevalence of Hashimoto's thyroiditis, while a mild excess of this element is associated with a higher prevalence of this autoimmune disease. Potential mechanisms by which iodine could induce thyroid autoimmunity include direct stimulation of the immune response in the thyroid gland, increased immunogenicity of highly iodinated thyroglobulin, and the direct toxic effect of iodine on thyrocytes through the generation of free radicals (30)(31)(32). Kahaly et al. followed a group of patients with endemic goiter who received iodine for 6 months and a group with the same condition who received T4. A high titer of thyroid antibodies was found in 16% of patients receiving iodine treatment. After they stopped taking iodine, antibody levels decreased significantly and after 4 years were normal in 4 of 6 patients (30).
The most common manifestation of radiation on the thyroid gland is hypofunction both due to direct destruction of the gland and due to stimulation of thyroid antibodies (29). Autoimmune diseases of the thyroid gland have also occurred with the therapeutic application of radiation (33), as well as with exposure to radiation in the environment (34). In a study conducted on 160 people who were exposed to radiation at the workplace, 10% of them met the criteria for the diagnosis of autoimmune thyroiditis, while in the control group only 3.4% met the criteria. Subjects who were exposed to radiation for more than 5 years were at greater risk (35).
Many pollutants present in the environment have been shown to cause autoimmune thyroid diseases (36). For example, a high prevalence of hypothyroidism was observed, with elevated values of anti-TPO and anti-Tg, in individuals exposed to polybrominated biphenyls. Bisphenol A, often used in the production of plastics, could bind to the TSHR as a competitive antagonist of T3 (31,36,37).
Several drugs play a role in the pathogenesis of autoimmune thyroid diseases. IFN-α, IL-2, lithium, amiodarone, and highly active retroviral therapy are the agents most commonly associated with thyroid dysfunction (29,31). For most of these drugs, it is true that patients with the highest risk of developing autoimmune thyroiditis are those who, before the use of this therapy, already had elevated levels of thyroid antibodies (29,31,36). Some drugs, such as lithium, although not direct triggers of autoimmunity, accelerate autoimmune processes by interfering with the synthesis of thyroid hormones. Thyroid function testing, as well as the measurement of the anti-TPO titer should be considered before the introduction of these drugs into therapy (24).
Mechanisms by which stress could induce thyroid autoimmunity are the induction of immunosuppression by antigen non-specific mechanisms, probably due to the effects of cortisol and CRH on immune cells, which is followed by immune hyperreactivity and consequent autoimmune disease of the thyroid gland. It is believed that postpartum thyroidism has a similar mechanism of origin. However, so far there is no evidence linking stress with thyroid autoimmunity, probably because the stressful event and the damage to this gland itself are separated in time (29,31,36).
Fetal cells have been identified in the thyroid glands of mothers suffering from autoimmune thyroiditis. Such cells could cause graft versus host disease in the thyroid gland and thus could play a significant role in the pathogenesis of Hashimoto's thyroiditis (38,39). This mechanism of thyroid autoimmunity is still at the level of a hypothesis.
These diseases are generally accompanied by the presence of anti-TPO (thyroid peroxidase), anti-Tg (thyroglobulin), or anti-TSH receptor antibodies. There are also antibodies against other target antigens (carbonic anhydrase 2, megalin, T3, T4, Na-I transporter, pendrin), but they are rarely encountered in practice (40). Thyroid peroxidase is a weakly glycosylated membrane-bound enzyme responsible for iodine oxidation and iodination of the tyrosyl residue of the thyroglobulin molecule (41). Anti-TPO antibodies from healthy individuals did not block TPO activity (42), while anti-TPO antibodies from patients with autoimmune thyroid diseases destroyed thyrocytes and inhibited the enzymatic activity of TPO by competitive inhibition (43). Anti-TPO antibodies are more common than anti-Tg antibodies and therefore a better indicator of thyroid autoimmunity (44). Anti-TPO antibodies are also an inducer of oxidative stress because they reduce the antioxidant potential (45). Although these antibodies have a cytotoxic effect on thyrocytes in Hashimoto's thyroiditis, they have no established role in Graves' disease (46).
Thyroglobulin is a large (600kDa) glycoprotein consisting of dimers and an average of 2-3 molecules of T4 and 0.3 molecules of T3. This molecule is heterogeneous in terms of content, glycosylation and structure. Antibody production against Tg can be induced by massive destruction of the thyroid gland, although high levels of Tg in the blood do not necessarily induce antibody production. Of the 40 epitopes on the Tg molecule that have been identified, according to some authors 6 and according to others 1-2 are immunogenic (47,48). Healthy individuals have low levels of anti-Tg antibodies, generally below the threshold required for laboratory detection. In the presence of elevated serum levels of Tg due to the destruction of thyroid tissue, changed conformation of the thyroglobulin molecule due to high levels of I2 and increased TSH, the titer of anti-Tg antibodies also increases abnormally (48). Administration of I2 to subjects induced anti-Tg antibody production in 8-20% of subjects, associated with intrathyroidal lymphocytic infiltrate in some patients (49).
