Hashimoto's thyroiditis


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.
Early on, symptoms may not be noticed. Over time, the thyroid may enlarge, forming a painless goiter. Most people eventually develop hypothyroidism with accompanying weight gain, fatigue, constipation, hair loss, and general pains. After many years, the thyroid typically shrinks in size. Potential complications include thyroid lymphoma. Further complications of hypothyroidism can include high cholesterol, heart disease, heart failure, high blood pressure, myxedema, and potential problems in pregnancy.
Hashimoto's thyroiditis is thought to be due to a combination of genetic and environmental factors. Risk factors include a family history of the condition and having another autoimmune disease. Diagnosis is confirmed with blood tests for TSH, thyroxine, antithyroid autoantibodies, and ultrasound. Other conditions that can produce similar symptoms include Graves' disease and nontoxic nodular goiter.
Hashimoto's is typically not treated unless there is hypothyroidism or the presence of a goiter, when it may be treated with levothyroxine. Those affected should avoid eating large amounts of iodine; however, sufficient iodine is required especially during pregnancy. Surgery is rarely required to treat the goiter.
Hashimoto's thyroiditis has a global prevalence of 7.5%, and varies greatly by region. The highest rate is in Africa, and the lowest is in Asia. In the US, white people are affected more often than black people. It is more common in low to middle-income groups. Females are more susceptible, with a 17.5% rate of prevalence compared to 6% in males. It is the most common cause of hypothyroidism in developed countries. It typically begins between the ages of 30 and 50. Rates of the disease have increased. It was first described by the Japanese physician Hakaru Hashimoto in 1912. Studies in 1956 discovered that it was an autoimmune disorder.

Signs and symptoms

Signs

In the early stages of autoimmune thyroiditis, patients may have normal thyroid hormone levels and no goiter or a small one. Enlargement of the thyroid is due to lymphocytic infiltration and fibrosis. Early on, thyroid autoantibodies in the blood may be the only indication of Hashimoto's disease. They are thought to be the secondary products of the T cell-mediated destruction of the gland.
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. Extended thyroid hormone deficiency may lead to muscle fibre changes, resulting in muscle weakness, muscle pain, stiffness, and rarely, pseudohypertrophy. 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. Graves disease may occur before or after the development of autoimmune thyroiditis.
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.

Symptoms

Many symptoms are attributed to the development of Hashimoto's thyroiditis. Symptoms can 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, a slowed heart rate, problems getting pregnant, miscarriages, and myopathy. 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. In non-medical settings, the term "flare" is used to refer to a sudden exacerbation of symptoms, whether hyper or hypo.
While most symptoms are attributed to hypothyroidism, similar symptoms are observed in Hashimoto's patients with normal thyroid hormone levels. According to one study, these symptoms may include lower quality of life, and issues of the "digestive system, endocrine system, neuropsychiatric system and mucocutaneous system."

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.

Genetics

Thyroid autoimmunity can be familial. Many patients report a family history of autoimmune thyroiditis or Graves' disease. The strong genetic component is borne out in studies on monozygotic twins, with a concordance of 38–55%, with an even higher concordance of circulating thyroid antibodies not in relation to clinical presentation. Neither result was seen to a similar degree in dizygotic twins, offering strong favour for high genetic etiology.
The genes implicated vary in different ethnic groups, 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.
The incidence of autoimmune thyroid disorders is increased in people with chromosomal disorders, including Turner, Down, and Klinefelter syndromes.

HLA genes

The first gene locus associated with autoimmune thyroid disease was the major histocompatibility complex region on chromosome 6p21. It encodes human leukocyte antigens. Specific HLA alleles have a higher affinity to auto-antigenic 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. 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

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

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, lower secretion of TGF-β, and mutations of FOXP3, an essential regulatory factor for the regulatory T cells development. Development of Hashimoto's disease was associated with mutation of the gene for TNF-α, causing its higher concentration.

Existential (endogenous environmental)

Sex

A study of healthy Danish twins divided into three groups 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.

Pregnancy

In one population study, two or more births were a risk factor for developing autoimmune hypothyroidism in pre-menopausal women.

Environmental

Medications

Certain medications or drugs have been associated with altering and interfering with thyroid function. There are two main mechanisms of interference:
Both excessive and insufficient iodine intake has been implicated in developing antithyroid antibodies. Thyroid autoantibodies are found to be more prevalent in geographical areas after increasing iodine levels. Several mechanisms by which excessive iodine may promote thyroid autoimmunity have been proposed:
  • Via thyroglobulin iodination: Iodine exposure leads to higher iodination of thyroglobulin, increasing its immunogenicity 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. Iodine also promotes thyrocyte apoptosis.
  • Via immune cell behaviour: Iodine influences immune cells.