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Chapter: Medical Immunology: Organ-Specific Autoimmune Diseases

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Autoimmune Diseases of the Thyroid Gland

Autoimmune factors have been implicated two major thyroid diseases: Graves’ disease and Hashimoto’s disease.

AUTOIMMUNE DISEASES OF THE THYROID GLAND

Autoimmune factors have been implicated two major thyroid diseases: Graves’ disease and Hashimoto’s disease.

A. Graves’ Disease

Graves’ disease, also known as thyrotoxicosis, diffuse toxic goiter, and exophthalmic goi-ter, is the result of the production of antibodies against the thyrotrophic hormone (TSH) receptor (thyroid receptor antibodies). 

The TSH receptor antibodies detected in patients with Graves’ disease stimulate the activity of the thyroid gland. For that reason they have been known by a variety of descriptive terms, including long-acting thyroid stimulator (LATS), thyroid-stimulating immunoglobulin (TSI), and thyroid-stimulating antibodies.

Thyroid-stimulating antibodies are detected in 80–90% of patients with Graves’ dis-ease, are usually of the IgG isotype, and have the capacity to stimulate the production of thyroid hormones by activating the adenylate cyclase system after binding to the TSH re-ceptor. Biopsy of the thyroid gland shows diffuse lymphoplasmocytic interstitial infiltra-tion.

Graves’ disease has its peak incidence in the third to fourth decade and has a female-to-male ratio of 4–8:1. Patients usually present with diffuse goiter, and 60–70% of patients have ocular disturbances. Symptoms of hyperthyroidism include increased metabolic rate with weight loss, nervousness, weakness, sweating, heat intolerance, and loose stools. Ab-normalities on physical examination include diffuse and nontender enlargement of the thy-roid, tachycardia, warm and moist skin, tremor, exophthalmos, and pretibial edema. Ex-ophthalmos (protrusion of the eyeball) can be unilateral or bilateral and may be associated with proptosis, conjunctivitis, and/or periorbital edema. Exophthalmos is classically at-tributed to an increased volume of extraocular tissues due to edema and/or to deposition of mucopolysaccharides. Recently, it has been proposed that an autoimmune response to a tis-sue antigen expressed on both thyroid and eye muscle membrane could induce orbital in-flammation and be responsible for the protrusion of the eyeball.

The diagnosis is usually investigated in patients with hyperthyroidism, found to have increased levels of thyroid hormones (triiodothyronine or T3 and thyroxine or T4 ) and in-creased uptake of T3. The diagnosis is confirmed by demonstration of anti-thyroid recep-tor antibodies using two types of assays:

1.           Those based on the inhibition of TSH binding by TSI antibodies (TSH-binding inhibition assay). This assay is relatively simple and precise, but the results ob-tained do not always correlate with disease activity, since nonstimulating anti-bodies can also block TSH binding.

 

2.           Those based on the functional consequences of thyroid receptor antibody bind-ing to TSH. This last group of assays measures true thyroid stimulating antibod-ies and includes (1) tests in which the endpoint for thyroid activation is the ac-cumulation of intracellular colloid droplets or the penetration of thrombogenic substrates into lysosomal membranes, (2) tests in which the activation of adeny-late cyclase is measured, and (3) tests in which cAMP accumulation is measured.

 

The functional assays correlate better with disease activity but are difficult to calibrate and reproduce, and when heterologous thyroid is used as substrate there is always the possibil-ity that some human TSI antibodies might not react across species.

Therapy is directed at reducing the thyroid’s ability to respond to stimulation by an-tibodies. This can be achieved surgically, by subtotal thyroidectomy, or pharmacologically, either by administration of radioactive iodine (131I) (which is difficult to dose), or by the use of antithyroid drugs such as propylthiouracil and methimazole, which are useful but slow in their effects.

B. Hashimoto’s Disease

Hashimoto’s thyroiditis (autoimmune thyroiditis) is, in its early stages, a subclinical dis-ease in which no thyroid dysfunction is evident and no therapy is needed. With time it evolves to hypothyroidism and replacement therapy may be needed. A cell-mediated au-toimmune reaction triggered by unknown factors is believed to be primarily responsible for the development of the disease. Several lines of evidence support this conclusion:

1.           The inflammatory infiltrate of the thyroid gland shows predominance of acti-vated, lymphokine-secreting T lymphocytes. Numerous plasma cells can also be seen. IL-1 predominates among the cytokines released by activated mononuclear cells, and it has been shown that this cytokine can induce the expression of Fas in thyroid cells, which also express FasL. It has been postulated that this dual ex-pression of Fas and FasL sets the stage for exaggerated apoptosis and may ex-plain the slowly progressive decline of thyroid function in these patients.

 

2.           Infusing lymphocytes from sick to healthy laboratory animals can easily transfer thyroiditis.

 

3.           Infants of mothers with active disease carrying IgG antibodies (which cross the placenta) are unaffected.

 

Whether or not autoantibodies against thyroglobulin and microsomal antigens fre-quently detected in those patients play any pathogenic role is unclear. The main argument supporting their involvement is a good correlation between their titers and disease activity. However, this relationship is also expected if those antibodies arise as a consequence of the activation of helper T cells. This could be a result of the presentation of high levels of  MHC-II–endogenous peptide complexes to anergic TH2 cells, breaking tolerance and caus-ing the inactivation of autoreactive B lymphocytes. Furthermore, these autoantibodies an-tibodies are detected in low titers in up to 15% of the normal adult female population.

Hashimoto’s thyroiditis is the most common form of thyroiditis, and it usually has a chronic evolution. Its incidence peaks during the third to fifth decades, with a female-to-male ratio of 10:1. It is characterized by a slow progression to hypothyroidism, and symp-toms develop insidiously. Patients often present with dysphagia or a complaint that their clothes are too tight around the neck. Most patients become hypothyroid with symptoms of malaise, fatigue, cold intolerance, and constipation. Signs include dry, coarse hair and a dif-fuse enlarged goiter, usually not tender.

The diagnosis is usually confirmed by the detection of anti-thyroglobulin antibodies. Sixty to 75% of the patients show a positive reaction by passive hemagglutination using thyroglobulin-coated erythrocytes (titers higher than 25, while normal individuals usually have titers up to 5). Although these antibodies are also found in other autoimmune disor-ders such as pernicious anemia, Sjogrën’s syndrome, and in 3–18% of normal individuals, the titer of autoantibodies is lower in all other groups with the exception of patients with Sjogrën’s syndrome. In patients with hypothyroidism, T3 and T4 levels and T3 uptake are low and TSH is increased.

The treatment of Hashimoto’s thyroiditis depends, largely, on the stage of the disease and the clinical symptoms. In the early stages glucocorticoids may be used as mild im-munosuppressants, with the aim of reducing the autoimmune response and extending the asymptomatic phase. When patients develop hypothyroidism, thyroid hormone replace-ment is indicated. In patients with large goiters, the administration of thyroxine and tri-iodothyronine may reduce the size of the thyroid gland.


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