Hashimoto's thyroiditis

Signs In the early stages of autoimmune thyroiditis, patients may have normal thyroid hormone levels and no goiter or a small one. Early on, thyroid autoantibodies in the blood may be the only indication of Hashimoto's disease. Patients with goiters who have had autoimmune thyroiditis for many years might see their goiter shrink in the later stages of the disease due to destruction of the thyroid. While rare, more serious complications of the hypothyroidism resulting from autoimmune thyroiditis are pericardial effusion, pleural effusion, both of which require further medical attention, and myxedema coma, which is an endocrine emergency. and myopathy. (also called "destructive thyrotoxicosis"). While most symptoms are attributed to hypothyroidism, similar symptoms are observed in Hashimoto's patients with normal thyroid hormone levels. == Causes ==

The causes of Hashimoto's thyroiditis are complex. Around 80% of the risk of developing an autoimmune thyroid disorder is due to genetic factors, while the remaining 20% is related to environmental factors (such as iodine, drugs, infection, stress, radiation). Genetics Thyroid autoimmunity can be familial. Many patients report a family history of autoimmune thyroiditis or Graves' disease. Susceptibility alleles are not consistent in Hashimoto's disease. In Caucasians, various alleles are reported to be associated with the disease, including DR3, DR5, and DQ7. CTLA-4 genes CTLA-4 is the second major immune-regulatory gene related to autoimmune thyroid disease. CTLA-4 gene polymorphisms may contribute to the reduced inhibition of T-cell proliferation and increase susceptibility to autoimmune response. CTLA-4 is a major thyroid autoantibody susceptibility gene. A linkage of the CTLA-4 region to the presence of thyroid autoantibodies was demonstrated by a whole-genome linkage analysis. CTLA-4 was confirmed as the main locus for thyroid autoantibodies. PTPN22 gene PTPN22 is the most recently identified immune-regulatory gene associated with autoimmune thyroid disease. It is located on chromosome 1p13 and expressed in lymphocytes. It acts as a negative regulator of T-cell activation. Mutation in this gene is a risk factor for many autoimmune diseases. Weaker T-cell signaling may lead to impaired thymic deletion of autoreactive T cells, and increased PTPN22 function may result in inhibition of regulatory T cells, which protect against autoimmunity. Immune-related genes IFN-γ promotes cell-mediated cytotoxicity against thyroid mutations causing increased production of IFN-γ were associated with the severity of hypothyroidism. Severe hypothyroidism is associated with mutations leading to lower production of IL-4 (Th2 cytokine suppressing cell-mediated autoimmunity), lower secretion of TGF-β (inhibitor of cytokine production), and mutations of FOXP3, an essential regulatory factor for the regulatory T cells (Tregs) development. Development of Hashimoto's disease was associated with mutation of the gene for TNF-α (stimulator of the IFN-γ production), causing its higher concentration. Existential (endogenous environmental) Sex A study of healthy Danish twins divided into three groups (monozygotic and dizygotic same sex, and opposite sex twin pairs) estimated that genetic contribution to thyroid peroxidase antibodies susceptibility was 61% in males and 72% in females, and contribution to thyroglobulin antibodies susceptibility was 39% in males and 75% in females. The high female predominance in thyroid autoimmunity may be associated with the X chromosome. It contains sex and immune-related genes responsible for immune tolerance. A higher incidence of thyroid autoimmunity was reported in patients with a higher rate of X-chromosome monosomy in peripheral white blood cells. Another potential mechanism might be skewed X-chromosome inactivation. Environmental Medications Certain medications or drugs have been associated with altering and interfering with thyroid function. There are two main mechanisms of interference: Estrogen, tamoxifen, heroin, methadone, clofibrate, 5-fluorouracil, mitotane, and perphenazine all increase thyroid binding globulin (TBG) concentration. Thyroid autoantibodies are found to be more prevalent in geographical areas after increasing iodine levels. by creating new iodine-containing epitopes or exposing cryptic epitopes. • Via thyrocyte damage: Iodine exposure has been shown to increase the level of reactive oxygen species. They enhance the expression of the intracellular adhesion molecule-1 on the thyrocytes, which could attract the immunocompetent cells into the thyroid gland. Addison disease, Sjogren's disease, and rheumatoid arthritis. Autoimmune thyroiditis has also been seen in patients with autoimmune polyendocrine syndromes type 1 and 2. Chronic stress continues this mechanism and has been shown to increase the incidence of Hashimoto's and other autoimmune conditions. Viral Infections There is implication for several viral infections triggering the development of Hashimoto's thyroiditis such as Hepatitis C, Epstein-Barr, Herpes Simplex, and human parvovirus B19. There are several mechanisms through which viral infections can lead to disease development, including immune upregulation and molecular mimicry. Environmental Toxins and Pollutants There are multiple environmental factors that can lead to Hashimoto's such as decreased temperature and sunlight, chemical pollutants, heavy metals and radiation. Other Other environmental factors include selenium deficiency, toxins, dietary factors, radiation exposure, and gut dysbiosis. == Mechanism ==

