Hashimoto's thyroiditis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]

Overview

Hashimoto's thyroiditis (HT) is characterized by lymphocytic infiltration of the thyroid gland and production of antibodies that recognize thyroid-specific antigens. The pathogenesis is not yet completely understood. Thyroid cells undergo atrophy or transform into a type of follicular cell rich in mitochondria called Hurthle cell. It is currently thought that the disease is caused by abnormalities in cellular and humoral immunity which results in a localized cell-mediated immune response directed toward the thyroid parenchymal cells. This results in the decreased production of thyroid hormones.

Pathophysiology

The control, synthesis, and release of the thyroid hormones is usually controlled by hypothalamus and pituitary gland. Thyroid hormones (T3 and T4) that regulate basal metabolic rate, influence oxygen consumption by tissues. They are crucial for normal development of the brain and growth of the body. Secretion of thyroid hormones follows upper control from the hypothalamus and the pituitary. Thyroid releasing hormone (TRH) acts on thyrotropes releasing cells in the pituitary causing them to release thyroid stimulating hormone (TSH). TSH acts on thyroid gland by binding to specific membrane receptors and activating an intracellular pathway involving cAMP that ends in the formation and secretion of thyroid hormones. Iodine is essential for the synthesis of thyroid hormones. Iodide is uptaken through a special Na/I transporter found in the membrane of thyroid follicular cell. After the iodide uptake, it goes through a series of organic reactions ending in the formation of the two forms of thyroid hormones: T3 (Triiodothyronine) and T4 (Thyroxine). T3 and T4 remain stored in the thyroglobulin of the follicles and are released in response to further stimulation by TSH to the thyroid follicles. While T3 is 3 to 5 times more potent than T4, it represents only one-fourth of the total hormone secretion. T3 is thought to be the biologically active form of the hormone. Most of the circulating T3 is due to peripheral conversion of T4 in the liver and peripheral tissues while only a small percentage is secreted directly from the thyroid gland itself. T3 and T4 act on nuclear receptors (DNA binding proteins) and cause the regulate the transcription of many proteins to regulate the metabolic rate of the body. The higher regulation of thyroxine secretion follows the negative feedback role, meaning that high levels of T3 and T4 will suppress TRH and TSH secretion and vice versa (Low levels of thyroxine will stimulate TRH and TSH secretion). This is useful in diagnosing the cause of hyperthyroidism. TSH will be low in primary hyperthyroidism where the gland is the source of the excess hormones. In secondary hyperthyroidism, TSH will be high as the pituitary or the hypothalamus are the sources of the disease.

Regulation of thyroid hormone secretion. Source:By CFCF; slightly modified by Geo-Science-International - This file was derived from Thyroid vector.svg:, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=47043638

Pathogenesis

Thyroid cells undergo atrophy or transform into a type of follicular cell rich in mitochondria called Hurthle cell. Cellular and humoral immunity is thought to be involved in the pathophysiology of Hashimoto's thyroiditis:

Cellular immunity

• Defects in regulatory T cell response to thyroid-specific antigens in autoimmune hypothyroidism resulting in failure of regulatory T cell function.
• Regulatory T cells can also dampen the immune response. Regulatory T cells are high in CD25 expression and have altered activity in Hashimoto thyroiditis.
• CD4+ cells are less sensitive to the inhibitory effect of TGFβ in Hashimoto thyroiditis.
• There is an increased number of follicular helper T cells in patients Hashimoto's thyroiditis, which correlates with thyroid-specifc antibody levels.

Humoral immunity

• Patients with Hashimoto thyroiditis have positive antibodies against thyroglobulin (TG) and thyroid peroxidase (TPO).
• Recently, a distinct variant of HT has been documented where the thyroid gland is infiltrated with IgG4-positive cells.
• Thyroid hormone receptor antibodies might be involved in the disease presentation as sometimes thyroiditis presents as hyperthyroidism. The balance between the thyroid stimulating antibodies (TSAb) and thyroid blocking antibodies (TBAb) explains the fluctuating hormone levels in patients with Hashimoto's thyroiditis. It should also be noted that thyroid stimulating antibodies (TSAb) might have a minor blocking action.
• The sodium-iodide symporter (NIS) mediates iodine uptake by the thyroid gland, while pendrin is responsible for the efflux of iodine through thyroid follicles. Antibodies against NIS and pendrin are also found in Hashimoto thyroiditis (HT).

