Hashimoto's thyroiditis

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Hashimoto's thyroiditis
Other namesChronic lymphocytic thyroiditis, autoimmune thyroiditis, struma lymphomatosa, Hashimoto's disease
Hashimoto thyroiditis - alt -- very low mag.jpg
A micrograph of the thyroid of someone with Hashimoto's thyroiditis
Specialty Endocrinology
Symptoms Weight gain, feeling tired, constipation, joint and muscle pain, cold intolerance, dry skin, hair loss, slowed heart rate [1]
Complications Thyroid lymphoma. [2]
Usual onset30–50 years old [3] [4]
Causes Genetic and environmental factors. [5]
Risk factors Family history, another autoimmune disease [3]
Diagnostic method TSH, T4, anti-thyroid autoantibodies, ultrasound [3]
Differential diagnosis Graves' disease, nontoxic nodular goiter [6]
Treatment Levothyroxine, surgery [3] [6]
Frequency2% at some point [5]

Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis, Hashimoto's disease, and autoimmune thyroiditis is an autoimmune disease in which the thyroid gland is gradually destroyed. [7] [1]

Contents

Early on, symptoms may not be noticed. [3] Over time, the thyroid may enlarge, forming a painless goiter. [3] Most people eventually develop hypothyroidism with accompanying weight gain, fatigue, constipation, hair loss, and general pains. [1] After many years the thyroid typically shrinks in size. [3] Potential complications include thyroid lymphoma. [2] Further complications of hypothyroidism can include high cholesterol, heart disease, heart failure, high blood pressure, myxedema, and potential problems in pregnancy. [1]

Hashimoto's thyroiditis is thought to be due to a combination of genetic and environmental factors. [5] [8] Risk factors include a family history of the condition and having another autoimmune disease. [3] Diagnosis is confirmed with blood tests for TSH, T4, antithyroid autoantibodies, and/or ultrasound. [3] Other conditions that can produce similar symptoms include Graves' disease and nontoxic nodular goiter. [6]

Hashimoto's is typically not treated unless there is hypothyroidism, or the presence of an enlarged gland (goitre), when it may be treated with levothyroxine. [6] [3] Those affected should avoid eating large amounts of iodine; however, sufficient iodine is required especially during pregnancy. [3] Surgery is rarely required to treat the goiter. [6]

Hashimoto's thyroiditis has a global prevalence of 7.5%, and varies greatly by region. [9] The highest rate is in Africa, and the lowest in Asia. [9] In the US white people are affected more often than black. It is more common in low to middle income groups. Women are more susceptible with a 17.5% rate of prevalence compared to 6% in men. [9] It is the most common cause of hypothyroidism in developed countries. [10] It typically begins between the ages of 30 and 50. [3] [4] Rates of the disease have increased. [9] It was first described by the Japanese physician Hakaru Hashimoto in 1912. [11] Studies in 1956 discovered that it was an autoimmune disorder. [12]

Signs and symptoms

Systemic manifestations of hypothyroidism Signs and symptoms of hypothyroidism.png
Systemic manifestations of hypothyroidism

Signs

Depiction of a goiter Hypothyroidism.jpg
Depiction of a goiter

Early stages of autoimmune thyroiditis may have a normal physical exam with or without a goiter. [13] A goiter is a diffuse, often symmetric, swelling of the thyroid gland visible in the anterior neck that may develop. [13] The thyroid gland may become firm, large, and lobulated in Hashimoto's thyroiditis, but changes in the thyroid can also be nonpalpable. [14] Enlargement of the thyroid is due to lymphocytic infiltration [15] and fibrosis, rather than tissue hypertrophy.

While their role in the initial destruction of the follicles is unclear, antibodies against thyroid peroxidase or thyroglobulin are relevant, as they serve as markers for detecting the disease and its severity. [16] They are thought to be the secondary products of the T cell-mediated destruction of the gland. [5]

As lymphocytic infiltration progresses, patients may exhibit signs of hypothyroidism in multiple bodily systems, including, but not limited to, a larger goiter, weight gain, cold intolerance, fatigue, myxedema, constipation, menstrual disturbances, pale or dry skin, and dry, brittle hair, depression, and ataxia. [13] [10] Extended thyroid hormone deficiency may lead to muscle fibre changes, with fast-twitching type II being replaced by slow-twitching type-I fibers, resulting in muscle weakness, muscle pain, stiffness, and rarely, pseudohypertrophy. [17]

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. [10]

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. [18]

Graves disease may occur before or after the development of autoimmune thyroiditis. [19]

Symptoms

Many symptoms are attributed to the development of Hashimoto's thyroiditis. The most common symptoms include: fatigue, weight gain, pale or puffy face, feeling cold, joint and muscle pain, constipation, dry and thinning hair, heavy menstrual flow or irregular periods, depression, panic disorder, a slowed heart rate, problems getting pregnant, miscarriages, [20] and myopathy. [17]

Some patients in the early stage of the disease may experience symptoms of hyperthyroidism due to the release of thyroid hormones from intermittent thyroid destruction. [10] [21]

While most symptoms are attributed to hypothyroidism, several studies have observed symptoms in hashimotos patients with normal thyroid hormone levels. [5] [22] [23] [15] [24] These symptoms may include lower quality of life, "digestive system (abdominal distension, constipation and diarrhea), endocrine system (chilliness, gain weight and facial edema), neuropsychiatric system (forgetfulness, anxiety, depressed, fatigue, insomnia, irritability, and indifferent) and mucocutaneous system (dry skin, pruritus, and hair loss)." [25]

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). [26] [8]

Genetics

Thyroid autoimmunity can be familial. [27] Many patients report a family history of autoimmune thyroiditis or Graves' disease. [13] The strong genetic component is borne out in studies on monozygotic twins, [10] with a concordance of 38–55%, with an even higher concordance of circulating thyroid antibodies not in relation to clinical presentation (up to 80% in monozygotic twins). Neither result was seen to a similar degree in dizygotic twins, offering strong favour for high genetic aetiology. [28]