The pathophysiology of autoimmune thyroiditis is not well-understood. However, once the disease is established, its core processes have been observed: Hashimoto's thyroiditis is a T-lymphocyte-mediated attack on the thyroid gland. Gross morphological changes within the thyroid are seen in the general enlargement, which is far more locally nodular and irregular than more diffuse patterns (such as that of hyperthyroidism). While the capsule is intact and the gland itself is still distinct from surrounding tissue, microscopic examination can provide a more revealing indication of the level of damage. Hypothyroidism is caused by replacement of follicular cells with parenchymatous tissue. Partial regeneration of the thyroid tissue can occur, but this has not been observed to normalise hormonal levels. Pathology Gross pathology of a thyroid with autoimmune thyroiditis may show a symmetrically enlarged thyroid. It is often paler in color, in comparison to normal thyroid tissue, which is reddish-brown. Microscopic examination (histology) will show lymphocytes (including plasma B-cells) diffusely infiltrating the parenchyma. The lymphocytes are predominately T-lymphocytes with a representation of both CD4+ and CD8+ cells. The plasma cells are polyclonal, with present germinal centers resembling the structure of a lymph node (also called secondary lymphoid follicles, not to be confused with the normally present colloid-filled follicles that constitute the thyroid). In late stages of the disease, the thyroid may be atrophic. Colloid-filled follicles shrink, and the cuboidal cells that usually line the follicles become Hürthle cells. Fibrous tissue may be found throughout the affected thyroid as well. Severe thyroid atrophy presents often with denser fibrotic bands of collagen that remain within the confines of the thyroid capsule. Generally, pathological findings of the thyroid are related to the amount of remaining thyroid function – the more infiltration and fibrosis, the less likely a patient will have normal thyroid function. A rare but serious complication is thyroid lymphoma, generally the B-cell type, non-Hodgkin lymphoma. == Diagnosis ==

Tests Physical exam Physicians will often start by assessing reported symptoms and performing a thorough physical exam, including a neck exam. There may be circulating antibodies before the onset of any symptoms. Biotin can cause this test to read "falsely low". with "a variation in TSH by a mean of between 0.95 mIU/mL to 2.0 mIU/mL". Hypothyroidism is diagnosed more often in samples taken soon after waking. T3 or T4 levels test These tests detect levels of two thyroid hormones: Thyroxine (T4) and Tri-iodothyronine (T3). Low levels of these hormones (hypothyroidism) may indicate autoimmune damage to the thyroid due to Hashimoto's, while elevated levels may indicate an attack of destructive thyrotoxicosis. as Free T3 immunoassay tests are less reliable at detecting low levels of thyroid hormone, and they are more susceptible to interference. LC-MSMS assays are rarer, but they are "highly specific, sensitive, precise, and can detect hormones found in low concentrations". Muscle biopsy Muscle biopsy is not necessary for diagnosis of myopathy due to hypothyroid muscle fibre changes, however it may reveal confirmatory features. == Treatment ==

