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50 years ago when antithyroid antibodies were found in the serum of patients with
Hashimoto’s thyoiditis, followed by the induction of experimental autoimmune thyroiditis in
animals.
Graves’ disease is common in the general population, with an incidence of 1-1.5 cases per
1000 population.
For example, autoimmune thyroid disease is more frequently associated with type I diabetes.
Studies of monozygotic twins have indicated that the disease has a concordance rate of 30-
60%.
One of the pathological features seen in Grave’s disease is infiltration of the thyroid gland
with activated lymphocytes. Increased expression of the major histocompatibility complex
(MHC) Class II antigens has been noted on these lymphocytes, as well as on the thyroid cells.
Because the presence of auto antibodies against the TSH receptor is the most important
pathogenic feature of Graves’ disease, the TSH receptor gene has also been an obvious
candidate for disease contribution. However, most studies have failed to show any significant
association of TSH receptor alleles in the genetics of Graves’ disease.GD-1, a locus on
chromosome 14 at 14q31, has been linked with susceptibility to Graves’ disease.
Together, the data suggest that Graves’ disease, like other autoimmune diseases, is a complex
genetic trait related to contributions from MHC and multiple non-MHC genes, most of which
have yet to be identified .Although a number of genes, most of which have yet to be
identified .Although a number of genes have been associated with susceptibility to
Graves’ disease, their relative contribution to its pathogenesis have yet to be clearly
defined.
Both human and animal studies have indicated that chronic excess iodine supplementation
may modulate the expression of autoimmune thyroid disease in genetically susceptible
individuals. The mechanism for this is unknown and may be multiple. For example iodine is
known to stimulate B lymphocytes to increase the production of immunoglobulins, enhance
T-lymphocyte activity, and influence the expression of MHC antigens.
Studies have shown that stress can change thyroid function by increasing iodine uptake and
stimulating TSH and thyroid hormones secretion. This may relate to studies showing that the
incidence of Graves’s disease increased significantly in populations exposed to a major war.
Graves’ disease has a marked female predominance(M.F ratio 7:1),and sex hormones have
been proposed to play a role in its development.
There is increasing evidence for a connection between infectious agents and the development
of Graves’ diasease.The frequency of antibodies to Yersinia enterocolitica , a grain –negative
bacillus, is significantly increased in patients with Graves’ disease.Furthermore,Yersinia
enterocolitica appears to have saturable TSH-binding sites, this bacillus may contain
antigenic determinants that cross- react with human thyroid auto antigens .
Pathogenesis
An immune response can be initiated when CD4+ T cells-recognize foreign or self-antigenic
peptides presented by MHC Class II molecules such thyrocytes.As mentioned above
,particular alleles of several Class II HLA molecules have been reported to be
associated with Graves’ disease. Abnormal or aberrant expression of these antigens on
thymocytes may possibly play a key role in the development of Graves’ disease.
It has been well established that TSH receptor antibodies (TRAb, previously named LATS),
cause Graves’ disease by binding to TSH receptors on thyroid follicular cells and inducing
excess production of thyroid hormones .The mechanism by which TRAb are induced is
still not fully known. It is likely that CD4+ T cells drive this response by recognizing
TSH peptides in conjunction with MHC Class II.Epitope mapping made possible by the
cloning of the TSH receptor gene .
Two types of TRAb exist in thyroid diseases. In Graves’ disease TRAb act as agonist and
are named thyroid –stimulating antibodies (TSAb) bind to the TSH receptor, stimulate
the release of thyroid hormones, and ultimately lead to hyperthyroidism .In atrophic
thyroiditis TRAb act as antagonist and are named thyroid -blocking antibody (TBAb).
Apart from the disease-specific TSAb, other autoantibodies against various components of
the thyroid gland , including thyroid peroxidase (TPO)and thymoglobulin , may also be
present in Graves’ disease.
Propylthiouracil and methimazole are the two antithyroid drugs that are most frequently used
by physicians. They not only inhibit the production of thyroid hormones, relieving
hyperthyroidism, but also reduce the size and vascularity of the goiter, making it more
amenable to a definitive therapy with surgery or radioactive iodine if necessary.
Both radioactive iodine and surgical subtotal thyroidectomy are definitive ablative
treatments.
Graves’ disease typically presents with a diffuse enlargement of the thyroid gland (goiter)
and thyrotoxicosis.The classic signs of hyperthyroidism are heat intolerance, hand
tremor,nervousness,irritability,warmmoist skin, weight los,muscle reflex
changes,hyperdynamic cardiovascular status with tachycardia, hyper defecation and changes
in mental status.
HASHIMOTO’S THYROIDITIS
It is believed to involve both genetic and environmental factors. Thyroid antibodies are found
with a high frequency among first-degree relatives, and there is a high degree of concordance
among identical twins. As with Graves’ disease, most genetic studies have focused on the
HLA region .In Caucasians HLA-DR5 has been associated with a 3-4 fold increased risk of
disease whereas HLA-DR3 was associated with a 5,7-fold increased risk of primary
myxedema.High frequencies of HLA –DRB4*0102 might have a protective role in the
development of disease as its frequency is reduced in patients with Hashmoto’s thyroiditis.