Hashimoto's thyroiditis is a chronic inflammation of the thyroid gland first described more than 100 years ago, but the etiopathogenesis is still not fully defined (50). It is considered the most common autoimmune disease (51,52), the most common endocrine disorder (53), as well as the most common cause of hypothyroidism (54,55).
Hashimoto's thyroiditis was first described by Dr. Hakara Hashimoto in 1912, studying thyroid specimens from 4 middle-aged women who had their glands removed for compressive symptoms. This disease was considered rare until the fifties of the last century, and now it is the most frequent autoimmune disease, with an incidence of 1 per 1,000 people per year, and a prevalence of 8 per 1,000 if the revisions of scientific articles in the field of endocrinology are taken as a source (50), and 46 per 1000 if only biochemically confirmed thyroiditis and thyroid antibodies are considered (56). This autoimmune disease is up to 8 times more common in women than in men, also the white and yellow races suffer more often than the black (50). In 2 Chinese studies, increased dietary iodine intake was correlated with an increased occurrence of Hashimoto's thyroiditis in the population (57,58). In Denmark, after the introduction of a mandatory salt iodization program, they saw an increase in the prevalence of elevated anti-TPO antibodies as well as Hashimoto's thyroiditis (59). Etiologically, this disease can be divided into primary and secondary forms.
Primary thyroiditis includes all cases without a clear etiology. Clinically-pathologically, primary Hashimoto's thyroiditis includes 6 entities: classic form (60), fibrotic form, IgG4 variant (61), juvenile form (62), Hashitoxicosis and painless (silent) thyroiditis (occurs as isolated and postpartum) (63). Clinically, the most common manifestation is enlargement of the thyroid gland (goiter), which goes with or without accompanying hypothyroidism. The most common pathological finding is significant lymphocytic infiltration of the thyroid gland. Primary Hashimoto's thyroiditis can manifest itself as an isolated disease, but it can often occur together with various other autoimmune diseases (diabetes type 1, Sjogren's syndrome), or thyroid gland diseases. Among the diseases of the thyroid gland, it is important to mention the association between primary Hashimoto's thyroiditis and papillary carcinoma of the thyroid gland, which is between 0.5 and 30%, depending on the source (60,64).
Secondary thyroiditis are forms of this disease with an established etiological agent. Most often, they are of iatrogenic origin, as a consequence of immunomodulatory drug therapy (eg the use of interferon-α in hepatitis C therapy) (65). During the past 10 years, the development of anticancer immunotherapy has led to the emergence of many immune-mediated diseases, including thyroiditis, which can be seen in the use of monoclonal antibodies that block CTLA-4 (66), as well as in the example of vaccines against malignant diseases (67).
Hashimoto's thyroiditis is a prototype organ-specific autoimmune disease. Often, patients with this disease either have other autoimmune diseases, or have someone in the family with other diseases of this type (68), which indicates the genetic origin of these diseases. Hashimoto's thyroiditis (69) and systemic lupus (70) are the first two autoimmune diseases for which a genetic component was proven in the early seventies of the last century, in the genes for MHC class II proteins. However, in the last 4 decades, only a few more genes associated with the tendency to thyroiditis have been found, although the mechanism by which they influence the occurrence of this disease has not been established (71).
In Hashimoto's thyroiditis, both thyrocytes and the interstitium surrounding the follicles are affected. The classic form of this disease is mainly presented by an enlarged, grayish thyroid gland, with characteristic interstitial infiltration by predominantly lymphocytes with some plasma cells and macrophages (50). Within the gland, lymphocytes are organized into lymph follicles (tertiary, ectopic), with all the structural characteristics of a true lymph follicle. Fibrosis of the interstitium also occurs. Thyrocytes are atrophic in some parts of the gland, and enlarged in others, with a hyperchromatized nucleus and a cytoplasm full of mitochondria (72). Fibrous type of thyroiditis is characterized by an enlarged, hard and lobulated thyroid gland. Fibrosis in this disease does not break through the capsule, in contrast to Riedel's thyroiditis, in which adhesions of the gland to the surrounding structures occur. Chronic inflammation of lymphocytes, also organized into follicles, occurs in this type as well. In the late stage of the disease, as in older patients, the fibrous variant manifests as idiopathic myxedema, where the thyroid tissue is reduced to a small fibrous bud (50).