There is no cure for Hashimoto's Thyroiditis. There is currently no known way to stop auto-immune lymphocytes infiltrating the thyroid or to stimulate regeneration of thyroid tissue. Levothyroxine has the benefits of a long half-life leading to stable thyroid hormone levels, ease of monitoring, and efficacy record, Some patients elect combination therapy with both levothyroxine and liothyronine (which is identical in molecular structure to tri-iodothyronine) however studies of combination therapy are limited, Side Effects Side effects of thyroid replacement therapy are associated with "inadequate or excessive doses". When treatment is first initiated, TSH levels may be monitored as often as every 6–8 weeks. Liothyronine can suppress TSH to a greater extent than levothyroxine. Short-acting Liothyronine's short half-life can result in large fluctuations of free T3 Patients may have to adjust their dosage several times over the course of the disease. Endogenous thyroid hormone levels may fluctuate, particularly early in the disease. Patients may sometimes develop hyperthyroidism, even after long-term treatment. Persistent symptoms Multiple studies have demonstrated persistent symptoms in Hashimoto's patients with normal thyroid hormone levels (euthyroid) Several different hypothesised causes are discussed in the medical literature: Although both molecules can have biological effects, thyroxine (T4) is considered the "storage form" of thyroid hormone with much less effect, while tri-iodothyronine (T3) is considered the active form used by body tissues. Thus, the body must convert thyroxine into triiodothyronine. Adequate conversion requires sufficient levels of the micronutrients zinc, selenium, and possibly vitamin A. Conversion rates may decline with age. Since deiodinase type 2 is necessary for T4 to T3 conversion in some peripheral tissues, "patients with DIO2 gene polymorphisms may have variable peripheral T3 availability", leading to localised hypothyroidism in some tissues. As standard immunoassay tests can overestimate blood T4 and T3 levels, Ultrafiltration LC-MSMS T4 and T3 tests may help to identify patients who would benefit from additional T3. or "the inflammatory nature of [...] persistently increased circulating cytokine levels". A systematic review and meta-analysis of selenium trials found that while selenium reduces TPO antibodies, there was a lack of evidence of effects on "disease remission, progression, lowered levothyroxine dose or improved quality of life". especially in comparison to use of myo-inositol and Vitamin D. Selenium, and metformin can reduce thyroid peroxidase antibodies. There is preliminary evidence that levothyroxine, aloe vera juice and black cumin seed may reduce thyroid peroxidase antibodies. Metformin can reduce thyroglobulin antibodies.. Surgery One study found surgical thyroid removal can substantially reduce anti-thyroid antibody levels, but post-operative complications were higher than expected: Other Zinc may increase free T3 levels. While soy isoflavones have the potential to theoretically affect T3 and T4 production, studies in those with sufficient iodine find no effect. == Prognosis ==

Overt, symptomatic thyroid dysfunction is the most common complication, with about 5% of people with subclinical hypothyroidism and chronic autoimmune thyroiditis progressing to thyroid failure every year. Transient periods of thyrotoxicosis (over-activity of the thyroid) sometimes occur, and rarely the illness may progress to full hyperthyroid Graves' disease with active orbitopathy (bulging, inflamed eyes). Rare cases of fibrous autoimmune thyroiditis present with severe shortness of breath and difficulty swallowing, resembling aggressive thyroid tumors, but such symptoms always improve with surgery or corticosteroid therapy. Although primary thyroid B-cell lymphoma affects fewer than one in 1000 persons, it is more likely to affect those with long-standing autoimmune thyroiditis, Myopathy as a result of muscle fibre changes due to thyroid hormone deficiency may take months or years of thyroid hormone treatment to resolve. Anti-thyroid antibodies Thyroid peroxidase antibodies typically (but not always) decline in patients treated with levothyroxine, One study of patients treated with levothyroxine observed that 35 out of 38 patients (92%) had declines in thyroid peroxidase antibody levels over five years, lowering by 70% on average. 6 of the 38 patients (16%) had thyroid peroxidase antibody levels return to normal. However, of children who develop anti-thyroid antibodies and hypothyroidism, up to 50% are later observed to have normal antibodies and thyroid hormone levels. == Epidemiology ==

