mpbp 301: endocrinology 2005 thyroid hormone objectives

M:\S30105Endo\S30105Thyroid.doc 6/17/2005

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MPBP 301: ENDOCRINOLOGY 2005

THYROID HORMONE

OBJECTIVES Explain the key phrases used to summarize the actions of thyroid hormone:

Differentiation. Basal metabolic Rate.

Describe the major signs and symptoms of excess or reduced thyroid hormone levels. Draw and explain the control system for thyroid hormone. Define key signals that regulate thyroid hormone secretion. Describe how and why thyroid hormone levels are affected by caloric status. Explain the production, physiologic significance and regulation of T3 and rT3 production

from T4. Describe the utility of palpation of the thyroid gland as a diagnostic tool. Describe the basis and utility of radio-isotopic scanning of the thyroid gland as a

diagnostic tool. Describe the thyroid follicular cell and the mechanisms and control of thyroid hormone

synthesis and release. Describe the mechanisms by which thyroid hormone influences Basal Metabolic Rate.

(BMR). Describe the relationship between thyroid hormone and the autonomic nervous system

and the mechanism involved. Describe the effects of thyroid hormone on fat metabolism. Describe the effects of thyroid hormone on carbohydrate metabolism. Describe the effects of thyroid hormone on protein metabolism. Describe the binding of thyroid hormone to proteins in the blood, its purpose and how the

phenomenon can complicate interpretation of measurements of thyroid hormone levels.

Describe the essential steps required to evaluate the thyroid feedback control system.


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I. SUMMARY OF EFFECTS OF THYROXINE / TRIIODOTHYRONINE (T4, T3) BMR Brain Development Increased (much of this due to an Required for normal brain development, increase in Na/K-ATPase). Especially nerve myelination. Cretinism, if hormone is missing during embryonic development. Carbohydrate 1. Gastrointestinal glucose uptake increased increased gluconeogenesis. Fat Protein 1. Mobilization of fat stores. 1. Required for normal growth. 2. Blood cholesterol decreased. 2. Increased levels cause catabolism, 3. Blood phospholipids decreased. These especially muscle. are decreased despite triglyceride mobilization from fat stores because lipid breakdown to make ATP is increased even more. 4. Many of the effects on lipid metabolism are due to changes in Autonomic Nervous System (ANS) function. Miscellaneous:

1. Synergistic involvement with the ANS. 2. High doses unmask diabetes mellitus. 3. High doses unmask failing heart.

Signs of Excess (adult): Signs of Deficit (adult): 1. heat intolerance 1. Lipemia 2. CNS changes 2. Cholesterolemia 3. sweating 3. Cold Intolerance 4. hyperglycemia 4. Myxedema (sometimes) 5. muscle catabolism 5. Obesity 6. exopthalmos (possibly due to TSH) 6. Slow Speech 7. cardiovascular axis activity 7. Poor cardiovascular axis function increased but efficiency decreased 8. BMR increased


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II. INTRODUCTION The thyroid gland is comprised of two lobes on either side of the trachea, situated near the cricoid cartilage and joined by an isthmus across the trachea. Its location offers an unusual advantage in terms of assessing thyroid function in that its size and contours easily can be palpated. Key indicators of abnormal thyroid function include increased or decreased size and the presence of discrete nodules. One must beware, however, that a small gland or an enlarged one each can be associated with hypo- or hyperthyroidism. Why this is true will be discussed in the section on testing the thyroid feedback loop. An additional property of thyroid tissue that provides another important means for assessing thyroid function is its ability to take up halides such as iodide. This property, essential for the formation of thyroid hormone, allows one to administer small amounts of radioactive halide or a surrogate (technetium) and then to scan the gland. By this means, one can identify such features indicative of pathology as discrete "hot spots" where aggressive uptake of halide is occurring; as well as "cold spots" where uptake has been shut down.


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II. CONTROL SYSTEM. The diagram below summarizes the feedback loop for the thyroid gland. Note the question marks regarding feedback into the hypothalamus and central nervous system. The nature of this feedback remains controversial. Additionally, as will be discussed below in the section on testing the feedback loop, what is critical to understanding diagnostic testing is the negative feedback on the adenohypophysis. The thyroid gland releases two substances, thyroxine (T4), which has four iodides covalently bound to it, and triiodothyronine (T3), which has three. T3 is the active hormone. The T4 that is released, therefore, amounts to a circulating reservoir or "prohormone" that can be converted to T3 as shown in the diagram. In the peripheral circulation, T4 is broken down either into biologically active T3, or into biologically inactive reverse T3 (rT3). In the latter case, a different one of the four iodides has been removed from T4. This process is regulated physiologically. The combination of T3 released directly from the gland and the T3 made from T4 in the peripheral circulation comprises the T3 that is measured in the blood as the active hormone.


