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I. Background
Hyperthyroidism is term used to describe a hyper-
functioning thyroid gland resulting in significant
increase of free circulating thyroxin (T3) and
triiodothyronine (T4) hormones, which alter the body to
a hyper-metabolic state, a condition called
thyrotoxicosis. Both terms are often used
interchangeably, even though they have distinct
meanings. As an example, excessive injection of
thyroxine to the body may cause thyrotoxicosis, but not
hyperthyroidism. Thus, precisely speaking,
hyperthyroidism is only one of many possible causes
of thyrotoxicosis.1
Thyroid hormone has very broad cellular effects, this
may include carbohydrate and lipid elevated
catabolism and protein synthesis stimulation in various
ranges of cells, resulting in the basal metabolic rate
increase. Accordingly the clinical manifestations of
thyrotoxicosis are related to oxygen consumption
increase associated with hypermetabolic rate, as well
resembling those found in cases of overactive
sympathetic nervous system. This may include
problems in gastrointestinal, cardiac, neuromuscular,
ocular, integumentary, and metabolic systems
throughout the body.1,2
Figure 1. Symptoms of Hyperthyroidism(3)
II. Etiologies of Hyperthyroidism
The origins of the hyperthyroidism can be divided to three main classifications, those are
thyroid hormone overproduction, thyroid gland destruction, and lastly drug effects on the
thyroid gland. Most commonly, hyperfunctioning gland resulting in thyroid overproduction
is caused by diffuse toxic goiter (Graves’ disease), a form of autoimmune disorder. Other
common primary etiologies for thyroid hormones overproduction are toxic multinodular
goiter and follicular adenoma. Excessive hormone production might also be secondary or
tertiary event following diseases such as pituitary adenoma and insensitivity, hypothalamic
disease, germ cells tumors, ovarian teratoma, also resulted from metastasized carcinoma
affecting thyroid gland.3,4
Other possible etiology is thyroid gland destruction, which later may release the stored
hormones, resulting in thyrotoxicosis condition. Lastly, prescription of certain drugs that
have receptors on the thyrocytes, altering the utilization of iodine, or causing inflammation
in the thyroid gland may also contribute to the development of hyperthyroidism leading to
thyrotoxicosis. More precisely, the etiologic classifications and brief pathogenetic
mechanism of each case are listed in the table below.4
Figure 2. Etiologies and Pathogenesis of Hyperthyroidism(4)
V.I Pathogenesis
Body’s lack of thyroid hormones induces negative feedback respond, wherein TSH
secretion will be elevated for compensatory mechanism, which resulting in hypertrophy
and hyperplasia of follicular cells within thyroid gland. In the long run, it ensues gland
enlargement that is visible in gross morphology appearance. The degree of gland
enlargement depends on the level and duration of the hormone deficiency, with time the
recurrent hyperplasia combine to produce more irregular thyroid enlargement, a condition
called multinodular goiter. In approximately 10% of the lesion, autonomously functioning
thyroid nodule (AFTN) may develop and function in a similar manner with toxic adenoma.
It is distinguished from Graves’ disease by the absence of ophtalmopathy and
dermopathy.1
VI. Thyroiditis
Inflammation of the thyroid may be
manifested as acute illness with
agonizing thyroid pain (e.g.,
granulomatous thyroiditis) or as
relatively insignificant inflammation
with thyroid dysfunction (e.g.,
subacute lymphocytic thyroiditis). The
gland looks diffused and enlarged
symmetrically, Microscopic
examination demonstrates scattered
infiltration of the parenchyma by a
mononuclear inflammatory infiltrate
containing small lymphocytes, plasma
cells, and well-developed germinal Figure 8. Microscopic specimen of Hashimoto's thyroiditis(1)
centers. The thyroid follicles are
atrophic and are encircled in many areas by epithelial cells distinguished by the presence
of abundant eosinophilic, granular cytoplasm, termed Hürthle, or oxyphil, cells.1
VI.I Pathogenesis of Chronic Lymphocytic (Hashimoto) Thyroiditis
Hashimoto’s thyroiditis is characterized by progressive thyroid failure due to autoimmune
destruction of thyroid gland. It is caused by malfunction in self-tolerance to thyroid
autoantigens. Thus in vast majority of patients with this condition, there can be found
circulating autoantibodies against thyroid antigens, along with the gradual replacement of
thyrocytes with mononuclear cell infiltrates and fibrotic tissues.1
The instigating factors leading to this condition still need further investigations, yet several
immunologic mechanisms that may play a part in cells damage are listed below:
CD8+ cytotoxic cell-mediated cell death, this immune cells may contribute to
follicular cells destruction
Cytokine-mediated cell death: T cells activation in massive amounts may incite the
production of cytokines such as interferon -γ in thyroid gland. The following
immunologic reaction may damage the follicles
Antithyroid antibodies binding (antithyroglobulin, and antithyroid peroxidase
antibodies), followed by antibody-dependent cell–mediated cytotoxicity
Studies demonstrated significant hereditary factor in the occurrence of the disease.
