Riedel's thyroiditis pathophysiology

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

The exact pathogenesis of Riedel’s thyroiditis is not fully understood. The presence of thyroid autoantibodies and lymphoid infiltration of the thyroid gland resembling that of Hashimoto’s thyroiditis might indicate an autoimmune etiology. It is considered that the infiltrating lymphocytes release cytokines which are responsible for the activation of fibroblasts responsible for the fibrosis. Riedel’s thyroiditis is characterized by a replacement of the normal thyroid parenchyma by a dense fibrosis that invades adjacent structures of the neck and extends beyond the thyroid capsule. This makes the thyroid gland stone-hard and fixed to adjacent structures. A shared mechanism with retroperitoneal fibrosis and sclerosing cholangitis has been suggested.

The control, synthesis, and release of the thyroid hormone is usually controlled by hypothalamus and pituitary gland.[1][2] Thyroid hormones (T3 and T4) are regulating 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 up taken through a special Sodium-iodide symporter(Na/I) 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 and T4. 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.

The exact pathogenesis of Riedel’s thyroiditis is not fully understood. The presence of thyroid autoantibodies and lymphoid infiltration of the thyroid gland resembling that of Hashimoto’s thyroiditis might indicate an autoimmune etiology.^[3]

• It is considered that the infiltrating lymphocytes (CD4+ and CD8+) release cytokines which are responsible for the activation of fibroblasts responsible for the fibrosis.^[4]
• Riedel’s thyroiditis is characterized by a replacement of the normal thyroid parenchyma by a dense fibrosis that invades adjacent structures of the neck and extends beyond the thyroid capsule.This makes the thyroid gland stone-hard and fixed to adjacent structures.^[5]
• Tissue eosinophilia and Major basic protein (MBP) identified in the thyroid gland on the histopathological analysis are also thought to play a role in the proliferation of fibroblasts.^[6]
• A shared mechanism with retroperitoneal fibrosis and sclerosing cholangitis is also suggested.^[7]

The following hypotheses regarding the pathogenesis of Riedel’s thyroiditis have been proposed:^[8]

According to this theory, Riedel’s thyroiditis (RT) might be a primary disease of fibroblasts triggered by autoimmune stimuli.^{[8][9][10][11][12][13]}

• It is proposed that the endothelial cells release oxidized low-density lipoprotein from atheromatous plaques following the injury resulting in an allergic hypersensitivity reaction.
• The natural consequence of this hypothesis is that the antigen initiating fibrosis is not localized within the thyroid but is affected secondarily by a systemic fibroinflammatory process.
• Thyroid follicular cells, peri-thyroid muscular cells, or intrathyroidal endothelial cells express antigens, cytokines, or adhesion molecules that might contribute to local activation of the disease. The evidence of a perivascular concentration of inflammatory cells in RT (occlusive phlebitis) might support the theory that the allergic process first involves blood vessels.
• Once the allergic reaction has started, a heavy inflammatory cell population such as B and T lymphocytes, plasma cells, monocytes, and eosinophils infiltrate tissues and produce several cytokines.
• The role of eosinophils in this context probably is central. When eosinophils migrate into the tissues involved by the disease, they degranulate and release cationic toxins into connective tissue including Major basic protein (MBP), eosinophil cationic protein, eosinophil peroxidase, and eosinophil-derived neurotoxin.
• Eosinophils also release cytokines, the most important of which are transforming growth factor β, transforming growth factor α, and granulocyte-macrophage colony-stimulating factor. This stimulates fibroblast proliferation that finally causes fibrosis.

This hypothesis was proposed for the multifocal fibrosclerosis which is associated with Riedel’s thyroiditis.^[14]

• The basis of this hypothesis was a report of multifocal fibrosclerotic disease in two brothers, whose parents were first cousins. They developed different combinations of the multifocal fibrosclerotic disease and a familial multifocal fibrosclerosis was hypothesized.
• It was thought that genetic factors might have played a partial role in an enzymatic defect in the tryptophan → serotonin → 5-hydroxyindolacetic acid pathway. However, such a relationship has never been proven, and the siblings described remain the only case of familial multifocal fibrosclerosis reported in the literature.

Riedel’s thyroiditis is associated with Hashimoto’s thyroiditis and de Quervain’s thyroiditis.^[15]

• It is proposed that Riedel’s thyroiditis might represent a late fibrotic stage of subacute or chronic thyroiditis. The fundamental concept of this theory is that the fibrosing process of RT is specific to the thyroid gland.

This hypothesis is also proposed primarily for multifocal fibrosclerosis. As Riedel’s thyroiditis is associated with multifocal fibrosclerosis this theory might explain the indirect association of Riedel’s thyroiditis with drugs.^[8][16]

• The production of fibrosis by the drugs might be determined by an increased serum serotonin concentration through competitive inhibition at the serotonin receptor level and a reaction of hypersensitivity causing vasculitis and plasma exudation resulting in fibrosis.
• Although drugs have been found to cause multi organ fibrosis, there are no reports regarding medication induced Riedel’s thyroiditis. This theory might explain the indirect association of Riedel’s thyroiditis with drugs as Riedel’s thyroiditis is associated with multifocal fibrosclerosis.

Riedel’s thyroiditis is associated various other autoimmune conditions including:^{[4][17][18][19][20][16]}

• Graves’ disease
• Hashimoto’s thyroiditis
• Multifocal idiopathic fibrosclerosis
• Addison’s disease
• Pernicious anemia
• Type 1 diabetes

On gross pathology the following findings are characteristic of Riedel’s thyroiditis:^[21]

• Dense, avascular white fibrous tissue
• Absence of a capsule
• Absence thyroid tissue

On microscopic histopathological analysis the following findings are usually seen:^[22][8]

• Destruction of thyroid follicle by inflammatory cells
• Inflammatory cells including lymphocytes, plasma cells, and eosinophils in a dense matrix of hyalinized connective tissue
• Fibrous tissues and invasion of surrounding structures

• 
  Histology of Riedel’s thyroiditis (Image courtesy of AFIP and PathologyOutlines.com; http://www.pathologyoutlines.com/topic/thyroidriedel.html )
• 
  Histology of Riedel’s thyroiditis (Image courtesy of AFIP and PathologyOutlines.com; http://www.pathologyoutlines.com/topic/thyroidriedel.html )
• 
  Histology of Riedel’s thyroiditis (Image courtesy of AFIP and PathologyOutlines.com; http://www.pathologyoutlines.com/topic/thyroidriedel.html )

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