Jade Stashin

May 31, 2018

Period 4

Ms. Keilty - 7th Grade Science

Integrated Project: Hashimoto’s Thyroiditis

For this year’s integrated research project, I chose to study endocrinology, the branch of

biology regarding the body’s system of hormone distribution. This particular subject spiked my

interest due to the various functions it performs to maintain the body’s health; from sleep to

sexual reproduction. Furthermore, I have prior experience with the subject from a previous

research project. The endocrine system controls and regulates hormone secretion. The system

consists of 7 glands: pineal, hypothalamus, pituitary, thyroid, parathyroids, pineal, adrenal

glands, pancreas, and ovaries/testes (Becker). Technically, the thymus, a gland positioned

beneath the thyroid, can be considered part of the digestive, as well as the endocrine system.

Hormone secretion starts in the brain; messages sent through neurons travel towards the

hypothalamus, an almond shaped gland that forms the ventral section of the diencephalon. The

hypothalamus acts as the “bridge” that joins the nervous system and endocrine stystem.

Connected to the hypothalamus via nerve fibers, lies the pituitary gland. The pituitary releases a

specific hormone (ATCH, LH, TSH, FSH) in order to stimulate ​another g​ land according to the

brain’s directive (Becker). Finally, the gland stimulated by the pituitary secretes the necessary
chemicals. Hormones flow through the bloodstream, throughout the body until the “target

cell”—the cell that the hormone was designed to alter—is

reached (Milas).

Hashimoto's thyroiditis (HT), or chronic lymphocytic thyroiditis, is an autoimmune

disorder that occurs in the thyroid, a gland located at the base of the neck and in front of the

larynx. The disease was named after Dr. Hakaru Hashimoto, who in 1912, made the first

diagnosis of chronic lymphocytic thyroiditis. The term ​lymphocytic​ refers to a class of antibody

called lymphocytes, while ​thyroiditis​ means “inflammation of the thyroid” in latin (Caturegli) .

HT transpires when mutated antibodies target and attack the gland follicular cells and tissue

(Milas). Follicular cells are also called thyrocytes. Thyroiditis can be classified into two forms:

primary and secondary. The most frequent cases of thyroiditis care categorized as primary.

Primary HT comprises of six variations: classic, juvenile, fibrous, postpartum, Hashitoxicosis,

and IgG4-related (Caturegli). Lymphocytic infiltration is a common characteristic of all six

adaptations. Unlike its more common form, secondary hashimoto’s was identified in the early

1970’s. Studies propose that this classification of Hashimoto’s has a hereditary aspect.

Additionally, specialists have already identified that the administration of immunomodulatory

medications, such as cancer vaccines, can provoke the development of secondary thyroiditis

(Caturegli). HT is a life threatening disease, and, unfortunately, the only therapy available to

treat HT is thyroid hormone replacement (Mayo Clinic).

There are more than 200,000 cases of Hashimoto’s thyroiditis a year, and more than 14

million cases in the US alone, making it the most common thyroid disease in the country

(Caturegli)(Diabetes.co.uk). Additionally, those of African decent, Asian, Latino, etc. have a 5%

lower chance of developing HT’s as opposed to Caucasians (Caturegli). Moreover, studies show

that Hashimoto’s is prominent in women, who are 8-10 times more likely to have Hashimoto’s

than men. The most common ages of manifestation are between years 40-60—12 out of every 13

patients are women. The age with the highest record of people with Hashimoto’s is between 40

yrs old to 60 yrs old—12 out of 13 patients are female. The data pattern repeats in all 6 variants

of HT’s (Figure A). Even at ages 10 through 18 (juvenile variant), 6 out of 7 patients are girls

(Caturegli). Diagnosis of other autoimmune disorders, such as celiac disease and polycystic

ovary syndrome (PCS), multiply one’s prevalence of HT by 6 folds. Other autoimmune disorders

that can increase the chance of Hashimoto's include autoimmune hepatitis, type 1 diabetes,

Addison’s disease, rheumatoid arthritis, etc. (National Institute...Diseases).

Figure A: Comparing female:male Hashimoto’s patients (Caturegli).

Hashimoto’s in an autoimmune disease, a disruption in the immune system that causes

antibodies to process healthy and benign cells as a threat to the rest of the body. The direct cause

of disease onset in unknown, however most speculations suggest that in genetically predisposed

individuals, the immune cell’s autoimmune response against antigens within the thyroid can be

prompted by the presentation of iodine, viral infection, toxins, and/or other environmental

triggers. At the exposure of environmental factors, an accumulation of antigen presenting cells

(APC)—various subclasses of macrophages, dendritic cells, and endothelial cells— start in the

thyroid. From the thyroid, APC travel through the bloodstream to a contiguous draining lymph

node, where the production of antibodies (B and T lymphocytes) occur. Interplay between APC

and AR, autoreactive meaning acting against its own cells or tissues, B and T lymphocytes take

place. The result of which, the clonal expansion of thyroid-specific antibodies. Immunological

tolerance, as in lack of response towards substances that would spur the immune response

otherwise, has been generally associated with genetics and gene mutation. Major

histocompatibility complex (MHC) class II molecules have also been suggested to have an

involvement with the malfunction as well. These molecules are most known for coding the

proteins that help lymphocytes recognize antigens. In the final stage of infiltration, autoreactive

T and B cells are stimulated by cytokines, proteins secreted by T helper 1 (TH1), and then

drained from the lymph node, where they then re-enter and accumulate in the thyroid. Mediated

by cytokines, T and B cells initiate the gradual decomposition of thyrocytes (Chistiakov).