The genes implicated vary in different ethnic groups [29] and the impact of these genes on the disease differs significantly among people from different ethnic groups. A gene that has a large effect in one ethnic group's risk of developing hashimoto's thyroiditis might have a much smaller effect in another ethnic group. [28]

The incidence of autoimmune thyroid disorders is increased in people with chromosomal disorders, including Turner, Down, and Klinefelter syndromes. [26]

HLA genes

The first gene locus associated with autoimmune thyroid disease was the major histocompatibility complex (MHC) region on chromosome 6p21. It encodes human leukocyte antigens (HLAs). Specific HLA alleles have a higher affinity to autoantigenic thyroidal peptides and can contribute to autoimmune thyroid disease development. Specifically, in Hashimoto's disease, aberrant expression of HLA II on thyrocytes has been demonstrated. They can present thyroid autoantigens and initiate autoimmune thyroid disease. [29] 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. [30] [31]

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. [32] 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. [33] CTLA-4 was confirmed as the main locus for thyroid autoantibodies. [34]

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. [35]

IFN-γ promotes cell-mediated cytotoxicity against thyroid mutations causing increased production of IFN-γ were associated with the severity of hypothyroidism. [36] Severe hypothyroidism is associated with mutations leading to lower production of IL-4 (Th2 cytokine suppressing cell-mediated autoimmunity), [37] lower secretion of TGF-β (inhibitor of cytokine production), [38] and mutations of FOXP3, an essential regulatory factor for the regulatory T cells (Tregs) development. [39] 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. [40]

Existential

Sex

Study of healthy Danish twins divided to 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. [41]

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. [42] A higher incidence of thyroid autoimmunity was reported in patients with a higher rate of X-chromosome monosomy in peripheral white blood cells. [43]

X-chromosome inactivation

Another potential mechanism might be skewed X-chromosome inactivation, [5] leading to the escape of X-linked self-antigens from presentation in the thymus and loss of T-cell tolerance.[ citation needed ]

Pregnancy

Two or more births are a risk factor for developing autoimmune hypothyroidism in pre-menopausal women. [44]

Environmental

Medications

Certain medications or drugs have been associated with altering and interfering with thyroid function. Of these drugs, there are two main mechanisms of interference that they can have. [45]

One of the mechanisms of interference is when a drug alters thyroid hormone serum transfer proteins. [45] Estrogen, tamoxifen, heroin, methadone, clofibrate, 5-flurouracile, mitotane, and perphenazine all increase thyroid binding globulin (TBG) concentration. [45] Androgens, anabolic steroids such as danazol, glucocorticoids, and slow release nicotinic acid all decrease TBG concentrations. Furosemide, fenoflenac, mefenamic acid, salicylates, phenytoin, diazepam, sulphonylureas, free fatty acids, and heparin all interfere with thyroid hormone binding to TBG and/or transthyretin. [45]

The other mechanism that medications can utilize to interfere with thyroid function would be to alter extra-thryoidal metabolism of thyroid hormone. Propylthiouracil, glucocorticoids, propranolol, iondinated contrast agents, amiodarone, and clomipramine all inhibit conversion of T4 and T3. [45] Phenobarbital, rifampin, phenytoin and carbamazepine all increase hepatic metabolism. [45] Finally, cholestryamine, colestipol, aluminium hydroxide, ferrous sulphate, and sucralfate are all drugs that decrease T4 absorption or enhance excretion. [45]

Iodine

Excessive iodine intake is a well-established environmental factor for triggering thyroid autoimmunity. Thyroid autoantibodies are found to be more prevalent in geographical areas with a higher dietary iodine levels. Several mechanisms by which iodine may promote thyroid autoimmunity have been proposed. Iodine exposure leads to higher iodination of thyroglobulin, increasing its immunogenicity by creating new iodine-containing epitopes or exposing cryptic epitopes. It may facilitate presentation by APC, enhance the binding affinity of the T-cell receptor, and activate specific T-cells. [46]

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 thyroid follicular cells, which could attract the immunocompetent cells into the thyroid gland. [47]

Iodine is toxic to thyrocytes since highly reactive oxygen species may bind to membrane lipids and proteins. It causes thyrocyte damage and the release of autoantigens. Iodine also promotes follicular cell apoptosis and has an influence on immune cells (augmented maturation of dendritic cells, increased number of T cells, stimulated B-cell immunoglobulin production). [48] [49]

Data from the Danish Investigation of Iodine Intake and Thyroid Disease shows that within two cohorts (males, females) with moderate and mild iodine deficiency, the levels of both thyroid peroxidase and thyroglobulin antibodies are higher in females, and prevalence rates of both antibodies increase with age. [50]

Comorbidities

Comorbid autoimmune diseases are a risk factor for developing Hashimoto's thyroiditis, and the opposite is also true. [3] Another thyroid disease closely associated with Hashimoto's thyroiditis is Graves' disease. [19] Autoimmune diseases affecting other organs most commonly associated with Hashimoto's thyroiditis include celiac disease, type 1 diabetes, vitiligo, alopecia, [51] Addison disease, Sjogren's syndrome, and rheumatoid arthritis. [13] [18] Autoimmune thyroiditis has also been seen in patients with autoimmune polyendocrine syndromes type 1 and 2. [19]

Other

Other environmental factors including selenium deficiency, [8] infectious diseases (e.g., hepatitis C virus, rubella virus, possibly Covid-19), [52] [53] [54] toxins, [5] dietary factors, [19] radiation exposure, [5] and gut microbiome, have been implicated in the development of autoimmune thyroid disease in genetically predisposed individuals.

