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Autoimmune Thyroid Disease

Autoimmune thyroid disease is a group of thyroid disorders in which autoimmune processes


target various constituents of thyroid tissues, including cells, receptors and enzymes.

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.

Grave’s disease accounts for most cases of hyperthyroidism.

Genetic and environmental factors

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.

The HLA region on chromosome 6 is therefore an obvious candidate as a Graves’ disease


susceptibility gene. A number of studies have suggested that there is an association between
Graves’ disease and HLA-DR3*0501 .Conversely, a few studies have implied that HLA-DQ
alleles play a role in resistance to autoimmune thyroid disease.

CTLA-4(cytotoxic T- lymphocyte antigen -4) plays an important role in the down-regulation


of T-cell activation. Genetic studies have provided evidence that particular alleles of the
gene encoding CTLA-4 are linked and associated with various organ-specific autoimmune
diseases in general, including Grave’s disease. These associations have been present in
different races.

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 .

Graves’ disease is characterized by T- and B- cell infiltration of the thyroid gland.CD4+ T


cells predominate .Studies of intrathyroidal T-cell receptor expression have demonstrated
limited & region expression and these activated CD4 T cells may be providing help for
antibody production by locally abundant B cells .Although CD8+ cells are usually only
a small fraction of infiltrating cells in early disease ,it is interesting that this subset may
increase after treatment with antithyroid drugs.

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).

These also bind to the receptor but fail to stimulate.


It has been proposed that some patients with Graves’ disease proceed to develop
hypothyroidism, not because the thyroid gland itself is eventually destroyed by autoreactive
cells, but because the TRAb switch from agonist to antagonist.

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.

Patient evaluation and differential diagnosis

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.

Approximately 20-25% of patients present with clinical thyroid –associated ophthalmopathy,


characterized by proptosis.

HASHIMOTO’S THYROIDITIS

Hashimoto’s thyroiditis was first described by Hashimoto in 1912 as struma


lymphomatosa.Autoantibodies present in this disorder were found in 1956 by Roitt et
al.Hashimoto’s thyroiditis is characterized by lymphocytic infiltration of the presence of
thyroid autoantibodies to thyroglobulin and to thyroid peroxidase .Hashimoto”s thyroiditis
is the most common underlying cause for hypothyroidism.It has been estimated that about
3-4% of the population suffers from Hashimoto’s thyroiditis.It is found most commonly in
middle –aged and elderly women.

Genetic and environmental factors

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

The thyroid gland in Hashimoto’s thyroiditis shows a dense accumulation of lymphocytes.


Plasma cells and macrophages with germinal centre formation. Thyroid follicles are damaged
and their numbers are reduced. Traditionally it is thought that the thyroid follicles are injured
by cytotoxicity, but there is recent evidence that apoptosis, or a combination of cytotoxicity
and apoptosis, plays a key role in this pathogenic process.

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.

Thyroid damage in Hashmoto’s thyroiditis is associated with infiltrating cytotoxic T cells


and evidence of increased apoptosis of follicular thyroid cells. Thyroid cells have been
shown to express molecules involved in apoptosis, such as TNF receptor and Fas .Fas –
mediated apoptosis of thyroid cells can be induced by CD8 cytotoxic T cells.The
mechanism of apoptosis in thyroid cells is under active investigation. Although Fas is
expressed constitutively on thyrocytes , normally it does not cause apoptosis even in the
presence of excess anti-Fas antibodies. The Fas-FasL pathway may therefore be regulated
in thyrocytes , and certain combinations of inflammatory cytokines may reverse the
inhibition. In addition, the normal thyroid may utilize the Fas-FasL system to protect against
invading lymphocytes. A recent study demonstrated that the process of lymphocytic
infiltration in an inflamed thyroid was inhibited by direct injection of a FasL-expression
vector, suggesting that apoptosis was induced in the infiltrating lymphocytes by the
expressed FasL on thyroid follicular cells.
In involved thyroid glands, thyroid cells show increased expression of intercellular
adhesion molecules ICAM-1,VCAM-1 and LFA-3 .Adhesion molecules are extensively
involved in a network of cell-cell and cell- matrix interactions in the immune system. They
are implicated not only in cell adhesion per se, but also in signal transduction ,leading to
cellular events such as activation and proliferation .The presence of these adhesion
molecules in patients with Hashimoto’s thyroiditis may enhance the binding of lymphocytes
to thyroid follicular cells and significantly increase thyroid cell damage. As mentioned
earlier, one of the important characteristics of Hashimoto’s thyroiditis is the formation of
germinal centers within the gland. Germinal centers constitute a specialized
microenvironment essential for the induction of antibody synthesis ,affinity maturation of
B cells, memory B- cell formation, and the maintenance of T- cell memory.

Prevention and patient management

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.

Patient evaluation and differential diagnosis

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.

Sometimes it may be difficult to differentiate Hashmoto’s thyroiditis from Graves’ disease


and other types of thyroiditis (focal lympho,subacutem,Riedel’s) .On occasion, the rapid
enlargement of one lobe of the thyroid gland in Hashimotos thyroiditis also needs to be
differentiated from malignant lymphoma or thyroid carcinoma. In subacute thyroiditis the
involvement of the gland is diffusely nodular and only rare nodules may be spared from
the process.In some patients fine- needle biopsy will be necessary to provide a pathologic
diagnosis.Cytologically ,Hashmotos’ thyroiditis is characterized by the presence of
lymphoid infiltration of follicles, follicular cells with oxyphilic changes of varying
degrees.polymorphus lymphocyte populations and histiocytes.

POSTPARTUM THYROIDITIS

Postpartum thyroiditis is characterized by the development of transient thyrotoxicosis and


/or hypothyroidism during the first 6 months of the postpartum period. A significant
percentage of these patients (25-30%) suffer from chronic hypothyroidism.

Genetic and environmental factors.

Iodine The development of postpartum thyroiditis is believed to involve genetic and


environmental factors. A familial form has been reported. A number of studies have
indicated that HLA antigens ,particularly DR antigens are associated with the
development of postpartum thyroiditis .A positive association of HLA –DR5 with disease
has been observed , suggesting that DR2 might confer a protective effect against the
disease.

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

Patient evaluation and differential diagnosis

The classic clinical cure of postpartum thyroiditis consists of a hyperthyroid phase,


followed by a hypothyroid phase and recovery .The hyperthyroidism is often mild and
not recognized, or does not occur at all. During his phase irritability and lack of energy
are prominent, even in autoantibody –positive women who do not develop thyroid
dysfunction .In contrast ,symptoms in the hypothyroid phase may be profound. Most
patients recover, and about 80% are euthyroid within 12 months after delivery.

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