Lecture 3 Endo Module - Thyroid Gland
What is thyroperoxidase (TPO)?
*enzyme that is necessary to make intracellular iodine to I2* -catalyzes: 1. intracellular I- to I2 2. organification of I2 into TG 3. coupling rxn of MIT and DIT --> T3/T4
What are some factors that affect thyroid hormones?
*stimulatory:* -TSH -thyroid-stimula ting immunoglobulins -increased TBG levels (i.e. pregnancy) *inhibitory:* -I- deficiency -deiodinase deficiency -excessive I- intake (Wolff-Chaikoff effect) -perchlorate; thiocyanate (inhibit Na+-I- cotransport) -propylthiouracil (inhibits peroxidase enzyme) -decreased TBG levels (i.e. liver disease)
What are other diagnostic signs of Grave's disease?
-Clubbing of fingers Soft tissue swelling that is pigmented and hyperkeratotic. Typically painless Plummer's nails Distal separation of the nail plate from nail bed
What is Hashimoto's thyroiditis?
-autoimmune destruction of thyroid gland Hypothyroidism The most common cause of hypothyroidism is autoimmune destruction of the thyroid gland (thyroiditis) USA)in which antibodies may either destroy the gland or block thyroid hormone synthesis. NOT TSH receptor Ab (Graves) ! Other causes Iatrogenic surgical removal of the thyroid as treatment for hyperthyroidism, over radiate over medicate Pituitary/hypothalamus tumor - prevent TSH release, TRH release I− deficiency. Increased TSH levels then have a trophic effect on the gland, causing goiter. The enlarged gland (which is otherwise normal) can often maintain normal blood levels of thyroid hormone (due to the high TSH levels); in that case, the person will be clinically euthyroid and asymptomatic. If the gland cannot maintain normal blood levels of thyroid hormone, then the person will be clinically hypothyroid In the US the most common cause of primary hypothyroidism 1 - 1.5 people per 1000 A blood test may confirm the presence of antibodies against thyroid peroxidase (TPO antibodies), More often in women than men
What is the thyroid gland?
-butterfly-shaped organ -location: anterior to trachea & inferior to larynx -medial region = isthmus, left and right lobes -embedded with parathyroid glands, primarily on their posterior surfaces. The tissue of the thyroid gland is composed mostly of thyroid follicles. The follicles are made up of a central cavity filled with a sticky fluid called colloid. Surrounded by a wall of epithelial follicle cells, the colloid is the center of thyroid hormone production, unique component: iodine -sx very vascular, parathyroids, recurrent laryngeal n
What are the early symptoms of secondary hypothyroidism?
-don't heal well -chronic disease that should have healed > UTI -acts "old" over timeaChief complaint "ADR"
Although extremely common, low thyroid is largely an unsuspected illness. Even when suspected, it is frequently undiagnosed. When it is diagnosed, it often goes untreated. When it is treated, it is seldom treated optimally?
-gradual development -non-specific symptoms (e.g. weight gain, tiredness, dry skin) -often misdiagnosed as depression, fibromyalgia, anxiety disorder, infertility, etc.
What are the different thyroid hormone diseases?
-hyperthyroid = clinical states of excess thyroid hormone -hypothyroid = deficiency of thyroid hormone -euthyroid = normal levels of thyroid hormone. -describe blood levels of thyroid hormone, not the size of the thyroid gland
What is the negative feedback mechanism for the thyroid gland?
-hypothalamis --> TRH --> anterior pitiutary --> TSH --> thyroid gland --> T3/T4 --> stop anterior pituitary from producing TSH
Why do many Himalayan women have a goiter?
-local salts and minerals lack iodine -lack of iodine in the diet and no supplement of I -if there is no iodine, cannot make T3/T4, so TSH and TRH will be increased. TSH is the hormone that causes proliferation of the thyroid gland
What is secondary hypothyroidism?