Mechanism

The pathophysiology of autoimmune thyroiditis is not well understood. [5] 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. [15] "Th1 cells activate macrophages and cytotoxic lymphocytes which directly destroy thyroid follicular cells" and "Th2 cells lead to an excessive stimulation and production of B cells and plasmatic cells, which produce antibodies against the thyroid antigens, leading to thyroiditis." [55] Lymphocytes produce antibodies targeting three different thyroid proteins: Thyroid peroxidase Antibodies (TPOAb), Thyroglobulin Antibodies (TgAb), and Thyroid stimulating hormone receptor Antibodies (TRAb). [27] The two antibodies most commonly implicated in autoimmune thyroiditis are antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb). [5] They are hypothesized to develop as a result of thyroid damage, where T-lymphocytes are sensitized to residual thyroid peroxidase and thyroglobulin, rather than as the cause of thyroid damage. [5] However, they may exacerbate further thyroid destruction by binding the complement system and triggering apoptosis of thyroid cells. [5]

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. [56]

Hypothyroidism is caused by replacement of follicular cells with parenchymatous tissue. [55]

Partial regeneration of the thyroid tissue can occur. [57] Regenerative processes have not been observed to normalise thyroid hormone deficiency in adults. [57]

Pathology

Marked lympocytic infiltration (purple areas) of the thyroid gland in a patient with chronic autoimmune thyroiditis Hashimoto's thyroiditis, HE 3.jpg
Marked lympocytic infiltration (purple areas) of the thyroid gland in a patient with chronic autoimmune thyroiditis
High powered magnification showing lymphocytic infiltration of the thyroid gland in autoimmune thyroiditis Hashimoto thyroiditis -- high mag.jpg
High powered magnification showing lymphocytic infiltration of the thyroid gland in autoimmune thyroiditis

Gross pathology of a thyroid with autoimmune thyroiditis may show an symmetrically enlarged thyroid. [5] It is often paler in color, in comparison to normal thyroid tissue which is reddish-brown. [5] Microscopic examination will show infiltration of lymphocytes and plasma cells. The lymphocytes are predominately T-lymphocytes with a representation of both CD4 positive and CD8 positive cells. [5] The plasma cells are polyclonal, with present germinal centers resembling the structure of a lymph node. [5] Fibrous tissue may be found throughout the affected thyroid as well. [5] Generally, pathological findings of the thyroid are related to the amount of existing thyroid function - the more infiltration and fibrosis, the less likely a patient will have normal thyroid function. [5] In late stages of the disease, the thyroid may be atrophic. [10]

Histologically, the hypersensitivity is seen as diffuse parenchymal infiltration by lymphocytes, particularly plasma B-cells, which can often be seen as secondary lymphoid follicles (germinal centers, not to be confused with the normally present colloid-filled follicles that constitute the thyroid). Atrophy of the colloid bodies is lined by Hürthle cells, cells with intensely eosinophilic, granular cytoplasm, a metaplasia from the normal cuboidal cells that constitute the lining of the thyroid follicles. Severe thyroid atrophy presents often with denser fibrotic bands of collagen that remains within the confines of the thyroid capsule. [56]

A rare but serious complication is thyroid lymphoma, generally the B-cell type, non-Hodgkin lymphoma. [27]

Diagnosis

Ultrasound imaging of the thyroid gland (right lobe longitudinal) in a person with Hashimoto thyroiditis Hashimoto-Thyreoiditis.JPG
Ultrasound imaging of the thyroid gland (right lobe longitudinal) in a person with Hashimoto thyroiditis

Tests

Some or all of the following tests may be performed, in any order:

Physical exam

Physicians will often start by assessing reported symptoms and performing a thorough physical exam, including a neck exam. [10] On gross examination, a hard goiter that is not painful to the touch often presents; [56] other symptoms seen with hypothyroidism, such as periorbital myxedema, depend on the current state of progression of the response, especially given the usually gradual development of clinically relevant hypothyroidism.

Antithyroid antibodies tests

Tests for antibodies against thyroid peroxidase, thyroglobulin, and thyrotropin receptors can detect autoimmune processes against the thyroid. However, seronegative (without circulating autoantibodies) thyroiditis is also possible. [58] There may be circulating antibodies before the onset any symptoms. [10]

Ultrasound

Ultrasound imaging of the thyroid showing Hashimoto's thyroiditis Hashimoto Thyroiditis.jpg
Ultrasound imaging of the thyroid showing Hashimoto's thyroiditis

An ultrasound may be useful in detecting Hashimoto thyroiditis, especially in those with seronegative thyroiditis, due to key features detected in the ultrasound of a person with Hashimoto's thyroiditis, such as "echogenicity, heterogeneity, hypervascularity, and presence of small cysts." [15]

When patients have normal laboratory values but symptoms of autoimmune thyroiditis, ultrasound plays a role in diagnosis. [18] Images obtained with ultrasound can evaluate the size of the thyroid and further support the diagnosis of autoimmune thyroiditis, reveal the presence of nodules, or provide clues to the diagnosis of other thyroid conditions. [18]

Nuclear medicine

Nuclear imaging showing thyroid uptake can also be helpful in diagnosing thyroid function

TSH plasma serum concentration test [59]

To detect if the pituitary is inciting an underperforming thyroid to produce more thyroid hormone. TSH secretion from the anterior pituitary increases in response to decreased serum thyroid hormones. If elevated, it signifies hypothyroidism. [18] The elevation is usually a marked increase over the normal range and is generally greater than 20 mg/dl. [13] "TSH is the initial test of thyroid function as it is more sensitive than free T4 to alterations of thyroid status in patients with primary thyroid disease." [60]

Time of day can affect the results of this test; TSH peaks early in the morning and slumps in the late afternoon to early evening, [61] with "a variation in TSH by a mean of between 0.95 mIU/mL to 2.0 mIU/mL". [62] Hypothyroidism is diagnosed more often in samples taken soon after waking. [63]