Hashimoto's Disease is estimated to affect 2% of the world's population. About 1.0 to 1.5 in 1000 people have this disease at any time. Other research suggests the difference in prevalence amongst genders is due to the effects of sex hormones. It is the most common cause of hypothyroidism in areas of sufficient iodine. Iodine deficiency disorder is combated using an increase in iodine in a person's diet. When a dramatic change occurs in a person's diet, they become more at risk of developing hypothyroidism and other thyroid disorders. Treating iodine deficiency disorder with high salt intakes should be done carefully and cautiously, as the risk for Hashimoto's may increase. Geographic trends of hypothyroidism vary across the world as different places have different ways of defining the disease and reporting cases. Populations that are spread out or defined poorly may skew data in unexpected ways. Hashimoto's thyroiditis disorder is thought to be the most common cause of primary hypothyroidism in North America. Incidence peaks in the fifth decade of life, but patients are usually diagnosed between age 30–50. It has been shown that the prevalence of positive tests for thyroid antibodies increases with age, "with a frequency as high as 33 percent in women 70 years old or older". In the US, the African-American population experiences it less commonly but has greater associated mortality. Autoimmune diseases Those who already have an autoimmune disease are at greater risk of developing Hashimoto's, as the diseases generally coexist with each other. See Causes > Comorbidities, above. Secular trends The secular trends of hypothyroidism reveal how the disease has changed over time, given changes in technology and treatment options. Even though ultrasound technology and treatment options have improved, the incidence of hypothyroidism has increased according to data focused on the US and Europe. Between 1993 and 2001, the disease was found to vary between 3.9 and 4.89 per 1000 women. Between 1994 and 2001, the disease increased from 0.65 to 1.01 per 1000 men. == History ==

Also known as Hashimoto's disease, Hashimoto's thyroiditis is named after Japanese physician Hakaru Hashimoto (1881−1934) of the medical school at Kyushu University, who first described the symptoms of persons with struma lymphomatosa, an intense infiltration of lymphocytes within the thyroid, in 1912 in the German journal called . This paper was made up of 30 pages and 5 illustrations all describing the histological changes in the thyroid tissue. Furthermore, all results in his first study were collected from four women. These results explained the pathological characteristics observed in these women especially the infiltration of lymphocyte and plasma cells as well as the formation of lymphoid follicles with germinal centers, fibrosis, degenerated thyroid epithelial cells and leukocytes in the lumen. == Pregnancy ==

Conception It is recommended that hypothyroidism be treated with levothyroxine before conception, to prevent adverse effects on the course of the pregnancy and the development of the child. Universal screening for thyroid diseases during pregnancy is controversial, however, one study "supports the potential benefit of universal screening". Pregnant women may have antithyroid antibodies (5%–14% of pregnancies The presence of antibodies is also associated with "a 2 to 4-fold increase in the risk of recurrent miscarriages, and 2 to 3-fold increased risk of preterm birth", however the reason why is unclear. Thyroid peroxidase antibodies are speculated to indicate other autoimmune processes against the placental-fetal unit. Immune changes during pregnancy Hormonal changes and trophoblast expression of key immunomodulatory molecules lead to immunosuppression and fetal tolerance. The main players in the regulation of the immune response are Tregs. Both cell-mediated and humoral immune responses are attenuated, resulting in immune tolerance and suppression of autoimmunity. It has been reported that during pregnancy, levels of thyroid peroxidase and thyroglobulin antibodies decrease. After giving birth, Tregs rapidly decrease, and immune responses are re-established. It may lead to the occurrence or aggravation of autoimmune thyroid disease. In up to 50% of females with thyroid peroxidase antibodies in the early pregnancy, thyroid autoimmunity in the postpartum period exacerbates in the form of postpartum thyroiditis. Higher secretion of IFN-γ and IL-4, and lower plasma cortisol concentration during pregnancy has been reported in females with postpartum thyroiditis than in healthy females. It indicates that weaker immunosuppression during pregnancy could contribute to postpartum thyroid dysfunction. Fetal microchimerism Several years after the delivery, the chimeric male cells can be detected in the maternal peripheral blood, thyroid, lung, skin, or lymph nodes. The fetal immune cells in the maternal thyroid gland may become activated and act as a trigger that initiates or exacerbates the autoimmune thyroid disease. In Hashimoto's disease patients, fetal microchimeric cells were detected in the thyroid in significantly higher numbers than in healthy females. == Other animals ==

Hashimoto's disease is known to occur in chickens, rats, mice, dogs, and marmosets, but Graves' disease does not. == See also ==