Individual Assignment

Metabolic Endocrine Module/2016/1st Term/3st Grade

By Nabilla Merdika Putri Kusuma, 1406642385

PBL-GD2: Etiologies, Pathogenesis, and Morphologies of Hyperthyroidism

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)

III. Diffuse Toxic Goiter (Grave’s Disease)

Grave’s disease is an autoimmune disease,
which serves as the most common endogenous
cause of hyperthyroidism. Additionally, it is
characterized by triad of thyrotoxicosis,
ophthalmopathy, and less-commonly
dermopathy. Morphology of this disease is
characterized by enlarged thyroid gland, usually
symmetrically. The gland is smooth and soft with
distinct capsule surrounding it. Microscopic
examination demonstrates taller, more columnar,
and more crowded follicular epithelial cells
compared to normal condition. Lymphocytes Figure 3. Graves' Disease Microscopic Specimen
infiltration can also be seen within the interstitium
along with pale appearance of colloid contained in follicular lumen.1
III.1 Pathogenesis
In this circumstance, the autoimmunity is inducing the thyroid gland activity wherein the
abnormal antibody targets the TSH-receptors causing excessive hormones production. In
90% patients with Graves’ disease, it has been found that their serum contains TSH-R
[stim] Ab acted on TSH receptors on follicular epithelial membrane. This antibody initially
called long-acting thyroid stimulator (LATS) or thyroid stimulating immunoglobulin (TSI).
This condition also favors thyrocytes to grow and along with the immune cells
accumulation within the gland, thyroid enlargement or known as goiter develops. Other
antibodies that are produced by the body druing the disease state include:
  Thyroid growth-stimulating immunoglobulins, causing thyroid follicular epithelium
proliferation and directed against TSH receptor
 TSH-binding inhibitor immunoglobulins, prevent TSH binding to its receptor, thus
inhibiting thyroid cell function. The ratio of stimulation and inhibition of thyroid differs
between persons thus sometimes patients with Graves’ disease may develop
hypothyroidism
The generation of aforementioned antibodies is still unclear, however there are scientific
evidences proving that Graves’ disease has familial tendency. This disorder is associated
with human leukocyte antigen (HLA)-DR3 and HLA-B8. First proposed mechanism
involves TSH receptor-homolog viral antigen. As for the second mechanism, it is proposed
that defect in suppressor T lymphocytes, allows T helper to stimulate B lymphocytes to
secrete the TSH-R [stim] antibodies directed to the TSH receptors.1,5

The ophthalmopathy, which occurs in up to one third of

persons with Graves disease, is thought to result from a
cytokine-mediated activation of fibroblasts in orbital tissue
behind the eyeball. Humoral autoimmunity also is
important; an ophthalmic immunoglobulin may exacerbate
lymphocytic infiltration of the extraocular muscles. The
ophthalmopathy of Graves disease can cause severe eye
problems, including tethering of the extraocular muscles
resulting in diplopia, involvement of the optic nerve, with
some visual loss, and corneal ulceration because the lids
do not close over the protruding eyeball (due to the
exophthalmos).1
Figure 4. Ophthalmopathy in Graves'
Disease(3)

IV. Follicular Adenoma

Thyroid or follicular adenoma is benign

neoplasm, often solitary, originated from
follicular epithelium. In this case, patient
may develop hyperthyroidism and
thyrotoxicosis due to autonomously
functioning thyroid nodule (AFTN), a small
portion of neoplasm that can produce
redundant amounts of T4 and T3
independently regardless of TSH control.
This condition yields in TSH-suppression.
Accordingly, the rest of surrounding normal
thyroid tissue is often suppressed. Follicular
adenoma is often solitary and spherical in
morphology, this lesion compresses adjacent
“normal” tissue and demarcated by well-
defined capsule. Microscopically, the cells
are arranged in uniform colloid-containing
follicles resembling the normal thyroid
parenchyma.1
IV.1 Pathogenesis
Any alteration constituting to the constant
activation of the cAMP pathway in the TSH- Figure 5a-b. Gross and microscopic specimens of
thyroid adenoma(1)
receptor signaling pathway may result in enhanced
autonomous growth and function of certain follicular
cells, and in the long run resulting in toxic adenoma.
In patients with toxic adenomas, study found that
there are several somatic mutations, most often are
within the TSH receptor structure at many different
domains, albeit all mutations resulting in increased
basal metabolic rate. Less commonly, there is also
mutation in GNAS1 gene that encodes for G-protein
alpha subunit utilized in secondary messenger
pathway. This alteration impairs the hydrolysis of
guanine triphosphate (GTP) to guanine diphosphate
(GDP), yielding in continuous adenylyl cyclase
activation, thus persistent cAMP signaling is
established. The causes of these mutations are
undetermined. However, it is suggested that
hereditary predisposition and thyrocytes
heterogeneity might play important roles in the
disease generation and iodine deficiency may serve
as modulating factor.1,2,5 Figure 6. cAMP secondary messenger pathway(2)

V. Toxic Multinodular Goiter (Plummer’s Syndrome)

Thyroid enlargement, known as goiter, shows the impairment of thyroid hormone
synthesis, in most cases are caused by iodine deficiency. Microscopically, the gland looks
multilobulate, asymmetrically enlarged, and massive in size. The nodules contain brown,
gelatinous colloid seen macroscopically and in closer examination they are lined by
flattened, inactive epithelium. The lesions often do not have intact demarcating capsule
and not compressing the adjacent tissues. Other lesions may include fibrosis, hemorrhage,
calcification, and cystic change.1

Figure 7a-b. Gross and microscopic specimens of plummer’s disease (1)

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

Figure 9. Proposed mechanisms of cells damage in Hashimoto's thyroiditis(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

VII. Follicular Thyroid Carcinoma

There are various types of carcinoma affecting the thyroid gland, most of them are
originated from thyroid follicular epithelium. One type is thought to induce hyperthyrodism,
which is follicular thyroid carcinomas type. Pictures below depict the differences in
microscopic specimens between adenoma and carcinoma of the thyroid gland. Follicular
carcinomas show capsular invasion (arrows) that may be minimal, as in this case, or
widespread, with extension into surrounding structures found in the neck.

Figure 10a-b. Follicular adenoma & Follicular thyroid carcinoma(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

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2007. p. 722-738.

2. Sherwood L. Introduction to human physiology. Pacific Grove, Calif.: Brooks/Cole; 2013.

p. 122.

3. Lippincott. Porth's pathophysiology + porth essentials of pathophysiology interactive

tutorials. Philadelphia: Wolters Kluwer; 2015. p. 1291-1293.

4. McPhee S, Lingappa V, Ganong W. Pathophysiology of disease. New York: Lange

Medical Books/McGraw-Hill; 2003. p. 475-479.

5. Silbernagl SLang F. Color atlas of pathophysiology. Stuttgart: Thieme; 2000. p. 280-

281.