T3 or T4 levels test

To detect a lack of thyroid hormones (hypothyroidism), or excess of thyroid hormones (hyperthyroidism). The two thyroid hormones are T4 and T3. Typically, Free T4 is the preferred thyroid hormone test for hypothyroidism, [59] as Free T3 immunoassay tests are unreliable at detecting hypothyroidism, [64] as they are more susceptible to interference. [59] Free T4 levels will usually be lowered, but sometimes might be normal. [65]

T4 and T3 can be measured by their total amount, or free amount. As the free amount reflects the amount available to body tissues, "The measurement of FT3 and FT4 are the most clinically relevant for the evaluation of thyroid disorders". [66] However, immunoassay tests of FT4 and FT3 may overestimate concentrations, particularly at low thyroid hormone levels, which is why results are typically read in conjunction with TSH, a more sensitive measure. [66] LC-MSMS assays are rarer, but they are "highly specific, sensitive, precise, and can detect hormones found in low concentrations." [66]

Muscle Biopsy

Muscle biopsy is not necessary for diagnosis of myopathy due to hypothyroid muscle fibre changes, however it may reveal confirmatory features. [17]

Misdiagnosis

Given the relatively nonspecific symptoms of initial hypothyroidism, Hashimoto's thyroiditis is often misdiagnosed as depression, cyclothymia, premenstrual syndrome, chronic fatigue syndrome, fibromyalgia, and less frequently, as erectile dysfunction or an anxiety disorder.

Treatment

There is no cure for Hashimoto's Thyroiditis. [67] There is currently no known way to stop auto-immune lymphocytes infiltrating the thyroid [25] [5] or to stimulate regeneration of thyroid tissue. [5] However, the condition can be managed. [67]

Molecular Structure of Thyroxine, Levothyroxine, and Levothyroxine Sodium Thyroxine vs Levothyroxine vs Levothyroxine Sodium.png
Molecular Structure of Thyroxine, Levothyroxine, and Levothyroxine Sodium

Managing hormone levels

Hypothyroidism caused by Hashimoto's thyroiditis is treated with thyroid hormone replacement agents such as levothyroxine (T4), liothyronine (T3), or desiccated thyroid extract (T4+T3). A tablet taken once a day generally keeps the thyroid hormone levels normal. In most cases, the treatment needs to be taken for the rest of the person's life.

The standard of care is levothyroxine therapy, which is an oral medication identical in molecular structure to endogenous thyroxine. [5] Levothyroxine sodium has a sodium salt added to increase the gastrointestinal absorption of levothyroxine. [68] Levothyroxine is preferred over Liothyronine due to its long half-life [23] leading to stable thyroid hormone levels, [69] ease of monitoring, [69] excellent safety [69] [70] and efficacy record, [66] and usefulness in pregnancy as it can cross the fetal blood-brain barrier. [15]

Levothyroxine dosing to normalise TSH is based on the amount of residual endogenous thyroid function and the patient’s weight, particularly lean body mass. [15] Usually the dose prescribed ranges from 1.6 mcg/kg to 1.8 mcg/kg, but can be adjusted based upon each patient. [10] For example, the dose may be lowered for elderly patients or patients with certain cardiac conditions, but should be increased in pregnant patients. [10] It should be administered on a consistent schedule. [5] Levothyroxine may be dosed daily or weekly, however weekly dosing may be associated with higher TSH levels, elevated hormone levels, and transient "echocardiographic changes in some patients following 2-4 h of thyroxine intake". [71] [72]

Some patients elect combination therapy with both levothyroxine and liothyronine, which is a synthetic T3, however studies of combination therapy are limited, [5] and five meta-analyses/reviews "suggested no clear advantage of the combination therapy." [15] However, subgroup analysis found that patients who remain the most symptomatic while taking levothyroxine may benefit from therapy containing liothyronine. [15]

Side effects of thyroid replacement therapy are associated with iatrogenic hyperthyroidism. [5] Symptoms to watch out for include, but are not limited to, anxiety, tremor, weight loss, heat sensitivity, diarrhea, and shortness of breath. More worrisome symptoms include atrial fibrillation and bone density loss. [5]

Monitoring

Thyroid Stimulating Hormone (TSH) is the laboratory value of choice for monitoring response to treatment with levothyroxine. [65] When treatment is first initiated, TSH levels may be monitored as often as a frequency of every 6–8 weeks. [65] Each time the dose is adjusted, TSH levels may be measured at that frequency until the correct dose is determined. [65] Once titrated to a proper dose, TSH levels will be monitored yearly. [65] TSH levels may be recommended to be kept under 3.0 mIU/l. [73]

Monitoring liothyronine treatment or combination treatment can be challenging. [69] [74] Liothyronine can suppress TSH to a greater extent than levothyroxine. [75] Short-acting Liothyronine's short half-life can result in large fluctuations of free T3 [74] over the course of 24 hours. [76]

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. [77] This can be due to a number of factors including autoimmune attacks on the thyroid resulting in rises in thyroid hormone levels (as thyroid hormones leak out of the damaged tissues). [21] After the attack subsides, the resulting destruction caused by ongoing attacks progressively lowers thyroid hormone levels.