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III. The Thyroid Follicular Cell. A. The plasma membrane iodide pump (“trap”). 1. This active transport process normally concentrates iodide in the follicular cell

30-40X over concentrations in the blood. 2. This pump is blocked by cardiac glycosides, such as ouabain and digitalis.

Thus, treatment of heart disease with these drugs can lead to important side effects on the function of the thyroid gland.

B. Organification: the coupling of iodide to thyroglobulin. 1. Occurs at the apical surface of the follicular cell very rapidly after iodide is taken

up. The enzyme responsible is thyroid peroxidase.

2. Thyroglobulin (TG) is a very large glycoprotein with tyrosine amino acid residues making up an unusually large portion of its peptide backbone as compared with most proteins. Iodide is coupled covalently to these tyrosines to make monoiodo-tyrosine (MIT) and diiodotyrosine (DIT). MIT and DIT are then coupled covalently to make thyroxine (T4: 2X DIT) or triiodothyronine (T3: MIT plus DIT) precursors which still are part of the thyroglobulin molecule.

3. Iodinated TG is exocytosed into colloid space where it is stored until needed.


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C. Resorption: Hormone Release. 1. Upon proper signal in the form of increased circulating levels of thyroid stimulating

hormone (TSH), colloid containing iodinated TG is pinocytosed at the apical surface. The resulting pinosomes fuse with lyzozomes, the digestive enzymes from which hydrolyze TG forming MIT, DIT, T4, T3, and amino acids. T4 and T3 diffuse into the circulation. An intracellular deiodinase takes the iodide molecules off of MIT and DIT so that they can be released. The released iodide can then be reused.

D. Actions of TSH on the Thyroid Gland. Multiple second messenger pathways are activated. The end result is increased release and synthesis of hormone.

IV. OVERALL FUNCTIONS OF THYROID HORMONE. Thyroid hormone has two overall functions. First, it is a critical hormone for development. T3 plays a central role in overall morphogenesis. The absence of sufficient levels of hormone at critical periods in fetal and early life leads to the group of symptoms called cretinism. A key pathology associated with cretinism includes poor axonal development and abnormal myelination of nerves. The second major role that thyroid hormone plays is in maintaining basal metabolic rate (BMR). T3 does so by affecting ATP utilization and through its synergistic effects with the autonomic nervous system (see below). To support these roles, thyroid hormone levels normally stay relatively constant on as daily or even weekly / monthly basis, especially compared with such hormones as insulin, glucagon, growth hormone or aldosterone. Thyroid hormone levels also are regulated by diet. Fasting causes a fall in T3. This is partially due to a fall in TRH and in TSH. It is also due to increased conversion of T4 to


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rT3, and a corresponding decreased conversion of T4 to T3.It makes good physiologic sense to reduce BMR in times of caloric restriction, such that precious calories can be diverted to vital functions such as assuring that the brain has a sufficient supply of glucose. V. KEY PHRASES: DEVELOPMENT

BMR VI. FOODSTUFF METABOLISM. T3 is a key regulator of the rate at which our metabolic machinery operates, i.e. BASAL METABOLIC RATE (BMR). Because of this, normal hormone levels are required for proper growth and metabolism. Excess hormone is associated with the need to mobilize energy reserves due to a very high metabolic rate. A. Fat.

Thyroid hormone in excess causes an increase in fat synthesis but an even greater increase in degradation. Hence blood levels of those fats actually fall and there is net breakdown of fat deposits. The autonomic nervous system plays a major role in these effects (see below). B. Carbohydrate. Excess thyroid hormone causes an increase in absorption of glucose from the gastrointestinal tract. Part of this is simply due to the fact the hyperthyroid individual eats more. High levels of thyroid hormone also promote gluconeogenesis as part of overall mobilization of energy stores.


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C. Protein.