Cytokines

• Increased plasma level and expressions of IL-17 and IL-22 are seen in HT.

Micro RNA

• MicroRNAs (miRNA), which are small noncoding RNA regions, have also been implicated in the pathogenesis of thyroid immunity. In HT tissue, a decreased level of miR-155_2 and an increase in miR-200a1 was found.

Genetics

• A family history of thyroid disorders is common, with HLA-B* 46:01 confers an increased risk of HT developing in Han Chinese children. HLA-A* 02:07 and HLA-DRB4 conferred susceptibility. The genes implicated vary in different groups and the incidence is increased in patients with chromosomal disorders, including Down's syndrome and Turner syndrome.

Associated conditions

The following conditions are associated with Hashimoto's thyroiditis:

• Type 1 diabetes
• Addison's disease
• Pernicious anemia
• Vitiligo
• Rheumatoid arthritis
• Premature ovarian failure

Gross Pathology

On gross pathology the characteristic findings of Hashimoto's thyroiditis are.

• The gland is usually diffusely enlarged, firm, and slightly lobular.
• The capsule is intact, and the cut surface is light-tan and has a slight lobular pattern.

A gross photograph of thyroid gland taken at autopsy. The gland is only slightly enlarged and has a firm texture.Images courtesy of Professor Peter Anderson DVM Ph.D. and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of Hashimoto's thyroiditis include:

• Massive infiltration of the thyroid gland by lymphocytes and plasma cells
• Germinal centers
• Thyroid follicles are usually absent and the few remaining follicles are devoid of colloid
• Hurthle cells
  • Large polygonal cells with eosinophilic cytoplasm
  • Have an abundance of mitochondria

Photomicrograph shows germinal centers; Case courtesy of Dr Andrew Ryan, Radiopaedia.org, rID: 17084	Micrograph of Hurthle cells Courtesy of PathologyOutlines.com; Source:
This is a low-power photomicrograph of thyroid from this case. Note that the tissue is more cellular than one would expect and there does not appear to be normal colloid-filled blue spaces in this gland.Images courtesy of Professor Peter Anderson DVM Ph.D. and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology	This is a higher-power photomicrograph of thyroid from this case. Note a large number of blue-staining inflammatory cells in this tissue. These cells appear to be forming germinal centers. Some residual thyroid gland tissue can be seen in this section (arrows).Images courtesy of Professor Peter Anderson DVM Ph.D. and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
This is another view of thyroid gland filled with inflammatory cells forming germinal centers (arrows).Images courtesy of Professor Peter Anderson DVM Ph.D. and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology	This is a higher-power photomicrograph of thyroid from this case showing the inflammatory cells and the residual thyroid tissue.Images courtesy of Professor Peter Anderson DVM Ph.D. and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
This is another higher-power photomicrograph of thyroid from this case showing the inflammatory cells and the residual thyroid tissue.Images courtesy of Professor Peter Anderson DVM Ph.D. and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology	This is a high-power photomicrograph showing the inflammatory cells infiltrating into the residual thyroid tissue (arrows).Images courtesy of Professor Peter Anderson DVM Ph.D. and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
This is a high-power photomicrograph showing the lymphocytes and plasma cells surrounding the thyroid gland epithelium.Images courtesy of Professor Peter Anderson DVM Ph.D. and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology	This high-power photomicrograph shows more clearly the lymphocytes and plasma cells surrounding the thyroid gland epithelium. Large, eosinophilic, degenerating thyroid gland cells (Hurthle cells) can be seen in this section (arrows).Images courtesy of Professor Peter Anderson DVM Ph.D. and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

References

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