Figure B: A scheme of autoimmune events in Hashimoto’s thyroiditis (Chistiakov).

Symptoms and indicators of Hashimoto’s classic variation advance at a gradual rate. The

most notable characteristic of HT’s is the grey color and firm texture of the thyroid gland

(Caturegli). Patients with Hashimoto’s most commonly experience lethargy and/or muscle

weakness, unexplained muscle aches, softening, or rigidness, pain or stiffness in joints, swollen

face, hair loss, dry skin, constipation, spontaneous weight gain, memory lapses, depression,

enlargement of tongue or thyroid gland, and/or extended or immoderate menstrual bleeding

(Mayo Clinic). Risk of hypothyroidism, a condition in which the thyroid is inactive and doesn’t

produce enough T3 and/or T4, and goiter, inflammation and swelling of the thyroid gland, are

increased in HT patients as well.

It is estimated that about 70-80% of thyroid autoimmune disorders caused by a genetic

mutation. If this hypothesis is indeed true, scientists have figured that a dysfunction in the CD40

protein,human leukocyte antigen (HLA), and the cytotoxic T-lymphocyte-associated (Ctla4)

protein may have an involvement with Hashimoto’s thyroiditis, as well as Grave’s disease (other

autoimmune thyroid disorder) (Caturegli)(Brent). All three of the following proteins monitor the

functions of antigens within our body. It can confirmed, however, that this disease does not

manifest in specific socioeconomic statuses. Like most diseases, Hashimoto’s is most likely

triggered by a hereditary gene mutation, which doesn’t anything to do with social class. An

example of which would be how the wealthy are most likely to be able to ​afford​ therapy for an

illness. However, this does not mean that people of that social class are ​less likely​ to develop it.

As long as a disease is genetic, economic standings ​do not matter​ in comparison to inherited

genes.

Although the exact cause of the disease has not yet been confirmed, there is evidence that

suggests thyroid activity and hormone production can be affected through exposure to

environmental agents. These environmental triggers can directly influence the thyroid—hormone

synthesis, secretion, etc., or, in some cases, can impact the pituitary gland production of TSH

(thyroid stimulating hormone). The most notable of which is iodine, which is a key ingredient in

the formulation of thyroid hormones. In fact, clinical trials propose that insufficient iodine intake

can lead to a decrease in the body’s thyroid hormone secretion. A temporary decrease decline in
thyroid hormone production can be a result of excessive iodine intake. Smoking, bacterial/viral

infection, radiation, and medications such as interferon or amiraderon all have an association

with the development of HT (Brent).

Consumption of isoflavones, chemical compounds found in soy products, has an obvious

correlation with abnormal thyroid function. In a study that compared children with autoimmune

thyroid diseases and those without, it was discovered that the children diagnosed with a disease

were fed a notably greater amount of soy as infants. Polychlorinated biphenyls (PCBs), a

synthetic chemical used in coolants, congeners, etc., have also appeared to trigger thyroid

autoimmune disorders. According to a recent research based in Slovakia suggested that people,

particularly women, frequently exposed to PCBs were subject to thyroid autoantibodies,

enlarged/swollen thyroid, and an increase of TSH (Brent).

Agent Example of Sources Mode of Action Associated as a

trigger or
accelerating
autoimmune thyroid
disease

Polychlorinated Found in coolants, TR Possible increase in

biphenyls PCBs lubricants, and agonist/antagonist, TSH, thyroid
multiple congeners can alter levels of T4 antibodies, thyroid
(substance in and TSH volume
alcoholic beverages)

Organochlorine Used as pesticide on Induce hepatic No human studies

 pesticides crops UDPGTs and establishing
glcoronidate T4, association
accelerating
metabolism

PBDEs Used in flame Bind to TRs, Possible increase in

retardants displaces T4 from HT
binding proteins

BPA Plastic water bottles Antagonize TR No human studies

establishing
association

Perchlorate Rocket fuel, fertilizer, Inhibits iodine intake No human studies

thiocyanate cigarettes (smoke) establishing
association

Triclosan Antibacterial in soaps Reduce serum T4, No human studies

disrupt amphibian establishing
development association

Isoflavones Soy products Inhibits TPO activity Possible increase in

HT

Figure C: Environmental agents associated with thyroid function hindrance (Brent).

