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Evolving Concepts of Thyroid Function
Symposium on Changing Concepts of Disease
Evolving Concepts of Thyroid Function Doris G. Bartuska, MD.,* and Mary B. Dratman, MD.**
Thyroid hormones are essential for normal brain and body development, normal reproduction, lifelong metabolic functions, and defense against some aspects of the aging process. Investigators in many disciplines are actively studying fundamental questions relevant to the biology of these hormones. Their discoveries have led to progressive improvement in methods of diagnosis and management of patients with thyroid disorders.
DIAGNOSIS OF THYROID DISEASE Parameters ,elated to levels of circulating thyroid hormones have been measured for several decades, with iodine serving as the marker for these measurements. From originally poorly informative data derived from analysis of unfractionated blood iodine,t4 methods have been progressively refined to permit estimation of protein bound iodine (PBI),t serum thyroxin (T4) as measured after separation of iodocompounds on ion exchange columns (T4 by column),48 T4 measured by displacement techniques (especially Murphy-Pattee),44 and both T4 and triiodothyronine (T3) as measured by gas chromatography34 and finally by radioimmunoassay.11. 19. 46 According to recent reports, 11.46 radioimmunoassay techniques for these substances are accurate, reproducible, and sensitive, are not altered by iodine contamination (this is also true of the Murphy-Pattee and gas chromatographic techniques), and, because of their relative ease of performance, may become increasingly available. t
tThe radioimmunoassay method, discovered and pioneered by Berson and Yallow has permitted great advances in biologic research and clinical medicine. Its impact on thyroidology has been highly significant.' *Associate Professor of Medicine, Assistant Professor of Clinical Pathology, Medical College
of Pennsylvania; Attending Physician, Veterans Administration Hospital, Philadelphia, Pennsylvania ':,* Associate Professor of Medicine, Medical College of Pennsylvania; Medical Investigator, Veterans Administration Hospital, Philadelphia, Pennsylvania
Medical Clinics of North America- Vo!. 57, No. 4, July 1973
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Protein-Binding of Thyroid Hormones Unfortunately, even precise knowledge of levels of circulating hormones does not alone rule out or indicate the presence of disorders of endocrine function. The very precision of available T3 and T4 measurements has made estimation of serum hormone binding capacity increasingly important. T4 is transported by three major protein fractions: thyroxinbinding globulin (TBG), thyroxin-binding prealbumin (TBP A) and thyroxin-binding albumin (TBA).47 The small fraction of hormone which is not bound to protein is called the free fraction and is presumably the metabolically active hormone. Protein-bound hormone may vary within wide limits without necessarily reflecting alterations of free hormone. Accordingly, total circulating hormones may be high, low, or normal, but these values will be correlated with their corresponding states of thyroid function only if the T. binding capacities are normal. T~
Resin Uptake*
Competitive resin binding techniques 43 have proved useful for estimating residual T3 and T. serum binding activity. In patients without binding abnormalities, the results also indicate the level of circulating hormone. Thus a low resin value indicates high binding activity of the serum (unfilled binding sites), and is ordinarily correlated with hypothyroidism, whereas a high resin value indicates low serum binding activity (binding sites filled up) and is correlated with hyperthyroidism. However, when the clinical picture and the total levels of circulating hormones are at odds with the T3 resin test, then disorders of binding capacity should be suspected, and should be assessed. This is often made possible by identifying a cause for thyroxin binding change (See Table 1) and making a rough correlation of degree of resin-binding abnormality and degree and direction of serum T. abnormality. Table 2 provides examples of frequently observed related changes in serum T3 and T4 levels and T3 resin uptake and the nature of the thyroid diagnosis which may be derived from correlating these changes. 21 ':'The T3 resin uptake test (sometimes called the T3 test) measures the residual T4 and Ta binding capacities of the serum proteins and is not specific for T 3; therefore its name is misleading. Since the advent of T3 measurement by radioimmunoassay, confusion about nomenclature has increased even further. A more explicit shorthand is required.'8
Table 1.