Reverse T3

Measuring reverse triiodothyronine (rT3) is often mentioned in the lay press as a possible marker to inform T4 or T3 therapy, "however, there is currently no evidence to support this application" as of 2023. [59]

It is unlikely that rT3 causes hypothyroid symptoms by out-competing T3 for receptors: "It is cited in the lay press that rT3 can act as a competitor of T3 action and as such is a potential cause of hypothyroid symptoms despite adequate serum fT3 concentration. Given the binding affinity of rT3 is at least 200-fold weaker than that of T3 for the thyroid hormone nuclear hormone receptors, this is improbable." [78]

It is also unlikely that rT3 causes poor T4 to T3 conversion: "rT3 has been shown in vivo to act as a competitive inhibitor of DIO1, so there is potential for rT3 to prevent DIO-mediated T4 to T3 conversion; however, this too is also thought unlikely at physiological hormone concentrations." [78]

Persistent Symptoms

Multiple studies have demonstrated persistent symptoms in euthyroid hashimotos patients [79] [15] [23] [80] and an estimated 10%-15% of patients treated with levothyroxine monotherapy are dissatisfied due to persistent symptoms of hypothyroidism. [81] [22]

Several different possible causes and hypothesised causes are discussed in the literature: [23] [15]

Inadequate T4 to T3 conversion

Although both molecules can have biological effects, Levothyroxine (T4) is considered the "storage form" of thyroid hormone, while Liothyronine (T3) is considered the active form used by body tissues. [82] [83] The body must convert Levothyroxine into Liothyronine in order to have biological effects. [83] Liothyronine is produced primarily by conversion in the liver, kidney, skeletal muscle and pituitary gland. [84] Sufficient levels of the micronutrients zinc, [85] selenium, [8] iron, [86] and possibly vitamin A [87] are important for adequate conversion. Conversion rates may decline with age. [88] As "15% of patients receiving LT4 alone fail to achieve normal serum T3 levels", [69] Patients with impaired conversion and no nutrient deficiencies may be recommended combination therapy of both levothyroxine and liothyronine. [89] [90] As standard immunoassay tests can overestimate T4 and T3 levels, Ultrafiltration LC-MSMS T4 and T3 tests may help to identify patients who would benefit from additional T3. [66]

TSH may be an inadequate marker for monitoring

TSH may reflect the state of thyroid hormones in the pituitary, but not other body tissues. [91] "TSH is not a perfect marker; consequently, there[sic] standard LT4 treatment may not result in a truly biochemically euthyroid state." [23] "The definition of euthyroidism, and whether TSH is the best indicator of euthyroidism, continue to be debated." [81] Patients may express a preference for "low normal or below normal TSH values" [91] and/or T4 and T3 monitoring. The monitoring of other biomarkers that reflect the action of thyroid hormone on tissue levels has also been proposed. [15]

Inaccuracy of Free T3 and Free T4 Tests

As immunoassay Free T3 and Free T4 tests can overestimate levels, particularly at low thyroid hormone levels, hypothyroidism may be undertreated. [66] LC-MSMS tests may provide more reliable measures. [66]

Gene polymorphisms

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. [23] [91] [15] [8] "In such cases LT4 treatment alone may not be enough" [23] and patients may have improvement on combination therapy. [8] Thr92Ala DIO2 polymorphism is present in 12–36% of the population. [23]

Extra-thyroidal effects of autoimmunity

Multiple studies find that antibodies coincide with symptoms even in euthyroid patients, [5] [23] [25] however "the found association does not prove a causality". [23] Nevertheless, it is hypothesised that autoimmunity, whether via antibodies or some other autoimmune mechanism, may play some role in euthyroid symptoms. [23] [25] Hypothesised mechanisms include "positive TPO-Ab may result in cross-reaction with other tissues, as activated TPO-Ab-producing lymphocytes may leave the thyroid gland and invade other distant tissue, contributing to extrathyroidal symptoms and inflammation." [23] [92] No treatment currently exists for hashimotos autoimmunity, although observed wellbeing improvements after surgical thyroid removal are hypothesised to be due to removing the autoimmune stimulus. [15] [92]

Other influences on thyroid hormone levels

Zinc may increase free T3 levels. [93] A small pilot study found Ashwagandha Root may increase T3 and T4 levels, however, it has a lack of strong evidence to confirm this benefit and has a potential to cause adrenal insufficiency. [93]

Improving wellbeing

A systemic review of three studies found selenium may improve wellbeing and/or mood; [94] one study found it did not improve wellbeing. [95]

One study demonstrated surgical thyroid removal may substantially improve fatigue and wellbeing, [5] [96] see Surgery considerations.

Reducing antibodies

The benefits of reducing antithyroid antibodies in Hashimoto's are not established. [15] While studies find that antibodies coincide with symptoms even in euthyroid patients, [5] [23] [25] and higher levels are associated with greater symptomatology, [5] "the found association does not prove a causality". [23] TPO antibody levels may correlate with the degree of lymphocyte infiltration of the thyroid. [97] [98] However, it is not shown that artificially reducing antibodies reduces symptomatology, lymphocytic infiltration or other inflammatory processes. A systemic 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". [8] Nevertheless, intervention studies frequently measure changes in antibody levels. [99]

Selenium, [100] [8] vitamin D, [101] and metformin [102] can reduce thyroid peroxidase antibodies. There is preliminary evidence that Levothyroxine, [103] [104] Aloe Vera Juice [105] and Black Cumin Seed [106] may reduce thyroid peroxidase antibodies. Metformin can reduce thyroglobulin antibodies. [102]

It is not established that a gluten-free diet can reduce antibodies when there is no comorbid coeliac disease. [107] [93] Gluten free diets have been shown in several studies to reduce antibodies, and in other studies to have no effect, however there were significant confounding issues in these studies, including not ruling out comorbid coeliac disease. [107]

One study found Surgical thyroid removal can substantially reduce anti-thyroid antibody levels, [5] see Surgery considerations.