-occurs when the hypothalamus produces insufficient thyrotropin-releasing hormone (TRH) or the pituitary produces insufficient TSH. Sometimes, deficient TSH secretion due to deficient TRH secretion is termed tertiary hypothyroidism. -accounts for about one of 1,000 hypothyroid patients Usually due to pituitary/ hypothalamus tumor, other Growth hormone deficiency, secondary hypothyroidism, and empty sella following treatment of childhood macroprolactinoma
T3 tests
-often useful to diagnosis hyperthyroidism or to determine the severity of the hyperthyroidism. Patients who are hyperthyroid will have an elevated T3 level. In some individuals with a low TSH, only the T3 is elevated and the FT4 or FTI is normal. T3 testing rarely is helpful in the hypothyroid patient, since it is the last test to become abnormal. Patients can be severely hypothyroid with a high TSH and low FT4 or FTI, but have a normal T3. In some situations, such as during pregnancy or while taking birth control pills, high levels of total T4 and T3 can exist. This is because the estrogens increase the level of the binding proteins. In these situations, it is better to ask both for TSH and free T4 for thyroid evaluation
What is a thyroidectomy?
-treatment option for hyperthyroidism, but it's not as commonly used as antithyroid medications or radioactive iodine There is a very small risk of damaging the structures around the thyroid gland. One such structure is the voice box nerve (known as the recurrent laryngeal nerve). If that nerve is damaged, your voice may permanently sound hoarse or scratchy. The parathyroid glands are also located near the thyroid gland, and so they too are at a small risk of injury. The parathyroid glands regulate the body's calcium levels. If they are damaged by the thyroidectomy, then hypoparathyroidism can occur. This may eventually trigger hypocalcemia (a condition of abnormally low levels of blood calcium). Even when parathyroids are working normally after your surgery, your body may be more prone to a temporary period of hypocalcemia that responds well to oral calcium supplements and fully recovers. This occurs becausehyperthyroidism can deplete the body of its calcium stores before surgery, and it takes some time to replenish this after surgery
What is hypothyroidism?
-underactive thyroid -hypothyroidism is based on symptoms and a finding of decreased levels of T3 and T4. Depending on the cause of the hypothyroidism, TSH levels may be increased or decreased. If the defect is in the thyroid gland (e.g., thyroiditis), TSH levels will be increased by negative feedback; the low circulating levels of T3 stimulate TSH secretion. If the defect is in the hypothalamus or pituitary, then TSH levels will be decreased
What is exophthalmos?
1) water trapped in eye d/t increases synthesis of GAGs 2) Lid retraction d/t increased adrenergic activity --> bright-eyed stare -when chronic --> leads to inflammation & serious problems -"too alert older person"
What are the stypes of thyroid hormone synthesis?
1. synthesis of TG; extrusion into follicular lumen 2. Na+, I- cotranspory 3. oxidation of I- --> I2 4. organification of I2 into MIT and DIT 5. coupling rxn of MIT and DIT into T3 and T4 6. endocytosis of TG 7. hydrolysis of T4 and T3 --> enter circulation 8. deiodination of resildual MIT and DIT --> recycling of I- and tyrosine
What are the 3 types of dwarfism?
1. thyroid hormone -serious mental retardation -normal body proportions 2. pituitary -normal body proportions -normal intelligence 3. achondroplastic (genetic) -stunted limbs, normal intelligence
T4 tests
Blood tests to measure TSH, T4, T3 and Free T4 are readily available and widely used. Tests to evaluate thyroid function include the following: T4 TESTS T4 circulates in the blood in two forms: 1) T4 bound to proteins that prevent the T4 from entering the various tissues that need thyroid hormone. 2) Free T4, which does enter the various target tissues to exert its effects. The free T4 fraction is the most important to determine how the thyroid is functioning, and tests to measure this are called the Free T4 (FT4) and the Free T4 Index (FT4I or FTI). Individuals who have hyperthyroidism will have an elevated FT4 or FTI, whereas patients with hypothyroidism will have a low level of FT4 or FTI. free thyroxine index (FTI) Combining the TSH test with the FT4 or FTI accurately determines how the thyroid gland is functioning. The finding of an elevated TSH and low FT4 or FTI indicates primary hypothyroidism due to disease in the thyroid gland. A low TSH and low FT4 or FTI indicates hypothyroidism due to a problem involving the pituitary gland. A low TSH with an elevated FT4 or FTI is found in individuals who have hyperthyroidism
TPO antibody results come back negative, ruling out Hashimoto disease. The patient is referred to an endocrinologist who, after confirming the laboratory findings, suggests that this may be a case of post-viral thyroiditis, which is often transient. The endocrinologist prescribes replacement therapy with levothyroxine (T4). What is the physiologic advantage to treatment with T4? Body tissues make the right amount of T3 less overdose What dz cause delayed healing?