Conditions Associated with Altered Thyroid Hormone Binding Capacity of Serum Proteins
DECREASED BINDING CAPACITY
INCREASED BINDING CAPACITY
Hereditary decreased TBG Protein-losing states Cirrhosis Major physical stress (surgery, acute illness) Corticosteroid therapy Dilantin therapy Androgen therapy
Hereditary increased TBG Pregnancy Infectious hepatitis Porphyria Estrogen therapy including most oral contraceptives
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Table 2.
Thyroid Hormone Levels and Serum Binding Proteins: Correlated Changes in Ta Resin Uptake
THYROID STATE
Euthyroid with normal binding capacity Euthyroid with decreased binding capacity Euthyroid with increased binding capacity Hypothyroid with normal binding capacity Hypothyroid with decreased binding capacity Hyperthyroid with normal binding capacity Hyperthyroid with increased binding capacity T 3 toxicosis
T3
T.
T3
RADIOIMMUNOASSAY
(MURPHY-PATTEE)
RESIN UPTAKE
normal
normal
normal
low
low
high
borderline high or high low
borderline high or high low
low
very low
very low
high
high
high normal or slightly increased high
high
high
very high
normal or low
low
normal or slightly decreased normal
Ta is much less tightly bound to plasma proteins than T 4, but binding is nevertheless a significant factor in determining circulating levels of this potent thyroid hormone. Abnormalities of binding capacity are reflected in quantitative alterations of T3 as measured by radioimmunoassay, similar to those found in the T4 fraction. However, there may be relatively rare but extremely important independent variations in blood levels of these two thyroid hormones, the most notable of which is "Tatoxicosis." In the latter condition, T4 levels and T4 binding capacity as measured by the T3 resin uptake are normal. Therefore, in patients who present with signs and symptoms suggestive of but not conclusive for thyrotoxicosis, with normal serum T 4 levels and normal Ta resin uptake tests, the measurement of Ta by radioimmunoassay may establish the diagnosis of this rare form of hyperthyroidism. a5, 60 Other Tests of Binding Capacity More direct estimation of serum binding is possible through the use of physical separation procedures (especially reverse flow electrophoresis) which indicate the extent of protein binding of radioactive hormone added to serum. 51 This test has a number of inherent sources of error, but it succeeds nevertheless in establishing an independent measure of binding capacity and is therefore of particular value in determining the state of thyroid function in individuals and families with major variations of thyroxin-binding proteins. Most recently, radioimmunoassay has provided precise information concerning the most important serum binding protein, namely, TBG.40 Already, this test has provided new insights into the relationship between TBG levels and systemic disease (liver disease, nephrosis), not necessarily related to primary functional thyroid abnormalities. Perhaps clinical
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information to be derived from this test will be limited by its specificity for a single binding protein. However, further investigation may make available precise tests for TBP A and TBA. If so, the direct measure of these extremely important protein fractions, yielding information about total serum binding capacity, may become standard procedure in assaying human thyroid function. Some physicians have found it useful to have available the T3 x T4 index - sometimes called the free thyroxin index or "T/'.36 This value establishes a relationship between T 4 levels and hormone binding capacity as measured by the T3 resin test. The free thyroxin index may be useful as part of the battery of screening procedures which are becoming increasingly helpful in medical diagnosis.