The IgG4 variant was first described in Japan in 2009. Pathologically, it is defined by pronounced lympho-plasmacytic infiltration, with the fact that in this variant of the disease, the infiltrate contains a large number of IgG4-producing plasma cells (>20 cells per visual field). Interstitial fibrosis is not expressed as in the previously described two forms.
The other 3 forms (juvenile, Hashitoxicosis, painless thyroiditis) rarely require thyroidectomy, therefore there are not many pathohistological samples taken from patients with these types of diseases. They have characteristics similar to the other forms, with the fact that the fibrosis is milder and the appearance of lymph follicles is not so common.
The diagnosis of Hashimoto's thyroiditis is made on the basis of clinical features, the presence of serum antibodies against thyroid antigens (anti-TPO, anti-TG) as well as findings of ultrasound of the thyroid gland. Additional tests that are performed less often, but contribute to better diagnosis, are scintigraphy of the thyroid gland to detect uptake of radioactive iodine isotope in the thyroid gland, as well as cytological examination of thyroid aspirate (50).
The manifestations of Hashimoto's thyroiditis vary according to the nature of the disease itself. Initially, patients may have hyperthyroid symptoms, caused by the initial destruction of thyroid cells and the subsequent release of thyroid hormones into the bloodstream. When the released hormones are metabolized, due to the destruction of thyroid cells, hypothyroidism occurs. The symptoms of hypothyroidism are insidious, variable and can affect almost any organ or organ system in the body.
Skin manifestations include dry skin, especially on the extensor sides of the hands and feet, pale skin due to accumulation of dermal mucopolysaccharides and consequent greater water retention, as well as myxedema in more severe forms of this disease. Hair growth is slowed, and hair is often brittle and dry. Alopecia is also a relatively common manifestation. Peripheral vascular resistance can drop up to 60%, and cardiac output can decrease up to 50%. Bradycardia may also occur. Fatigue, dyspnea on exertion, as well as exertion intolerance occur due to limited pulmonary and cardiac reserve, as well as due to muscle weakness. Early symptoms may include constipation, fatigue, dry skin, and weight gain. In the later stages of the disease, there is cold intolerance, reduced sweating, peripheral neuropathies, lack of energy, depression, dementia, memory loss, muscle spasms, joint pain, hair loss, apnea, menorrhagia, as well as compressive symptoms in the neck area due to an enlarged thyroid gland and hoarseness. During the examination, attention should be paid to cold and dry skin, periorbital edema, brittle nails, bradycardia, delayed tendon reflex relaxation phase, increased blood pressure, slowed speech, ataxia and macroglossia (73).
Vitamin D is a steroid molecule produced mainly in the skin, which regulates the expression of a large number of genes (74). There are two forms of vitamin D, vitamin D3 (cholecalciferol), and vitamin D2 (ergocalciferol). Cholecalciferol is produced in the skin after exposure to UVB radiation, although it can also be found in some foods such as some fatty fish, while ergocalciferol is produced by plants and fungi (75,76). Vitamin D is incorporated from the digestive tract into chylomicrons, which reach the lymphatic system and then the venous blood. This vitamin, whether from the skin or from the diet, is biologically inert until it undergoes its first hydroxylation in the liver to form 25(OH)D. Vitamin D requires another hydroxylation in the kidneys, when the biologically active form of vitamin D 1,25(OH)2D is formed (77). This active form of vitamin D stimulates the intestinal absorption of calcium. Without vitamin D, only 10-15% of calcium and about 60% of phosphorus are absorbed from food (77,78). The receptor for vitamin D is found in almost all tissues and cells in the body. 1,25(OH)2D has a wide range of effects in the body, such as inhibition of cell proliferation, induction of terminal cell differentiation, inhibition of angiogenesis, stimulation of insulin production and inhibition of renin production (79)(80)(81). The biologically active form of vitamin D is responsible for the activation and suppression of between 200 and 500 genes, which constitutes about 3% of the human genome (82). The main role of vitamin D is regulation of bone metabolism and regulation of calcium and phosphorus homeostasis. Recent research has shown that vitamin D deficiency, which is widespread, could also have manifestations beyond the bone system, in the form of autoimmune diseases, tumors, metabolic syndromes, etc. (74,83,84). Low serum vitamin D levels are also associated with autoimmune thyroid diseases such as Hashimoto's thyroiditis and Graves' disease (82,85,86). Autoimmune diseases of the thyroid gland are caused by a combination of genetic predisposition and triggers from the environment (Iodine, Selenium, drugs, smoking, infections, stress). These diseases are characterized by