Normal thyroid hormone levels are required for growth. High levels of thyroid hormone, however, cause net protein catabolism. The amino acids which are released are used for gluconeogenesis. This is necessitated by the need to produce ATP. VI. CHANGING BMR. Two basic mechanisms have been proposed. To understand the first, it is necessary to recall that metabolic pathways cannot be force fed. Rather, the rate at which glucose and fat molecules are metabolized to form ATP, carbon dioxide, water and heat is determined by the availability of ADP. Thus, if thyroid hormone is to increase metabolism, it must do so by creating an energy sink that uses ATP much faster than usual, thereby forming increased amounts of ADP. It must affect energy charge. A major way that thyroid hormone does this is by increasing the activity of Na+/K+ ATPase. Energy Charge = [ATP] / [ADP] + [AMP] Thyroid hormone also causes other energy drains. This includes its dramatic effect in excess on cardiac work, as well as the overall increased turnover of carbohydrate, fat and protein in what amount to be very energy wasteful processes. A major cause of this is related to the effects of thyroid hormone on the function of the autonomic nervous system. VII. THYROID HORMONE AND THE AUTONOMIC NERVOUS SYSTEM. T3 is well-known to potentiate the actions of catecholamines: a given amount of catecholamine has a greater effect when T3 levels are elevated. Thus, it should not be surprising that many of the clinical manifestations of thyrotoxicosis resemble those of excess adrenal medullary activity. Because of this the β-receptor blocker, propranolol, has been used successfully in the management of some of the symptoms of thyrotoxicosis. It does not, of course, deal with the underlying cause of the problem.


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T3 does not appear to alter the number or affinity of ß-adrenergic receptors, or the amount of adenylate cyclase but rather the sensitivity of cells to β-receptor activation. This is accomplished byT3 regulation of the amount and/or activity of the G-protein, Gi-α. For example, in hypo-thyroid disease, Gi-α levels are increased, thus reducing the rise in cyclic-AMP levels caused by ß-receptor activation. VIII. MECHANISM OF ACTION Thyroid Hormone works through the same general mechanism as steroid hormones. It first binds to cytoplasmic and / or nuclear receptors which once activated will migrate to the nucleus to regulate the transcription of specific genes. EXAMPLES of genes affected: Growth / development; Na+ / K+-ATPase, Giα, connective tissue proteins, cardiac myosin (not discussed). IX. THYROID HORMONE BINDING IN THE BLOOD Many substances carried in the blood are bound either specifically or non-specifically to blood proteins, including albumin. This includes the steroid hormones and thyroid hormone. Of physiologic importance, the bound hormone serves as a reservoir in times


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of need, one that can last a substantial length of time. At the same time, remember that it is the FREE hormone that is biologically active, T3 in the case of the thyroid system. Historically, the presence of binding proteins has created difficulty when it comes to measuring hormone in the blood. Until recently, many assays for thyroid hormone, for example, measure total hormone in the blood. The problem is that there are many things that change binding capacity in the blood but have no effect on the operation of the thyroid feedback loop which pays attention only to free hormone. The reason for the problem is that, unless interpreted correctly, the laboratory results indicate a thyroid disorder when none is present. The figure below shows an electrophoretogram indicating to which blood proteins thyroid hormone will bind. Most is bound to Thyroid Binding Globulin (TBG) with lesser amounts to Albumin and Pre-Albumin (PA: migrates faster than the main albumin peak).

Next shown are the binding equations that govern the relationship between bound and free hormone. Shown are the equations for T3, but they are the same for T4. The equilibrium constants are such that greater than 99% of T4 and T3 are bound normally. To simplify discussion, only the equation for TBG is shown, since that is where most T4 and T3 are bound.

Let’s follow the sequence of events when binding capacity changes, specifically when there is an INCREASE in binding capacity such as occurs during pregnancy or when birth control pills containing estradiol are used. The immediate event is that some of the free hormone (even though not much is there) becomes bound to the new protein binding sites now available. This immediately is detected by the pituitary feedback


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system as reduced levels of free hormone. With less negative feedback, there is an increase in TSH secretion. The elevated TSH will cause the thyroid gland to produce enough hormone to restore the free hormone levels exactly to normal (assuming the thyroid system is OK). Thus, the feedback system is designed to assure that T3 in the last equation above remains constant. The end result is an elevated total blood T3, but a normal level of free T3. You will learn in the clinics about a method that measures thyroid hormone binding capacity, usually called a T3-resin or T3-resin uptake test. If you use this test PLUS a test for total hormone, you can calculate free hormone, the stuff you care about. X. TESTING THE FEEDBACK LOOP. A. Introduction. There are three essential steps that must be taken when one is assessing the function of an endocrine feedback loop (or anything else for that matter). First, one MUST take a thorough history. This is the bottom line. If lab tests don’t then add up, then send new samples to the lab. Second send samples to the lab to test the key signal molecules, in this case TSH and free T3. Third, you must challenge the feedback loop to see if it behaves normally. This is essential since the normal range of values (for TSH and T3) can include values that are, in fact, abnormal and vice versa. An electronic Thyroid Feedback Module has been placed on BLACKBOARD. Its purpose is to allow you to explore of the feedback system works and allow you to test your understanding. There are two unique tools for testing the thyroid. The first is real cheap: one can palpate the thyroid. Is it large? Small? of normal configuration? Second one can test the gland’s ability to take up iodide, or these days technetium, as shown in the figure below.