Hashmoto’s thyroiditis has also been associated with particular alleles of CTLA-4 .As
discussed above; the CTLA-4 gene has been known to be associated with Grave’s disease and
other autoimmune diseases.
Although 95% of patients with Hashimoto’s thyroiditis are women, the basis for this gender
effect remains unclear. Rodent studies have shown that testosterone suppresses and estrogen
exacerbates experiment autoimmune thyroiditis.
It is interesting that the use of interferon-α(IFN- α) for the treatment of hepatitis has
been associated with a significantly increased incidence of autoimmune thyroid disease.
Pathogenesis
A key immunologic event may relate to the increased HLA Class II antigen expression on
infiltrating lymphocytes and thyrocytes in affected glands. Both CD4+ T cells and CD8+
cytotoxic T cells are increased. It is hypothesized that infiltrating T cells recognize processed
peptides of thyroid peroxidase (TPO) and thyroglobulin.With assistance from T cells; B cells
produce antibodies to thyroid antigens which are exposed or modified by the destructive
process. Depending upon the methods of detection used 55-90% of patient’s exhibit
antithyrogllobulin antibodies, and 82-91% exhibit anti-TPO anti-bodies. In addition,
intrathyroidal lymphocytes and surrounding lymphoid tissues may still be capable of
producing thyroid antibodies in patients with negative serology.TPO antigen can also be a
central antigen for cytotoxic antibodies in Hashimoto’s thyroiditis.The molecular nature of
TPO antibodies has been characterized and the variable-region genes involved are restricted
mainly to VH1,VH3,VK1 and VKIII family members, which are among the most common
V families.
Treatment usually consists of thyroid hormone replacement for hypothyroidism, and this is
generally required lifelong to prevent recurrence .A response to thyroid hormone
replacement therapy often includes a decrease in the levels of ant thyroid antibodies. If the
patient has a symptomatic goiter, adose of thyroid hormones that suppresses TSH secretion
may reduce the size of the gland. Although corticosteroids and immunosuppressive therapy
may reduce thyroid enlargement, the high risk/benefit ratio does not support their use in the
treatment of this disease. Patients with coexisting thyrotoxicosis should be treated with
antithyroid drugs and levels of thyroid hormones carefully monitored. Thyroid hormone
therapy may result in a decrease in the size of the gland in some cases, but an increase in
others.
Occasionally Hashimoto’ thyroiditis coexists with Graves’ disease, and patients often
present with typical symptoms of hyperthyroidism.Antithyroid treatment should be handled
with extreme caution in such cases, because patients with both diseases are more likely
to become hypothyroid after surgical or radioactive iodine therapy than are those with
Graves’ disease alone.
A consistent physical sign seen in Hashimoto’s thyroiditis is an enlarged thyroid gland. The
goiter is often symmetrical, large and feels very firm. Fine modularity is also often present.
The size of an enlarged thyroid gland and the number of nodules are variable, depending
on the amount of lymphocytic infiltration, the formation of fibrosis and the degree of
compensatory hyperplasia. Lymph nodes surrounding the gland often become enlarged, and
lymphoma must be excluded. Sometimes patients will show symptoms of other autoimmune
diseases, such as generalized vasculitis with urticaria and nephritis, and these are believed
to be caused by the cross-reaction of antithyroid auto-antibodies with other organs with
other organs, or the presence of circulating immune complexes containing thyroid antigens
,predominantly thymoglobulin.
Patients with hyperthyroidism are differentiated from those with Graves’ disease by the
demonstration of patchy or decreased uptake on a radioiodine scan of the thyroid.
Screening tests for specific auto-antibodies against thyroid (antithyroglobulin and antithyroid
TPO) may be helpful diagnostically in certain patients.
POSTPARTUM THYROIDITIS
Consumption may affect the incidence or severity of postpartum thyroiditis , and this
concept is in agreement with the fact that the administration of iodine exacerbates
autoimmune thyroid disease.
Pathogenesis
Complement -fixing anti-TPO antibodies are present in the majority of patients with
postpartum thyroiditis , and the titer of this autoantibody is closely associated with the
severity of the disease.
Thus, the degree of hypothyroidism, determined by TSH levels, correlates with TPO antibody
titers obtained both early in pregnancy and 5-7 months postpartum. Although serum anti-
TPO antibody levels are significantly elevated ,the role they play in the pathogenesis of
postpartum thyroiditis remains unclear. As the histomorphologic changes seen in
postpartum thyroiditis are similar to those in Hashimoto’s thyroiditis, it is possible that
the damage is executed by lymphocyte, complement- and apoptosis-mediated mechanism
similar to those of Hashimoto’s thyroiditis.
Patient managements
Treatment is usually not recommended for the thyrotoxic phase unless symptoms are severe.
In the hypothyroid phase the management of this disorder is similar to that of hypothyroidism
caused by other diseases. Thyroid hormone therapy is not required unless hypothyroidism is
clinically and biochemically significant