Diabetes mellitus Hypothyroid Liver failure >hypoalbuminemia etc Cushings Cancer Any systemic disease Smoking EtOH obesity
What are thyroid scintigrams?
Five different scintigrams taken from thyroids with different syndromes: Iodine123 (A) Normal thyroid; (B) Graves disease, diffuse increased uptake in both thyroid lobes; (C) Plummer disease (toxic multinodular goiter); (D) Toxic adenoma; -cancer (E) Thyroiditis (marker 99Tc)
Thyroid hormones regulate growth by stimulating which of the following? A. GH gene expression in somatotrophs 2. estrogen/ Testosterone gene expression in ovaries/ testes 3. androgen gene expression in adrenal gland 4. SRIF expression in hypothalamus
GH gene expression in somatotrophs
The blood work indicates elevated TSH with reduced free T4. What is the most likely cause of such a finding and what test should be ordered to confirm the diagnosis?
Hashimoto disease. Therefore, PTO( thyroid peroxidase antibody) antibodies should be elevated. A positive finding would support the diagnosis
A 35-year-old woman is seen in the endocrine clinic for evaluation of thyroid disease. The patient complains of weight loss, irritability, and restlessness. Physical examination reveals enlargement of the thyroid gland, weakness in maintaining the leg in an extended position, warm and moist skin, and tachycardia. Family history identifies the patient's mother as exhibiting hypothyroidism after the birth of the patient's brother and an aunt with Hashimoto disease. Based on the history and physical examination, what would be a reasonable initial diagnosis?
Hyperthyroidism --> Grave's Disease
The Ab titers indicate that the patient has Graves disease. What treatment would be appropriate for this patient?
Radioactive iodine PTU-inhibits thyroid peroxidase Propylthiouracil If thyroid levels increase after removal of the drug, then thyroidectomy indicated If thyroid is resected, monitor parathyroid (located behind the thyroid) to make sure the surgeon did not injure parathyroid
Is this the same reason for iodine pills after a nuclear bomb?
Radioactive iodine-131 was produced from plutonium
Why were people given iodine pills after the Tsunami- related nuclear reactor failure in Fukushima/ Daiichi?
Radioactive iodine-131 was produced from uranium Pills Saturates thyroid gland so that radioactive iodine will not be accumulated
thyroid function tests
T4 and T3 circulate almost entirely bound to specific transport proteins, and there are some situations which these proteins could change their level in the blood, producing also changes in the T4 and T3 levels (it happens frequently during pregnancy, women who take control birth pills, etc). Another measurement done to assess the thyroid status of patients is the Free T4 measurement. The Free T4 avoids any change the proteins could have, giving us a more accurate value for the T4 level Blood tests to measure TSH, T4, T3 and Free T4 are readily available and widely used. Tests to evaluate thyroid function include the following: TSH TESTS A high TSH level indicates that the thyroid gland is failing because of a problem that is directly affecting the thyroid (primary hypothyroidism). TSH level is low, usually indicates that the person has an overactive thyroid that is producing too much thyroid hormone (hyperthyroidism). Occasionally, a low TSH may result from an abnormality in the pituitary gland, which prevents it from making enough TSH to stimulate the thyroid (secondary hypothyroidism). In most healthy individuals, a normal TSH value means that the thyroid is functioning normally
A child is born with a very rare mutation disorder in which deiodinases in target tissues are defective. In this severe case, the child presented with growth delay, failure to thrive, mental retardation and immune deficits. Which of the following do you predict?