These two “tests” can be very helpful. However, as you may have figured out, you can have a big thyroid with hypo- or hyper-disease, or a small gland with either disease. Or for example, you can have a large thyroid gland and be euthyroid. Similarly, iodide (technetium) uptake only can be interpreted in the context of a history and the other key measurements (T3 and TSH).


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There are several other challenge tests one could do. For example, if one is dealing with a normal individual, administration of TSH should cause an increase in T3 (after a lag) and also an increase in iodide / technetium uptake. If one gives T3, one should see a fall in TSH. If one gives TRH, one should see a rise in TSH and eventually a rise in T3. Results in cases where there is malfunction depend on what is broken. If the thyroid cannot make T3 , then its levels would be low, TSH levels would be high and giving TSH would NOT cause T3 to rise. TRH would cause a large rise in TSH with no feedback. The thyroid gland would be large. Signs and symptoms would indicate hypothyroid disease. If the pituitary has a tumor secreting TSH (and ignoring feedback) then TSH and T3 will be elevated (with signs and symptoms of hyperthyroid disease). The thyroid gland will be large. Giving T3 will NOT cause TSH to go down as it normally would. TRH administration will still cause a rise in TSH because the pituitary tumor is ignoring the feedback signal. If, as an otherwise normal person, one chooses to take thyroid hormone (e.g. synthroid: an awful, life-threatening idea but some do it anyway to lose weight) then the symptoms of hyperthyroid disease would occur (if one took enough) TSH levels would be low and there would be a very little rise, if any, in TSH when I give TRH. In opposite fashion, if one lives in a part of the world where there is little available iodide in the diet, but otherwise was normal, one might become hypothyroid (if the iodide deficiency was severed) T3 levels would fall, TSH levels would rise, the thyroid gland would become enlarged and a large rise in TSH would occur in response to TRH. It turns out that there is one challenge test, when combined with signs, symptoms and other lab tests, that essentially sorts everything out. The test is to give TRH. One can do the other challenge tests mentioned as well, but one usually does not learn much more.


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A. The TRH test. The next set of figures is designed to remind you of the mechanism by which hormones such as T3 exert their negative feedback effect on the anterior pituitary. You first saw them in the section on the Hypothalamus and Pituitary.


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Now let’s take a closer look at what a TRH test actually looks like. First looking only at the NORMAL RANGE (hatched) TRH administration causes a transient increase in TSH levels, peaking at 15-30 min (see figures below). The effect is short-lived because of the short half-life of TRH. Thyroid hormone levels subsequently increase at 90-150 min for a more sustained period of time: this is not shown in the diagrams below but is shown as part of the Thyroid Module exercise.

The above diagram also shows what the results are for hyperthyroid disease. Starting with primary disease (gland is at fault), TSH levels are low even before the test dose of TRH is administered. Note that in the two cases shown the initial TSH level still is in (or at the border) of the normal range. The problem here is one to which you were introduced in GEE and also discussed in the thyroid feedback module). Normal values are based on large groups of subjects: people with disease are individuals. In the two primary hyperthyroid cases shown above, the starting values for TSH almost certainly are LOW for the individual patients, compared to the normal TSH values for them. Now the test dose of TRH is administered. The rise in TSH that subsequently occurs is severely blunted. That is because the pituitary is normal in these individuals. It recognizes the high level of thyroid hormone feeding back, TRH receptors are severely down-regulated and so TRH has little effect. Next look at the curve for secondary hyperthyroid disease. This time it is the pituitary that is broken. In most cases, and as shown here, there is a pituitary TSH-producing tumor that results not only in more TSH-secreting cells but also ignores the thyroid hormone feedback signal. Hence, the blood TSH level is high to begin with and then rises far more than in normal individuals (note the break in the axis and curve).