Surgery considerations

Surgery is not the initial treatment of choice for autoimmune disease, and uncomplicated Hashimoto's thyroiditis is not an indication for thyroidectomy. [5] Patients generally may discuss surgery with their doctor if they are experiencing significant pressure symptoms, or cosmetic concerns, or have nodules present on ultrasound. [5] One well-conducted study of patients with troublesome general symptoms and with anti-thyroperoxidase (anti-TPO) levels greater than 1000 IU/ml (normal <100 IU/ml) showed that total thyroidectomy caused the symptoms to resolve and median anti-thyroid peroxidase levels to reduce from 2232 to 152 IU/mL, [5] [96] but there were post-operative complications in 14%. [92]

Other

As of 2022, there are "no studies demonstrating the efficacy of low-dose naltrexone in autoimmune thyroid disorders and there is no evidence to support its use." [93] and "There are no studies showing that the elimination of dairy in patients with autoimmune thyroid disease who do not have lactose intolerance is of any clinical benefit." [93] While soy isoflavones have the potential to theoretically affect T3 and T4 production, studies in euthyroid people with sufficient iodine find no effect. [93]

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, [108] as there is a 67- to 80-fold increased risk of developing primary thyroid lymphoma in patients with Hashimoto's thyroiditis. [109]

Myopathy as a result of muscle fibre changes due to thyroid hormone deficiency may take months [17] or years [110] of thyroid hormone treatment to resolve.

Anti-thyroid antibodies

Thyroid peroxidase antibodies are observed to decline in patients treated with levothyroxine, with decreases varying between 10% and 90% after a follow-up of 6 to 24 months. [111] 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. [111]

Children

Many children diagnosed with hashimoto's disease will experience the same progressive course of the disease that adults do. [112] However, of children who develop anti-thyroid antibodies and hypothyroidism, and up to 50% are later observed to have normal antibodies and thyroid hormone levels. [5] [113] [114] [112]

One case of true remission has been observed in a 12 year old girl. Her thyroid was observed via ultrasound to progress from early inflammation to severe end-stage Hashimoto's thyroiditis with hypothyroidism, and then return to "almost normal with only minimal features of inflammation" and euthyroidism. [115]

Epidemiology

Hashimoto's Disease is estimated to affect 2% of the world's population. [5] [28] About 1.0 to 1.5 in 1000 people have this disease at any time. [56]

Sex

Anyone may develop this disease, but it occurs between 8 and 15 times more often in women than in men. [5] Some research suggests a connection to the role of the placenta as an explanation for the sex difference. [116] The difference in prevalence amongst genders is due to the effects of sex hormones. [19]

High iodine consumption

Autoimmune thyroiditis has a higher prevalence in societies that have a higher intake of iodine in their diet, such as the United States and Japan, and among people who are genetically susceptible. [108] It is the most common cause of hypothyroidism in areas of sufficient iodine. [10] Also, the rate of lymphocytic infiltration increased in areas where the iodine intake was once low, but increased due to iodine supplementation. [27] [117]

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 iron deficiency disorder with high salt intakes should be done carefully and cautiously as risk for Hashimoto's may increase. [117]

Geography plays a large role in which regions have access to diets with low or high iodine. Iodine levels in both water and salt should be heavily monitored in order to protect at-risk populations from developing hypothyroidism. [118]

Geographic trends of hypothyroidism vary across the world as different places have different ways of defining disease and reporting cases. Populations that are spread out or defined poorly may skew data in unexpected ways. [28]

United States of America

Hashimoto's Thyroiditis may affect up to 5% of the United States' population. [119] Hashimoto's thyroiditis disorder is thought to be the most common cause of primary hypothyroidism in North America. [56]

Age

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." [27]

Hashimotos Thyroiditis can occur at any age, including children, [108] but more commonly appears in middle age, particularly for men. [120] Incidence peaks in the fifth decade of life, but patients are usually diagnosed between age 30–50. [18] [119] The highest prevalence from one study was found in the elderly members of the community. [121]

Race

The prevalence of Hashimoto's varies geographically. The highest rate is in Africa, and the lowest in Asia. [9] In the US, the African-American population experiences it less commonly but has greater associated mortality. [122] It is also less frequent in Asian populations. [123]

Autoimmune diseases

Those that already have an autoimmune disease are at greater risk of developing Hashimoto's as the diseases generally coexist with each other. [28] See Causes > Comorbidities, above.

The secular trends of hypothyroidism reveal how the disease has changed over the course of 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, per 1000 women, the disease was found varying between 3.9 and 4.89. Between 1994 and 2001, per 1000 men, the disease increased from 0.65 to 1.01. [121]

Changes in the definition of hypothyroidism and treatment options modify the incidence and prevalence of the disease overall. Treatment using levothyroxine is individualized, and therefore allows the disease to be more manageable with time but does not work as a cure for the disease. [28]

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, [124] 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 Archiv für Klinische Chirurgie . [4] [125] 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 lymphoid and plasma cells as well as the formation of lymphoid follicles with germinal centers, fibrosis, degenerated thyroid epithelial cells and leukocytes in the lumen. [4] He described these traits to be histologically similar to those of Mikulic's disease. As mentioned above, once he discovered these traits in this new disease, he named the disease struma lymphomatosa. This disease emphasized the lymphoid cell infiltration and formation of the lymphoid follicles with germinal centers, neither of which had ever been previously reported. [4]

Despite Dr. Hashimoto's discovery and publication, the disease was not recognized as distinct from Reidel's thyroiditis, which was a common disease at that time in Europe. Although many other articles were reported and published by other researchers, Hashimoto's struma lymphomatosa was only recognized as an early phase of Reidel's thyroiditis in the early 1900s. It was not until 1931 that the disease was recognized as a disease in its own right, when researchers Allen Graham et al. from Cleveland reported its symptoms and presentation in the same detailed manner as Hakaru. [4]

In 1956, Drs. Rose and Witebsky were able to demonstrate how immunization of certain rodents with extracts of other rodents' thyroid resembled the disease Hakaru and other researchers were trying to describe. [4] These doctors were also able to describe anti-thyroglobulin antibodies in blood serum samples from these same animals. [4]

Later on in the same year, researchers from the Middlesex Hospital in London were able to perform human experiments on patients who presented with similar symptoms. They purified anti-thyroglobulin antibody from their serum and were able to conclude that these sick patients had an immunological reaction to human thyroglobulin. [4] From this data, it was proposed that Hashimoto's struma could be an autoimmune disease of the thyroid gland.