Polymorphism in multiple immune regulation-associated genes is also believed to have
roles in disease generation, the most significant is the linkage to cytotoxic T lymphocyte–
associated antigen-4 gene (CTLA4), which codes for a negative regulator of T cell
function.1
VI.II Pathogenesis of Subacute Granulomatous (de Quervain) Thyroiditis
The underlying mechanism of this disease is believed to be mediated by viral infections. In
vast majority of cases, patients have previous history of upper respiratory infection prior to
the onset of thyroiditis. De Quervain thyroiditis is also considered as self-limiting disease
because of the limited immune response elicited by the body.1,5
VI.III Subacute Lymphocytic Thyroiditis
Commonly known as silent or painless thyroiditis. The proposed mechanism involves
pregnancy as underlying factor that influences autoimmunity to be induced, as circulating
anti-thyroid antibodies are found in most patients, which leads to tissue damage and may
result in thyrotoxicosis. This condition is thought to be self-limiting and may resolve within
months to euthyroid state.1
VI.I Pathogenesis
Many forms of cancer are believed to be multifactorial in origin, means that both of genetic
and environmental factors play important roles in generation of the disease. It also applies
on follicular thyroid carcinomas. In normal pathway, specific growth factor and tyrosine
kinase receptor binding is needed to evoke autophosporylation of cytoplasmic domain of
the receptor resulting in intracellular signal transduction. In disease state, mutations
occurring along components of this pathway lead to continuous activation regardless of
the ligand absence, thus advancing carcinogenesis.1,5
One third to one half of the cases of follicular thyroid
carcinomas harbor PI-3K/AKT signaling pathway
mutation resulting in constitutive activation of the rest
following pathway. Point mutations occur in RAS and
PIK3CA genes, favoring the amplification of PIK3CA
protein function. It is also accompanied by loss of
PTEN function, the gene responsible in suppressing
tumor and eliciting negative feedback. In one half of
the cases, a translocation creating the fusion gene
encompasses portion of PAX8, a gene responsible in
thyroid development, and the peroxisome proliferator–
activated receptor gene (PPARG) utilized in final
differentiation of thyrocytes.1
Ionizing radiation serves as major environmental risk
factor contributing to the development of thyroid
cancer, particulary during the first 20 years of life.
Figure 11. Point mutations in thyroid
Another environmental risk comprises iodine carcinomas (1)
deficiency linkage to the incidence of thyroid follicular
carcinomas.1,5
Conclusion
Hyperthyroidism is hyperfunctioning of thyroid gland that may induce a condition termed
thyrotoxicosis, the body hypermetabolic state, due to increasing levels of free thyroid
hormones in bloodstream. It is caused by various etiologies, which are generally divided to
three classifications; hormones overproduction, gland destruction, or certain drugs
prescription. Furthermore, any multifactorial diseases affecting thyroid gland growth and
function may play important role in disease generation with specific pathogenetic
mechanism. Most clinically significant ones, also serving as primary causes, include
Graves’ disease, thyroid adenoma, Plummer’s disease, any types of thyroiditis, and
carcinoma of the thyroid gland.1,3
References