Hypothyroidism Case File

Hypothyroidism Case File

Eugene C.Toy, MD, William E. Seifert, Jr., PHD, Henry W. Strobel, PHD, Konrad P. Harms, MD

❖ CASE 45

A 65-year-old female presents to the clinic feeling tired and fatigued all the time. She has also noticed an increasing problem with constipation despite adequate fiber intake. She is frequently cold when others are hot. Her skin has become dry, and she has noticed a swelling sensation in her neck area. On examination she is afebrile with a pulse of 60 beats per minute. She is in no acute distress and appears in good health. She has an enlarged, nontender thyroid noted on her neck. Her reflexes are diminished, and her skin is dry to the touch.

◆ What is the most likely diagnosis?

◆ What laboratory test would you need to confirm the diagnosis?

◆ What is the treatment of choice?

ANSWERS TO CASE 45: HYPOTHYROIDISM

Summary: A 65-year-old female presents with weakness, fatigue, cold intolerance, constipation, dry skin, and goiter.

◆ Diagnosis: Hypothyroidism

◆ Laboratory tests: TSH and free T4

◆ Treatment: Thyroid hormone replacement with levothyroxine

CLINICAL CORRELATION

Hypothyroidism is quite common in older adults and may present with an indolent course, or it may induce dramatic mental changes such as coma or pericardial effusion with tamponade. The most common etiology is primary hypothyroidism, or failure of the thyroid gland to manufacture and release sufficient thyroid hormone. The diagnosis is established by an elevated thyroidstimulating hormone (TSH). The treatment is by thyroxine replacement.

APPROACH TO THYROID GLAND

Objectives

1. Be familiar with thyroid hormone metabolism.

2. Know about the regulation of thyroid hormones.

3. Understand the role of iodine on synthesis of thyroid hormone.

Definitions

Graves disease: An autoimmune disorder in which antibodies overstimulate the production of thyroid hormones leading to a condition of hyperthyroidism, or elevated thyroid hormone synthesis and secretion.

Hashimoto thyroiditis: An autoimmune disorder in which the thyroid gland is destroyed by the action of antibodies leading to a condition of hypothyroidism, or decreased thyroid hormone synthesis and secretion.

Thyroid response elements: TRE; A domain on deoxyribonucleic acid (DNA) that will bind the complex formed by thyroid hormone binding to the thyroid hormone receptor. When the complex binds to the TRE, which are located in the promoter region of the DNA, it activates transcription of the gene. When thyroid hormone is not bound to the receptor the receptor acts as a transcription repressor.

Thyroxine: T4; a thyroid hormone derived from the amino acid tyrosine that contains four iodine atoms per molecule.

TRH: Thyrotropin-releasing hormone; a tripeptide hormone that is released by the hypothalamus and that acts on the anterior pituitary to stimulate the release of thyroid-stimulating hormone.

Triiodothyronine: T3; a thyroid hormone derived from the amino acid tyrosine that contains three iodine atoms per molecule.

TSH: Thyroid-stimulating hormone or thyrotropin; a glycoprotein hormone released from the anterior pituitary in response to increased levels of TRH. TSH binds to TSH receptors on the basal membrane of epithelial cells of the thyroid gland to stimulate the release of the thyroid hormones, T3 and T4.

DISCUSSION

The major circulating forms of thyroid hormone are thyroxine (T4), containing four iodine atoms per molecule, and triiodothyronine (T3), with three iodine atoms per molecule (Figure 45-1). Of these, T3 is eightfold more active. These are synthesized in the thyroid gland after stimulation by thyroid-stimulating hormone (TSH). TSH binds a G protein–coupled receptor to activate adenylate cyclase and trigger a signaling cascade leading to thyroid hormone biosynthesis. TSH is released from the pituitary in response to negative feedback by circulating levels of thyroid hormone as well as regulation by circulating levels of thyrotropin-releasing hormone (TRH), a tripeptide synthesized in the hypothalamus.