"Following these discoveries, the concept of organ-specific autoimmune disease was established and HT recognized as one such disease." [4]

Following this recognition, the same researchers from Middlesex Hospital published an article in 1962 in The Lancet that included a portrait of Hakaru Hashimoto. [4] The disease became more well known from that moment, and Hashimoto's disease started to appear more frequently in textbooks. [126]

Pregnancy

Conception

It is recommended that hypothyroidism be treated with levothyoxine before conception, to prevent adverse effects on the course of the pregnancy, and on the development of the child. [15] In IVF, embryo transfer is improved when hypothyroidism is treated. [127]

Pregnancy

The Endocrine Society recommends screening in pregnant women who are considered high-risk for thyroid autoimmune disease. [128] Universal screening for thyroid diseases during pregnancy is controversial, however, one study "supports the potential benefit of universal screening". [129]

Pregnant women may have anti-thyroid antibodies (5%–14% of pregnancies [15] ), poor thyroid function resulting in hypothyroidism, or both. Each is associated with risks. [15]

Anti-thyroid antibodies in pregnancy

The presence of Thyroid Peroxidase antibodies at the outset of pregnancy are associated with a greater risk to the mother of hypothyroidism and thyroid impairment in the first year after delivery. [130]

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. [15]

Levothyroxine treatment in euthyroid women with thyroid autoimmunity does not significantly impact the relative risk of miscarriage and preterm delivery, or outcomes with live birth. "Therefore, no strong recommendations regarding the therapy in such scenarios could be made, but consideration on a case-by-case basis might be implemented." [15]

Hypothyroidism in pregnancy.

Women who have low thyroid function that has not been stabilized are at greater risk of complications for both parent and child. Risks to the mother include gestational hypertension including preeclampsia and eclampsia, gestational diabetes, placental abruption, and postpartum hemorrhage. [15] Risks to the infant include miscarriage, preterm delivery, low birth weight, neonatal respiratory distress, hydrocephalus, hypospadias, fetal death, infant intensive care unit admission, and neurodevelopmental delays (lower child IQ, language delay or global developmental delay). [129] [127] [15]

Successful pregnancy outcomes are improved when hypothyroidism is treated. [127] Levothyroxine treatment may be considered at lower TSH levels in pregnancy than in standard treatment. [15] Liothyronine does not cross the fetal blood-brain barrier, so liothyronine (T3) only or liothyronine + levothyroxine (T3 + T4) therapy is not indicated in pregnancy. [15]

Close cooperation between the endocrinologist and obstetrician benefits the woman and the infant. [129] [131] [132]

Immune changes during pregnancy

Hormonal changes and trophoblast expression of key immunomodulatory molecules lead to immunosuppression and fetal tolerance. Main players in 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. [133]

Postpartum

Postpartum thyroiditis can occur up to 1 year after delivery in healthy women and should be differentiated from Hashimoto's thyroiditis as it is treated differently. [134]

Thyroid peroxidase antibodies testing is recommended for women who have ever been pregnant regardless of pregnancy outcome. "[P]revious pregnancy plays a major role in development of autoimmune overt hypothyroidism in premenopausal women, and the number of previous pregnancies should be taken into account when evaluating the risk of hypothyroidism in a young women [sic]." [44]

After giving birth, Tregs rapidly decrease and immune responses are re-established. It may lead to the occurrence or aggravation of the autoimmune thyroid disease. [133] 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. [135] 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 the postpartum thyroid dysfunction. [136]

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 may initiate or exaggerate the autoimmune thyroid disease. In Hashimoto's disease patients, fetal microchimeric cells were detected in thyroid in significantly higher numbers than in healthy females. [137]

Other animals

Hashimoto's disease is known to occur in chickens, rats, mice, dogs, and marmosets, but Graves' disease does not. [138]

Pseudoscience

Pseudoscientific claims and "rogue practitioners" pose increasing risks to patients. [139]

"We have seen practitioners who proclaim themselves to be experts in hormonal therapy without any formal training and who often promote hormonal treatments without adequate endocrine evaluations. We have seen practitioners who make astonishing promises regarding the benefits of herbal, supplemental, and other unproven therapies that they themselves sell in their offices and/or online. And we have seen what we know to be frankly harmful and even dangerous products that contain animal whole organ (most commonly thyroid and/or adrenal) extracts or hormonal injections that produce highly elevated levels of sex hormones (especially testosterone) without any concern for short-term patient safety or longterm outcomes. And we have heard anecdotal stories from patients who visited these practitioners and had no beneficial results or frankly concerning on-treatment results at a surprisingly high financial cost, even though they had been promised symptom improvement, safety, and full insurance coverage." [139]

See also

Related Research Articles

<span class="mw-page-title-main">Hyperthyroidism</span> Clinical syndrome caused by excessive thyroid hormone

Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. Some, however, use the terms interchangeably. Signs and symptoms vary between people and may include irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, hand tremor, and weight loss. Symptoms are typically less severe in the elderly and during pregnancy. An uncommon but life-threatening complication is thyroid storm in which an event such as an infection results in worsening symptoms such as confusion and a high temperature; this often results in death. The opposite is hypothyroidism, when the thyroid gland does not make enough thyroid hormone.

<span class="mw-page-title-main">Thyroid</span> Endocrine gland in the neck; secretes hormones that influence metabolism

The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the isthmus. Microscopically, the functional unit of the thyroid gland is the spherical thyroid follicle, lined with follicular cells (thyrocytes), and occasional parafollicular cells that surround a lumen containing colloid.