lymphocytic infiltration of the thyroid gland and the production of specific antithyroid antibodies (87,88). In genetically predisposed individuals, the disruption of immune-endocrine interactions by environmental factors leads to an imbalance between Th1 and Th2 immune responses. This results in a Th1 cell-mediated autoimmune reaction with thyrocyte destruction and hypothyroidism in Hashimoto's thyroiditis, and a hyperreactive Th2-mediated humoral response directed at the TSH receptor with stimulatory antibodies leads to hyperthyroidism in Graves' disease (87). Vitamin D plays a significant role in modulating the immune response, enhancing the native and inhibiting the acquired immune response (75,89). Most immune cells, primarily T lymphocytes, B lymphocytes, APCs such as dendritic cells and macrophages have VDR (vitamin D receptor) and 1α-hydroxylase (75,76,90). At the level of antigen-presenting cells, 1,25(OH)₂D inhibits the surface expression of MHC class II proteins and costimulatory molecules and prevents the differentiation and maturation of dendritic cells as well as their activation and survival, which leads to a decrease in antigen presentation and cellular activity. Also, 1,25(OH)₂D indirectly inhibits the production of IL-12 and IL-23, and promotes the release of IL-10. Therefore, 1,25(OH)₂D indirectly shifts the balance of the immune response from Th1 and Th17 immune responses, to Th2 immune responses (90,91). 1,25(OH)₂D inhibits the proliferation, differentiation and production of cytokines (IL-2 and interferon-γ) of Th1 cells, as well as Th-17 cytokines (IL-17 and IL-21), but also promotes the production of anti-inflammatory Th2 cytokines (IL-3, IL-4, IL-5 and IL-10). The active form of vitamin D also inhibits the proliferation of B lymphocytes and their differentiation into plasma cells, suppresses the secretion of immunoglobulins (IgG and IgM), prevents the formation of memory B lymphocytes and induces apoptosis of B lymphocytes (75,76,(89)(90)(91)(92). The ability of 1,25(OH)₂D to suppress the acquired immune system helps develop immune tolerance and has been shown to be beneficial in a number of autoimmune diseases (75,76).
Iron is an important micronutrient for maintaining cellular energy and metabolism (93). Iron is widely distributed on Earth and is an essential component of every living organism (94,95). Despite the widespread distribution of this element, iron is often a limiting factor in the environment (96). This apparent paradox is a consequence of iron's ability to form oxides in contact with oxygen, which are very insoluble and therefore unavailable for absorption by the living world. Various cellular mechanisms have been developed so that iron from the environment can be used in a biologically useful form. Siderophores secreted by microorganisms (97), as well as the mechanisms for the reduction of iron from the insoluble trivalent to the soluble divalent form in some yeasts (98) are good examples of the aforementioned cellular mechanisms.
Iron occurs in the diet in 2 forms: Heme and non-Heme. The primary source of heme iron is hemoglobin and myoglobin from meat and fish, while non-heme iron is present in grains, legumes, fruits and vegetables. Heme iron has a better availability from food (15-35%) than non-heme iron (2-20%) (99). Admittedly, non-heme iron is present to a greater extent in the diet, so regardless of its poor utilization, more iron in this form is taken into the body than in the Heme form (100).
Iron deficiency manifests as low serum iron and lower ferritin levels. It is considered the most common nutritional deficiency and can lead to undesirable effects on thyroid metabolism in women of reproductive age as well as pregnant women (101,102). Research has shown that iron deficiency negatively affects thyroid function by interfering with oxygen transport or affecting thyroid peroxidase activity (103,104). According to some studies, iron deficiency doubles the risk of developing hypothyroidism (105,106). It should be emphasized that these studies did not examine the association between iron deficiency and thyroid autoimmunity.
Regarding the effect of iron deficiency on the levels of antibodies to thyroid antigens (anti-TPO, anti-Tg, anti-TSH), one study says that the presence of these antibodies is more often seen in subjects with a deficiency of this micronutrient (107), while others say that even in subjects with a deficiency, antithyroid antibodies are less often seen (108). Studies showing an association between thyroid autoimmunity and iron deficiency are rare (109,110). Studies in rats have shown that iron deficiency reduces serum thyroid hormone concentrations by reducing hepatic thyroxine deiodinase activity, disrupting peripheral conversion of T4 to T3, and reducing the TSH response to TRH.
Iron deficiency is thought to affect thyroid hormone feedback, stimulating the pituitary gland to secrete TSH. Also, iron plays an important role in the normal functioning of thyroperoxidase (TPO), a heme-dependent protein. Iron also participates in enhancing the action of iodine in the thyroid gland (112,113).