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The next diagram shows the normal range plus hypothyroid disease. Starting with primary hypothyroid disease (gland at fault) TSH levels are high to begin with. That is because the pituitary is normal and recognizes that there is little thyroid hormone feedback signal. With little feedback, TRH receptors are up-regulated and therefore, the TRH response is exaggerated. In secondary hypothyroid disease, the pituitary simply is unable to put out sufficient TSH. TSH levels, therefore, are low to begin with. Even though there is lower than normal thyroid hormone feedback, TRH has little effect: the pituitary gland simply cannot make much TSH.

There are many other disorders or defects in the thyroid feedback system that you will encounter as physicians. These are described in the Thyroid Feedback Module. To see if you understand how the system works, try to figure out what happens if:

1. There is an antibody circulating that ACTIVATES the TSH receptor on the otherwise normal thyroid gland.

2. There is an antibody circulating that INACTIVATES the TSH receptor. 3. There is a tumor in the lung that makes TSH in uncontrolled fashion. 4. One gives thyroid hormone to an otherwise normal individual in an amount that

makes the individual hyperthyroid. Then there are the cases of tertiary disease that involve the Central Nervous System and / or hypothalamus, the results for which are shown in the above diagram. This is equivalent to changing the set point for the thyroid control system (“changing the setting on the thermostat”). With tertiary hyperthyroidism, blood levels of thyroid hormone are above normal levels. That SHOULD result in lower than normal TSH levels. As you note, however, TSH levels are in the middle of the normal range, i.e. are “inappropriately” high. The pituitary is


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normal and what has happened is that the positive signal coming from the hypothalamus is elevated (thermostat turned up) due to the tertiary disease. The pituitary, however, does recognize that the feedback signal is strong and TRH receptors are down regulated so the rise in TSH when TRH is administered is blunted. In the case of tertiary hypothyroid disease, the CNS / hypothalamus have lowered the “thermostat” setting and the affected individual has lower than normal thyroid hormone levels. TSH levels start out in the low range of normal. When TRH is given, there is a rise in TSH, but the rise is much more modest than one would expect for the low circulating levels of thyroid hormone. REFERENCES Bahn and Heufelder (1993). NEJM, 329:1468. Pathogenesis of Grave’s Ophthalmopathy. Bunevicius, et al. (1999). Thyroid hormone therapy in hypothyroid disease.

New Engl. J. Med., 340:424. Chin (1992). Thyroid Today, XV(3):1. Current Concepts of Thyroid

Hormone Action. Chin, et al. (1993). Rec. Prog. Horm. Res., 48:393. Thyroid hormone regulation of TSH gene expression. Comi, et al. (1987). NEJM, 317:12. Treating secondary hyperthyroidism

with long-acting somatostatin. Davies (1992). Thyroid Today, XV:1. Immunology of Grave’s Disease. Green and Chambon (1986). Nature, 324:615. The oncogenic hormone receptor family. Hancock. (1991). Thyroid disease with Hodgkin's treatment. New Engl. J. Med., 325:599. Jackson, I.M.D. (1982). NEJM, 306:145. Review of TRH. Malbon, et al. (1978). J. Biol. Chem., 253:671. Thyroid-ANS interactions. Thyroid hormone may sensitize cyclase to activated receptors. Savin, et al. (1994). NEJM, 331:1249. Thyroid hormones and heart function. Strakosch, et al. (1982). NEJM, 307:1499. Immunology of autoimmune thyroid disease. Surks and Sievert. (1995). Drugs and thyroid function. New Engl. J. Med., 333:1688. Toft (1999). Update on thyroxine therapy. New Engl. J. Med., 340:469. Tsai and O'Malley (1994). Ann. Rev. Biochem., 63:451. The steroid/thyroid receptor superfamily. Thompson, et al. (1987). Science, 237:1610. Multiple T3 receptors. Utiger (1990). NEJM, 323:127. Review of therapy for hypothyroidism. Utiger 1991). NEJM, 325:278. Pathogenesis of autoimmune thyroid disease. Utiger (1995). NEJM, Cigarette smoking and thyroid disease.

Weinberger, et al. (1986). Nature, 324:641. C-erb-A gene encodes a thyroid hormone receptor.

mpbp 301: endocrinology 2005 thyroid hormone objectives

Health & Medicine

effects of thyroid hormone

thyroid hormone levels

actions of thyroid hormone

thyroid hormone secretion

formation of thyroid

binding of thyroid hormone

thyroid hormonelevels

thyroid feedback loop