Running head: HYPOTHYROIDISM 1

A Closer Look at Hypothyroidism- Part 1

Allison Rogers

King University
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A Closer Look at Hypothyroidism

Disorders of thyroid function can result from many different causes and present in many

different ways. The most common two types of thyroid dysfunction present as primary, a disease

affecting the thyroid gland and thyroid hormones (TH), triiodothyronine (T3) and thyroxine (T4)

levels, or secondary, meaning the disorder is stemming from the pituitary gland or hypothalamus

and is associated with altered production of thyroid stimulating hormone (TSH) (Bello & Bakari,

2012; Brashers, Jones, & Huether, 2014). The most common disorder of thyroid function is

hypothyroidism (Brashers et al., 2014).

Introduction to the Disease

As with disorders of the thyroid function, hypothyroidism has many different causes and

presentations as well. Primary hypothyroidism is classified by a decreased, or insufficient,

production of TH, which in turn signals negative feedback on the pituitary, causing increased

TSH, and hypothalamus causing increased thyroid-releasing hormone (TRH) (Brashers et al.,

2014). This is usually caused by a malfunction of the thyroid tissue. Primary hypothyroidism is

the most prevalent (Brashers et al., 2014) and is associated in approximately 95% of diagnosed

cases of hypothyroidism (Bello & Bakari, 2012). Causes of primary hypothyroidism include

autoimmune thyroiditis (Hashimoto disease), loss of thyroid tissue by thyroid surgery or

radiation therapy of the thyroid, head, or neck area (Bello & Bakari, 2012; Brashers et al., 2014),

or iodine deficiency (Brashers et al., 2014). Secondary, or central, hypothyroidism is seen

considerably less frequent and is defined as decreased TSH production by the pituitary gland or a

decrease in TRH by the hypothalamus. During pituitary malfunction, there is a decrease in TSH

production causes decrease in TH levels, negative feedback to the hypothalamus causes

increased TRH production. Hypothalamic malfunction causes decreased TRH production, which
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in turn triggers low levels of TSH and TH. The most common causes associated with secondary

hypothyroidism are pituitary and hypothalamic malfunctions such as pituitary tumors or

consequences of the treatment for pituitary tumors (Brashers et al., 2014). When there are little

or no symptoms but there are abnormal lab values present, subclinical thyroid disease, or mild

thyroid failure, is suspected. Subclinical thyroid disease is prevalent in 4- 8% of the general

population (Brashers et al., 2014; So, MacIsaac, & Grossmann, 2012) and in up to 15- 18% of

women over the age of 60 (So et al., 2012). Subclinical thyroid disease typically presents with

elevated levels of TSH and normal circulating levels of TH (Bello & Bakari, 2012; Brashers et

al., 2014; So et al., 2012). Congenital hypothyroidism (CH) is caused by a thyroid hormone

deficiency that is present at birth and is associated with approximately one out of every 3000 to

4000 live births worldwide (Brashers et al., 2014; Rezaelean, Poorolajal, Moghimbegi, &

Esmalinasab, 2013).

Risk Factor Identification

There are many risk factors known to be associated with hypothyroidism. There is a

higher incidence among women, and there is an increased risk with age, the risk significantly

rises with persons over 60 years of age. Other risk factors associated with hypothyroidism

include, too much or too little iodine intake or decreased synthesis of ingested iodine due to

autoimmune disorder, previous hyperthyroidism resulting in goiter, thyroid surgery, radiation

therapy to the thyroid, head, or neck, family history of thyroid disorders, autoimmune diseases,

genetic disorder affecting females (such as Turner syndrome), six months or less postpartum

(Bello & Bakari, 2012; Brashers et al., 2014; National Institute of Diabetes and Digestive and

Kidney Diseases [NIDDK], 2013). Taking some medications put one at risk for the development

of primary hypothyroidism such as amiodarone, interferon alpha, thalidomide, lithium,

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interleukin-2, and stavudine (Bello & Bakari, 2012; NIDDK, 2013). Risk factors associated with

CH are female infant (Brashers et al., 2014; Rezaelean et al., 2013), twin birth, being born in the

winter time, born by cesarean section, cigarette smoking by parents, gestational age less than

thirty-seven weeks or greater than forty weeks, mother older than 35 years, or a mother who had

had anemia or a goiter during pregnancy (Rezaelean et al., 2013).