Thyroidal Uptake of 131 1 This test of the capacity of the thyroid gland to transport and retain iodide is of value in the diagnosis of hyperthyroidism. 25 Rarely, the thyroid may be so active that at 24 hours it may already have discharged a high percentage of its incorporated 131J into the circulation in the form of 1311_T4 and 1311_T3. Under these circumstances the per cent retained in the thyroid may fall within normal limits. In such instances, the 2 hour uptake will be helpful in identifying increased thyroidal iodine metabolism. If both 2 hour and 24 hour 131 1 uptake studies are borderline, but the clinical picture suggests hyperthyroidism, demonstration of nonsuppressibility of 131 1 uptake will be helpful in diagnosis. One week of treatment with 75 micro grams of T3 (Cytomel) daily, reduces the uptake of a normal thyroid to almost background. Hyperthyroid glands and autonomously functioning hot nodules do not change their concentration and retention of iodide under these circumstances. 8 Increased 1311 uptake does not always mean hyperthyroidism. Iodine deficiency, inborn or acquired biosynthetic defects of thyroid gland fun~ tion, and certain phases of thyroiditis are associated with high uptakes. However, these rarely lead to a mistaken diagnosis of hyperthyroidism since in most cases the patient is not toxic clinically and may in fact be hypothyroid. The exceptions relate to certain phases of thyroiditis when the patient may appear somewhat toxic and have an increased thyroidal uptake of 1311. Tenderness over the thyroid and the transient nature of the "toxic" state (weeks) often followed by signs of hypothyroidism are helpful in differentiating between Graves' disease and thyroiditis. However, prolongation of the so-called toxic phase of Hashimoto's thyroiditis has ied to its identification as a specific entity sometimes called "Hashi-toxicosis." It is reported that patients with "T3-toxicosis" may have normal 131J uptake values, but their thyroids as in most cases of Graves' disease are autonomous, i.e., nonsuppressible. In geographic areas of high iodine intake, normal 131 1 uptake levels are lower than in regions of lesser iodine availability. As the years pass and more iodine is ingested, normal values are revised downward,18 and are now in a range too low to allow them to be differentiated from those in hypothyroidism. The 131 1 uptake is decreased in all instances of
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iodine contamination of body fluids, as seen following use of iodinated radioopaque diagnostic materials.
Thyroid Scans The thyroid gland varies in size and shape from one individual to another, and distribution of functioning tissue changes not only with disease of the gland but also with age and with availability of iodine. Therefore the thyroid scan must be correlated with independent criteria of disease in order to be properly interpreted. Irregular uptake may indicate the presence of thyroiditis or multinodularity, but only if related to other evidence of these disorders. The interpretation of hot or cold areas must depend on history and physical findings, including the presence of palpable nodules. Conversely, a normal scan does not rule out the presence of significant thyroid disease since a critical mass is required fur a variant area to be visible in the scan. Thyroid scanning may be performed either with 131 1, 1231, or with technetium}O Since uptake studies are usually requested at the time of scanning procedures, it is reasonable that most scans be done with 131 I or 1231. However, in cases of low 131 1 uptakes incompatible with satisfactory scans, it may be better (because ofless radiation exposure) to use technetium rather than larger doses of the iodine isotope. Radioimmunoassay of TSH In spite of increasing precision of serum iodocompound measurement and of serum protein-binding capacity, some cases of hypothyroidism cannot be diagnosed early in the course of disease by either clinical or the above described laboratory methods. Thyrotropin (TSH) measurement by radioimmunoassay is now widely available and has sustained its initial promise of providing precise information concerning the presence of early hypothyroidism due to disease of the thyroid gland. 30 Although the exact mechanisms are not fully understood, it is clear that the hypothalamic-pituitary system is exquisitely sensitive to changes in concentrations of circulating thyroid hormones. In the presence of a normally functioning hypo thalamus providing adequate amounts of releasing hormones, the pituitary thyrotrophic cells respond to reduction ofT3 and T4 by increasing the release ofTSH into the circulationY Because the serum TSH test is reliably elevated in hypothyroid patients with intact hypo thalamic-pituitary function, it is now possible to make the diagnosis of hypothyroidism in many cases before signs and symptoms become obvious and the disease becomes well established. This may be very important in newborn infants and young children with a positive family history of thyroid disease, or in instances of prepartum treatment of the mother with antithyroid drugs. It is also important in adults: after surgery or irradiation as with 131 1, in relation to thyroiditis; in instances of etiologically unidentified atrophic change of the gland; in inherited or acquired biosynthetic defect; and in patients with untreated, clinically evident hypothyroidism where the primacy of the defect-hypothalamus, pituitary, or thyroid-is in question. Since placental TSH