<span class="mw-page-title-main">Graves' disease</span> Autoimmune endocrine disease

Graves' disease, also known as toxic diffuse goiter or Basedow’s disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.

<span class="mw-page-title-main">Hypothyroidism</span> Insufficient production of thyroid hormones by the thyroid gland

Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, extreme fatigue, muscle aches, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<span class="mw-page-title-main">Levothyroxine</span> Thyroid hormone

Levothyroxine, also known as L-thyroxine, is a synthetic form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken orally (by mouth) or given by intravenous injection. Levothyroxine has a half-life of 7.5 days when taken daily, so about six weeks is required for it to reach a steady level in the blood.

Ord's thyroiditis is an atrophic form of chronic thyroiditis, an autoimmune disease where the body's own antibodies fight the cells of the thyroid.

<span class="mw-page-title-main">Thyroid peroxidase</span> Enzyme expressed mainly in the thyroid gland

Thyroid peroxidase, also called thyroperoxidase (TPO), thyroid specific peroxidase or iodide peroxidase, is an enzyme expressed mainly in the thyroid where it is secreted into colloid. Thyroid peroxidase oxidizes iodide ions to form iodine atoms for addition onto tyrosine residues on thyroglobulin for the production of thyroxine (T4) or triiodothyronine (T3), the thyroid hormones. In humans, thyroperoxidase is encoded by the TPO gene.

<span class="mw-page-title-main">Thyroid disease</span> Medical condition

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

Desiccated thyroid extract (DTE), is thyroid gland that has been dried and powdered for medical use. It is used to treat hypothyroidism, but less preferred than levothyroxine. It is taken by mouth. Maximal effects may take up to three weeks to occur.

<span class="mw-page-title-main">Subacute thyroiditis</span> Medical condition

Subacute thyroiditis refers to a temporal classification of the different forms of thyroiditis based on onset of symptoms. The temporal classification of thyroiditis includes presentation of symptoms in an acute, subacute, or chronic manner. There are also other classification systems for thyroiditis based on factors such as clinical symptoms and underlying etiology.

Postpartum thyroiditis refers to thyroid dysfunction occurring in the first 12 months after pregnancy and may involve hyperthyroidism, hypothyroidism or the two sequentially. According to the National Institute of Health, postpartum thyroiditis affects about 8% of pregnancies. There are, however, different rates reported globally. This is likely due to the differing amounts of average postpartum follow times around the world, and due to humans' own innate differences. For example, in Bangkok, Thailand the rate is 1.1%, but in Brazil it is 13.3%. The first phase is typically hyperthyroidism. Then, the thyroid either returns to normal or a woman develops hypothyroidism. Of those women who experience hypothyroidism associated with postpartum thyroiditis, one in five will develop permanent hypothyroidism requiring lifelong treatment.

<span class="mw-page-title-main">Hypothalamic–pituitary–thyroid axis</span> Part of the neuroendocrine system

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

<span class="mw-page-title-main">Hashimoto's encephalopathy</span> Human disease (neurological condition)

Hashimoto's encephalopathy, also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a neurological condition characterized by encephalopathy, thyroid autoimmunity, and good clinical response to corticosteroids. It is associated with Hashimoto's thyroiditis, and was first described in 1966. It is sometimes referred to as a neuroendocrine disorder, although the condition's relationship to the endocrine system is widely disputed. It is recognized as a rare disease by the NIH Genetic and Rare Diseases Information Center.

<span class="mw-page-title-main">Thyroid hormones</span> Hormones produced by the thyroid gland

Thyroid hormones are any hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine, derived from food. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.

Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present as a pre-existing disease in pregnancy, or after childbirth. Uncorrected thyroid dysfunction in pregnancy has adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Due to an increase in thyroxine binding globulin, an increase in placental type 3 deioidinase and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards. This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.

Antithyroid autoantibodies (or simply antithyroid antibodies) are autoantibodies targeted against one or more components on the thyroid. The most clinically relevant anti-thyroid autoantibodies are anti-thyroid peroxidase antibodies (anti-TPO antibodies, TPOAb), thyrotropin receptor antibodies (TRAb) and thyroglobulin antibodies (TgAb). TRAb's are subdivided into activating, blocking and neutral antibodies, depending on their effect on the TSH receptor. Anti-sodium/iodide (Anti–Na+/I−) symporter antibodies are a more recent discovery and their clinical relevance is still unknown. Graves' disease and Hashimoto's thyroiditis are commonly associated with the presence of anti-thyroid autoantibodies. Although there is overlap, anti-TPO antibodies are most commonly associated with Hashimoto's thyroiditis and activating TRAb's are most commonly associated with Graves' disease. Thyroid microsomal antibodies were a group of anti-thyroid antibodies; they were renamed after the identification of their target antigen (TPO).

<span class="mw-page-title-main">Thyroid's secretory capacity</span> Medical diagnostic method

Thyroid's secretory capacity is the maximum stimulated amount of thyroxine that the thyroid can produce in a given time-unit.

The sum activity of peripheral deiodinases is the maximum amount of triiodothyronine produced per time-unit under conditions of substrate saturation. It is assumed to reflect the activity of deiodinases outside the central nervous system and other isolated compartments. GD is therefore expected to reflect predominantly the activity of type I deiodinase.

Thyroid disease in women is an autoimmune disease that affects the thyroid in women. This condition can have a profound effect during pregnancy and on the child. It also is called Hashimoto's thyroiditis (theye-royd-EYET-uhss). During pregnancy, the infant may be seriously affected and have a variety of birth defects. Many women with Hashimoto's disease develop an underactive thyroid. They may have mild or no symptoms at first, but symptoms tend to worsen over time. If a woman is pregnant and has symptoms of Hashimoto's disease, the clinician will do an exam and order one or more tests.

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