Risk Factor Argument

I feel there are many important risk factors associated with any disease, especially

hypothyroidism. It has been documented by several sources that increasing age plays an

important role in the development of hypothyroidism. Bello & Bakari (2012) report that

hypothyroidism is most prevalent in the elderly with up to 20% of that age group having some

form of the disease. [Thyroid peroxidase] TPO catalyzes the iodination and subsequent

coupling of tyrosine residues in thyroglobulin, resulting in the synthesis of the thyroid hormones

T4 and T3 (Balmiki et al., 2014, p. 290). When there are mutations on this gene due to genetic

predisposition there are alterations in its functioning. I feel that genetics is the biggest risk factor

because if genetics mutates or alters chromosomes to the point that the body is unable to

synthesize its TH, then regardless of age, or even in the absence of all other risk factors, the body

will be unable to use the hormones properly that it already has.

Genetics and Epigenetics

There is a strong association between genetics and hypothyroidism. Balmiki et al. (2014)

report that previous studies have shown mutations in genes including sodium iodide symporter,

thyroglobulin, pendrin, dual oxidase 2, duel oxidase maturation factor, duel oxidase maturation

factor 2, and TPO have all been associated with thyroid biosynthesis disruption. TPO was
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reported to be the most common and most severe of the gene mutations. TPO is ultimately

responsible for the synthesis of T3 and T4 (Balmiki et al., 2014). Balmiki et al. (2014) state that

hypothyroidism is a heterogeneous disorder and mutations are typically inherited as autosomal

recessive traits (p. 290). According to Panicker (2011), Phosphodiesterase 8B (PDE8B) found

on chromosome 5 encodes a protein which catalyses the hydrolysis and inactivation of cyclic

AMP (cAMP) (p.167). A study showed that single nucleotide polymorphism of this gene is

responsible for approximately 2.3% of TSH variation in the population studied (Panicker, 2011).

It is suspected but not proven, that the polymorphism may reduce cAMP activity in the thyroid,

resulting in a decreased response of the thyroid gland to TSH stimulation, which leads to an

increase in TSH (Panicker, 2011, p. 167). Lymphoid tyrosine phosphatase [PTPN22] is a

negative regulator of T cell antigen receptor (CD3) signaling (Panicker, 2011, p. 167). Single

nucleotide polymorphism associated with this gene results in more inhibition of CD3 signaling

after engaging an MHC [major histocompatibility complex] antigen (Panicker, 2011, p. 167).

Cytotoxic T-lymphocyte antigen-4 (CTLA4) has also shown association with autoimmune

thyroid disease and an elevation of thyroid antibodies (Panicker, 2011).

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References

Balmiki, N., Bankura, B., Guria, S., Das, T. K., Pattanayak, A. K., Sinha, A., Das, M. (2014).

Genetic analysis of thyroid peroxidase (TPO) gene in patients whose hypothyroidism was

found in adulthood in West Bengal, India. Endocrine Journal, 61(3), 289-296. doi:

10.1507endocrj.EJ13-0237

Bello, F. & Bakari, A. G. (2012). Hypothyroidism in adults: A review and recent advances in

management. Journal of Diabetes and Endocrinology, 3(5), 57-69. doi:

10.5897/JDE11.017

Brashers, V. L., Jones, R. E., & Huether, S. E. (2014). Alterations of hormonal regulation. In

McCance, K. L., Huether, S. E., Brashers, V. L. & Rote, N. S. (Eds.), Pathophysiology:

The biologic basis for disease in adults and children (7th ed.) (pp. 717-767). Saint Louis,

MO: Elsevier Mosby.

National Institute of Diabetes and Digestive Kidney Diseases [Internet]. Bethesda (MD):

National Institutes of Health (US) (2013, March). Hypothyroidism. Retrieved from:

http://www.niddk.nih.gov/health-information/health-

topics/endocrine/hypothyroidism/Pages/fact-sheet.aspx

Panicker, V. (2011). Genetics of thyroid function and disease. The Clinical Biochemist Reviews,

32(4), 165-175. Retrieved from:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219766/

Rezaeian, S., Poorolajal, J., Moghimbegi, A., & Esmailnasab, N. (2013). Risk factors of

congenital hypothyroidism using propensity score: A matched case-control study.

Journal of Research in Health Sciences, 13(2), 151-156. Retrieved from:

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http://web.b.ebscohost.com.ezproxy.king.edu/ehost/pdfviewer/pdfviewer?sid=0d1fd4e2-

de24-4e88-9133-c7bbd0e8f5b6%40sessionmgr115&vid=11&hid=116

So, M., MacIsaac, R., Grossmann, M. (2012). Hypothyroidism: Investigation and management.

Australian Family Physician 41(8), 556-562. Retrieved from:

http://search.proquest.com.ezproxy.king.edu/docview/1035299831?accountid=56775