Thyroid hormones are the only major biochemical species known to incorporate iodine. In fact, in third-world countries, iodine deficiency is the major cause of hypothyroidism (deficiency of thyroid hormones). Iodine deficiency is characterized by the development of a goiter, representing enlargement of the thyroid gland. In the developed world, where iodine deficiency is rare because of the use of iodized salt, autoimmune disorders are a leading cause of thyroid disease. These are characterized by the presence of antibodies in the blood that either stimulate or damage the thyroid gland. The most common examples are Graves disease, characterized by antibody overstimulation of thyroid hormone production, and Hashimoto thyroiditis, leading to autoimmune destruction of the thyroid gland. In addition, inherited human disorders resulting in mutations in the thyroid hormone receptor abolishing hormone binding have been reported. These individuals exhibit symptoms of hypothyroidism as well as a high incidence of attention-deficit disorder. This trait is genetically dominant, indicating that the mutant receptors act in a dominant negative manner.

Thyroid hormone biosynthesis (Figure 45-2) involves the concentrative uptake of iodide into thyroid cells where it is converted into iodine by thyroid peroxidase in the colloid space of the follicular lumen. Iodine is incorporated into tyrosine residues of thyroglobulin contained within the colloid space at the basal surface of the thyroid follicular cell. Tyrosine residues are iodinated

Figure 45-1. Structures of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Also shown are the intermediates monoiodotyrosine (MIT) and diiodotyrosine (DIT) that are also formed on thyroglobulin.

at either one or two sites, and then these residues are coupled to generate either T3 or T4 residues within thyroglobulin. The iodinated thyroglobulin is then taken up from the extracellular matrix into the cytoplasm of the thyroid cell where lysosomal proteases cleave T3 and T4 from thyroglobulin. The hormones are then carried in the blood bound primarily to thyroid-binding globulin. T4 is converted to T3 in the liver and to a lesser extent other tissues, accounting for 80 percent of circulating T3.

Thyroid hormones stimulate protein synthesis in most cells of the body. They also stimulate oxygen consumption by increasing the levels of the Na+, K⁺-ATPase ion transporter. The generation of plasma membrane Na⁺ and K⁺gradients by the Na⁺, K⁺-ATPase is a major consumer of cellular adenosine triphosphate (ATP), leading to stimulation of ATP synthesis in the mitochondria

Figure 45-2. Biosynthesis of the thyroid hormones T3 and T4 in the thyroid follicular cell and release into the bloodstream. Abbreviations are as follows: TG, thyroglobulin; MIT, monoiodotyrosine; DIT, diiodotyrosine; T3, triiodothyronine; T4, thyroxine.

thus directly increasing mitochondrial energy metabolism. By this means, thyroid hormones aid the conversion of food into energy and heat. In all of its known actions, thyroid hormone exerts its effects by interaction with its receptor in the cell nucleus and activation of transcription of the target genes.

Thyroid hormone receptors are members of a large nuclear receptor superfamily that includes receptors for steroid hormones, vitamin D3, and retinoic acid. Members of this receptor superfamily contain a DNA-binding domain responsible for binding to hormone response elements contained within the

promoters of target genes. In addition, members of this superfamily contain a region responsible for specific binding to the hormone or biologically active agent. DNA-binding specificity is mediated by receptor sequence motifs known as zinc fingers, owing to their chelation of one zinc ion per loop, or finger. In the case of thyroid hormone, receptors bind thyroid response elements (TREs). Thyroid-hormone receptors can bind TREs as monomers, as homodimers, or as heterodimers with the retinoid X receptor, another member of this superfamily. The latter exhibits the highest DNA-binding affinity and is the major functional form of the receptor.

In essence, these receptors serve as hormone-activated transcription factors that directly regulate transcription of messenger ribonucleic acid (mRNA) from target genes. In contrast to other members of this superfamily, thyroid hormone receptors bind their sites on the promoter regions of DNA in the absence of bound hormone, usually resulting in transcriptional repression. Binding of thyroid hormone triggers a conformational change in the receptor, converting it to a transcriptional activator. In this state, it is competent to bind a group of coactivator proteins including histone transacetylase, an activity that serves to create a more open configuration on adjacent chromatin. Mammalian thyroid receptors are encoded by two different genes, each of which can be alternatively spliced, yielding four different receptor isoforms. These isoforms differ in their functional characteristics as well as their tissuespecific and developmental stage–dependent expression, underscoring the complexity of the multiple physiologic effects of thyroid hormones.