PCBs, polychlorinated biphenyls; TR, thyroid hormone receptor; T4 thyroxine; TSH,

thyrotropin; UDPGTs, uridine diphosphate glucuronyltransferase; PBDE, polybrominated

diphenyl ethers; HT, Hashimoto’s thyroiditis; BPA, Bisphenol A; TPO, thyroid peroxidase.

Although it can be treated, currently, the cure for Hashimoto’s remains an unknown

variable. This is partially due to cause yet to be identified. Hashimoto’s thyroiditis is most

known to prompt hypothyroidism in most patients. As previously stated, hypothyroidism is a

condition whereby the thyroid suffers from thyroid hormone deficiency ( the thyroid’s inability

to produce hormones); not to be confused with ​hyperthyroidism,​ when the gland generate an
excessive amount of thyroxine (T4) and/or triiodothyronine (T3) . As a result of this condition,

patients take doses of synthetic levothyroxine (L-T4), such as synthroid or levoxyl

(Caturegli)(Mayo Clinic). This administration of synthetic hormones is called synthetic hormone

replacement therapy, a technique used to treat various endocrine-related disorders. The method

doesn’t focus pathogenesis of Hashimoto's, rather than the symptoms of hypothyroidism.

Normally, a patient will orally take doses of around 1.6 to 1.8 micrograms; dosages are measured

depending on body weight. Advanced bone deterioration is more likely to occur in the event of

medication overdose (Mayo Clinic). One benefit of this treatment is its affordable price. In the

US, years worth supply of 112 microgram tablets has an estimated cost of around $120 dollars

for a genetic variation, and $320 for a brand name drug. The invention of synthetic thyroxine

was a global success, and with no need to replace the product, it is the only available, and most

efficient, drug used to treat the symptoms hypothyroidism. The treatment continues to be

doubted by many, despite efficiency of the medication (Caturegli). And although it doesn’t fully

“cure” Hashimoto’s, L-T4 is an overall inexpensive and effective treatment.

One thing that intrigued me the most about, not specific to Hashimoto’s, autoimmune

thyroid disorders is that they are most frequent in women, rather than men. Scientists theorize

that pregnancy is one of the main causes of thyroid hormone deficiency In fact, the sufficient

level of iodine intake is raised to an average of 220 ug per day; in the US, the average daily

iodine intake is 100 ug. A shortage of iodine supply can easily be associated with thyroid

malfunction (Brent). Also, during pregnancy, a woman’s immune system temporarily shifts. A

developing fetus has a combination of it’s parent’s DNA. During the period of pregnancy,

particles shed from the fetus’ growth flow pass the placenta and into the bloodstream, exposing
the mother to both maternal ​and​ unfamiliar paternal DNA. Thus, to protect the maturing fetus

and mother, the body enters a stage called immunosuppression, the partial or complete

suppression of the immune system (McCoy). However, after birthing, the immunity system

immediately regains strength. This sudden release of suppression is known to trigger the

advancement of autoimmune diseases, more specifically, postpartum thyroiditis. The release of

the fetus’ cells is called fetomaternal microchimerism, also known as fetal microchimerism or

simple FMc, has also been associated with the onset of thyroid autoimmune disorders (Brent).

Another theory suggests that reason behind the increased probability is ​in​ their chromosomes

​ chromosomes, women have double

[15]. It is well known that while males have double X ​and Y

X chromosomes. Scientists propose that the X chromosome can be associated with various

autoimmune disease, Hashimoto’s included. Having two X chromosomes instead of just 1,

doubles the risk of certain disease. However, this is just a theory and further research is being

conducted. Other probable factors include female immune system response and hormone release

[15].

The discovery of Hashimoto’s thyroiditis was over a century ago, made by Dr. Hakaru

Hashimoto in 1912. Since the first diagnosis, multiple advancements and significant progress has

been made in the better understanding the disease. Hormone replacement therapy, currently the

only working and available treatment to patients with Hashimoto's, was introduced in 1965.

More recently, in 2005, Japanese scientists first recognized IgG4 thyroiditis as a variation of

Hashimoto’s. Additionally, other autoimmune systems occurring in various locations of the body

have lately been associated with HT’s as well (Yoo and Chung). More recently, in 2012, research

found a 26.6% increase of the occurrence of goiter and a 65% increase in women with Polycystic
Ovary Syndrome (PCOS). Also, a meta-analysis, including 1605 women and 6 different studies,

conducted in 2013 showed an increase in thyroid peroxidase (TPO) antibodies, thyroglobulin

(TG) antibodies, excess serum TSH, and a significantly greater HT predominance [link3]. In

other words, the data displays the clear connection between PCOS and HT. To this today, studies

continue to be performed in hopes of finding a cure.

In the future, it is most certain that the direct cause(s) of the disease will be identified.

Based on current advancements in genetics, there is a high chance that researchers will discover

the mutation that prompts HT. That is, if the disease is, in fact, genetic. Immediate findings

should not be expected, however. Hashimoto’s is a recently recognized disease, having only been

acknowledged for a little over a century. Fortunately, everyday, greater innovations in genetic

and molecular technologies are invented; with each one, a step closer towards a remedy.