T4 is the main hormone released by the gland, the target tissue makes changes to T3. The main active hormone that does the feedback inhibition at the pituitary and it does the action at the organ (pituitary) is T3. T3 has a bigger impact. Since, no T3, means TSH is increased. T4 is primarily released, but the actions are mainly T3. The gland releases T4.
A 55-year-old construction worker is seen by you in December complaining of fatigue, weight gain, and poor appetite. The patient comments that he is always cold when working outside and that this has never been a problem before. He has also noticed that small cuts on his hand seem to take a long time to heal. Physical examination reveals that the patient is obese, with a body mass index of 35 kg/m2. Skin is dry, hair is course, complexion is sallow (pale yellowish), and heart rate is slow. You suspect hypothyroidism . What laboratory tests should be ordered to support a diagnosis of hypothyroidism and what would you expect?
TSH high Free T3/T4 low
What is Grave's disease?
TSH receptor on the thyroid cells also is activated by thyroid-stimulating immunoglobulins, --antibodies to the TSH receptor. TSH effect = thyroid immunoglobulin effect Graves disease, a common form of hyperthyroidism, = autoimmune disease caused by increased circulating levels of thyroid stimulating immunoglobulins the thyroid gland is intensely stimulated by the antibodies, > levels of thyroid hormones increase In Graves disease, they produce the same response in thyroid cells as TSH: stimulation of thyroid hormone synthesis and secretion and hypertrophy and hyperplasia of the gland (i.e., hyperthyroidism). TSH levels are actually lower than normal because the high circulating levels of thyroid hormones inhibit TSH secretion by negative feedback Goiter (i.e., enlarged thyroid) can be associated with certain causes of hyperthyroidism and also, perhaps surprisingly, with certain causes of hypothyroidism and euthyroidism The most common form of hyperthyroidism is Graves disease, -Other causes of hyperthyroidism are thyroid neoplasm, excessive secretion of TRH or TSH, and administration of excessive amounts of exogenous thyroid hormones too much meds! The diagnosis of hyperthyroidism is based on symptoms and measurement of increased levels of T3 and T4. -use TSH to locate lesion TSH levels may be decreased or increased, depending on the cause of the hyperthyroidism. If the cause of hyperthyroidism is Graves disease, thyroid neoplasm (i.e., the disorder is in the thyroid gland), or exogenous administration of thyroid hormones (factitious hyperthyroidism), then TSH levels will be decreased by negative feedback of the high levels of T3 on the anterior pituitary. However, if the cause of hyperthyroidism is increased secretion of TRH or TSH (i.e., the disorder is in the hypothalamus or anterior pituitary), then TSH levels will be increased -high free T4 -low TSH -increased I= uptake -autoimmune dz --> thyroid-stimulating immunoglobins
A 25-year-old woman complains of weight loss, heat intolerance, excessive sweating, and weakness. TSH and thyroid hormones are elevated; goiter is present; and no antibodies acting at the thyroid system are detected. Which of the following is the most likely working diagnosis consistent with these symptoms? A. Graves disease B. Peripheral thyroid hormone resistance hypothyroidism C. Myxedema D. Acute Hashimoto disease E. TSH-secreting pituitary tumor
TSH-secreting pituitary tumor
What is a thyroid biopsy?
Thyroid nodules are common and usually benign, the risk of malignancy varying from 5 to 10%. Steps to diagnose malignancy should include a careful clinical evaluation, laboratory tests, a thyroid US exam and a fine-needle aspiration (FNA) biopsy. Thyroid FNA biopsy is the most accurate test for determining malignancy
What is the second effect of thyroid gland issues in pregnancy?