COMPREHENSION QUESTIONS

[45.1] A 25-year old female sought treatment for her constant fatigue, lethargy, and depression. She was small in stature and had previously been diagnosed with attention-deficit disorder. On physical examination she was found to have an enlarged thyroid gland (goiter). Blood tests revealed elevated levels of T3, T4, and TSH, yet she did not exhibit typical symptoms of hyperthyroidism. Which one of the following possibilities offers the most likely explanation of her symptoms?

A. Thyroid hormone overproduction because of a thyroid gland tumor

B. Hypersecretion of TSH because of a pituitary tumor

C. Genetic alteration in the thyroid receptor reducing its ability to bind thyroid hormone

D. Mutation in the TSH receptor in the thyroid gland reducing its ability to bind TSH

E. Iodide deficiency in the diet

[45.2] In individuals with iodide deficiency, which one of the following is most likely?

A. TSH levels are elevated and directly stimulate growth of the thyroid gland to a very large size.

B. Mono- and diiodinated thyroid hormone molecules are produced, and elevated levels of these derivatives compensate for the deficiency.

C. TSH levels are decreased, relieving their inhibitory effects on thyroid cell proliferation.

D. Synthesis of the Na+, K+-ATPase is increased.

E. Tissue utilization of oxygen is increased.

[45.3] In women taking thyroid hormone replacement pills, the dosage must be adjusted if they start taking birth control pills. Which one of the following best explains this situation?

A. Thyroid hormones block the action of estrogens, so the estrogen dose must be increased.

B. Estrogens block the action of thyroid hormones, so the dose of thyroid hormone must be increased.

C. Progestins block the action of thyroid hormone, so the dose of thyroid hormone must be increased.

D. Thyroid hormones stimulate the action of estrogens, so the estrogen dose must be decreased.

E. Estrogens stimulate the action of thyroid hormone, so the dose of thyroid hormone must be decreased.

Answers

[45.1] C. The patient exhibits symptoms of hypothyroidism including goiter, yet thyroid hormone levels are elevated. This pattern can only be explained by resistance of target cells to thyroid hormone, for example, a mutation of the receptor decreasing its binding affinity for hormone. Iodide deficiency would lead to goiter but not increased hormone levels.

[45.2] A. Elevation of TSH is the mechanism for goiter formation. Decreased thyroid hormone levels reduce feedback inhibition of TSH secretion by the pituitary. TSH secretion is therefore increased. TSH acts as a growth factor for the thyroid gland, increasing its mass and therefore its capacity to synthesize thyroid hormones.

[45.3] B. Estrogens partially block the action of thyroid hormones, making them less effective.

BIOCHEMISTRY PEARLS

❖ The major circulating forms of thyroid hormone are thyroxine (T4), containing four iodine atoms per molecule, and triiodothyronine (T3), with three iodine atoms per molecule.

❖ TSH binds a G protein–coupled receptor to activate adenylate cyclase and trigger a signaling cascade leading to thyroid hormone biosynthesis.

❖ In developed countries, where iodine deficiency is rare because of the use of iodized salt, autoimmune disorders are a leading cause of thyroid disease.

❖ Thyroid hormone receptors bind their sites on the promoter regions of DNA in the absence of bound hormone, usually resulting in transcriptional repression.

❖ Binding of thyroid hormone triggers a conformational change in the receptor converting it to a transcriptional activator.

References

Barrett EJ. The thyroid gland. In: Boron WF, Boulpaep EL. Medical Physiology: A Cellular and Molecular Approach. Philadelphia, PA: W.B. Saunders, 2003. 

Litwack G, Schmidt TJ. Biochemistry of hormones I: polypeptide hormones. In: Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations, 5th ed. New York: Wiley-Liss, 2002. 

Pathophysiology of the endocrine system. An online textbook from Colorado State University: http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/

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