hCG has similarities with TSH Can lead during and after pregnancy to thyroid changes (e.g. hyperthryoidism followed by hypothyroidism)
A 50-year-old woman complains of chronic fatigue, aching muscles, and general weakness. Physical examination reveals a modest weight gain, dry skin, and slow reflexes. Laboratory findings include TSH: >10 mU/L (normal range 0.5-5 mU/L), free T4: low to normal. With of the following is the most likely explanation? A. hyperthyroidism due to autoimmune thyroid disease B. hyperthyroidism due to iodine excess C. hyperthyroidism secondary to a hypothalamic-pituitary defect D. hypothyroidism due to autoimmune thyroid disease E. hypothyroidism secondary to a hypothalamic-pituitary defect
hypothyroidism due to autoimmune thyroid disease
A 32-year old woman (not pregnant, two children ages 10 and 14) complains of excessive tiredness, weight gain, and constipation. She reports breast discharge and amenorrhea. Laboratory results indicate that serum TSH is markedly decreased. What additional laboratory finding would most likely be present in this patient? A. Decreased TRH B. Increased GH C. Increased TRH D. Increased T3 E. Increased T4
increased TRH
Which of the following best applies to the Iodide transporter across the basolateral membrane of the thyroid follicular cell? A. It requires very high iodide concentration B. It requires active TPO (peroxidase) C. It occurs by cotransport with potassium D. It occurs by cotransport with sodium E. It is activated by perchlorate and thiocyanate
it occurs by cotransport with sodium
How does Hashimoto disease lead to goiter?
persistent inflammation of the thyroid and necrotic damage leads to hypothyroidism --> increased TSH > more nonfunctioning thyroid tissue
How is goiter avoided in the US?
potassium iodate or potassium iodine in table salt
What inhibits peroxidase in thyroid hormone production?
propylthiouracil (Methimazole)
What are the two associated hormones with the thyroid gland?
thyroxine, triiodothyronine and calcitonin
What are the main processes does the thyroid gland contribute to?
1. body growth 2. brain development 3. CV system -*hyperthyroid* patients --> increased CO & HR -*hypothyroid* patients --> decreased HR & may cause low LDL and high cholesterol 4. SNS -potentiate stimulation of heart rate and force of contraction potentiate stimulation of lipolysis and glycogenolysis -potentiate stimulation of the central nervous system
From a blood sample, what hormone concentration would you ask the laboratory to measure and what would you expect the results to be?
2. TSH Low 2. free T3/T4 High b3. Ab to TSH receptor to be increased
What are the 2 abbreviatons for thyroid gland testing?
Measuring levels of thyroid antibodies may help diagnose the cause of the thyroid problems. Positive anti-thyroid peroxidase and/or anti-thyroglobulin antibodies in a patient with hypothyroidism make a diagnosis of Hashimoto's thyroiditis. TPO test If the antibodies are positive in a hyperthyroid patient, the most likely diagnosis is autoimmune thyroid disease.Graves thyrotropin receptor antibodies (TRAb) or thyroid stimulating immunoglobulins (TSI)
How do yor treat for hypothyroidism?
Synthetic hormones replacement therapy with thyroid hormone > for life This usually involves daily use of the synthetic thyroid hormone levothyroxine (Levoxyl, Synthroid, others). Synthetic levothyroxine is identical to thyroxine, The oral medication restores adequate hormone levels and reverses all the symptoms of hypothyroidism. Treatment with levothyroxine is usually lifelong, but because the dosage needed may change -check TSH level about every 12 months
What is the main secretory product of the thyroid gland?
The major secretory product of the thyroid gland is T4, which is not the most active form of thyroid hormone. T3 active > T4 + This "problem" is solved in the target tissues by the enzyme 5′ iodinase, which converts T4 to T3 by removing one atom of I2 Major control of the synthesis and secretion of thyroid hormones is via the hypothalamic-pituitary axis. Thyrotropin-releasing hormone (TRH) is secreted by the hypothalamus and acts on the thyrotrophs of the anterior pituitary to cause secretion of thyroid-stimulating hormone (TSH). TSH then acts on the thyroid gland to stimulate the synthesis and secretion of thyroid hormones. + TSH has a trophic effect on the thyroid gland. This trophic effect is exhibited when TSH levels are elevated for a sustained period of time and leads to hypertrophy and hyperplasia of thyroid follicular cells and increased thyroidal blood flow. Goiter Thyroid hormones act on virtually every organ system in the human body: Thyroid hormones act synergistically with growth hormone and somatomedins to promote bone formation; they increase basal metabolic rate (BMR), heat production, and oxygen consumption; and they alter the cardiovascular and respiratory systems to increase blood flow and oxygen delivery to the tissues. Revs the engine!