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does not cross react with pituitary TSH in the radioimmunoassay procedure, it will not interfere with the diagnosis of maternal hypothyroidism during pregnancy. High levels of circulating TSH are found during the first few hours of life; these fall to normal by the third day.17.28 Therefore, if thyroid function of the newborn is in question, TSH levels will be reliable if blood for the test is drawn on or after the third day of life. Although TSH is readily and reproducibly detected by radioimmunoassayat levels slightly above normal and beyond, it is not possible to differentiate low from normal values because of technical limitations of the test. Therefore, the serum TSH will be reported as falling within the normal range in cases of hypothyroidism from hypothalamic or pituitary disease associated with deficient production of TSH. If the patient is hypothyroid by clinical criteria, with low T 4, low T3 resin uptake, and low T3 by radioimmunoassay, the TSH should be elevated; if instead it is within the normal range, then TSH deficiency may be inferred. TSH levels are not helpful in the diagnosis of thyroid overactivity since high levels of T3 and T4 found in hyperthyroxinemia of all causes suppress radioimmunoassayable pituitary TSH, and suppressed levels cannot be differentiated from normal. However, there are at least four case reports of TSH excess causing hyperthyroidism. 16, 26 The unknown stimulator of the thyroid in Graves' disease is not detected in the TSH assay. Radioimmunoassay of TSH, however, may be helpful during and after treatment for hyperthyroidism. Although the clinical status of the patient is the best guide to adjustments of doses of antithyroid drugs, the serum TSH is the best objective guide for purposes of monitoring the patient after toxic symptoms have come under some measure of control. Elevations of TSH will occur promptly as the patient develops hypothyroidism, indicating the need for reduction or cessation of antithyroid treatment. In the case of hypothyroidism following 131 1, serial TSH testing (every year, or when suggestive symptoms develop) will allow early detection of the hypothyroid state.
Thyrotropin-Releasing Hormone Tests Neuronal cells of the hypothalamus release specific chemical substances, the releasing hormones, into the portal venous circulation supplying the pituitary. These hormones are highly specific in their action and are essential for coordinated endocrine function of the pituitary gland. Thyrotropin-releasing hormone (TRH) was the first releasing hormone to be purified and synthesized. 5 , 20 Many of its properties have been defined as a result of well controlled studies in normal persons and in patients with a variety of thyroid disorders. 56 The synthetic tripeptide, pyroglutamyl-histidyl-proline amide, in every measurable way identical to TRH isolated from hypothalamus, releases TSH from the pituitary gland and raises TSH and prolactin concentration in the systemic circulation within 30 minutes after intravenous administration. 56 TRH, also known as thyrotropin-releasing factor (TRF)2° is under active investigation in a number of clinical research centers. 23, 56 The full range of its ap-
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plicability for thyroid diagnosis is not yet known. However, it is safe (no LD50 can be defined), free of significant side effects, and highly potent. Patients with normal thyroid and pituitary function respond to TRF with changes in circulating TSH as illustrated in Figure 1. The response is quite different in patients with differing forms of thyroid disease. As noted in Figure 1, patients with thyroidal hyPothyroidism have elevated resting TSH levels and show hyperresponsiveness to TRH. Patients with hypothyroidism due to hypopituitarism have low basal TSH levels and they respond poorly or not at all to TRH. Individuals with low basal TSH levels due to hypo thalamic disorders (TRH failure) but with intact pituitary glands will show blunted and delayed TSH response to one injection of TRH, but will improve their responsiveness with repeated injections of the releasing hormone. Therefore, individuals with primary hypothalamic, pituitary, or thyroidal deficiency may be identified by means of their differential response to TRH.
E
...
::J
Q)
'" Q)
E ::J
(5
>
"-
::c
(/)
I-
hyperthyroidism
(c) euthyrOid
(d) hYpotha/amic h YPothyroidism
o
60
120
180
Time: min
(f) Groves' disease and/or hyperthyroxinemia Figure 1. Responses to thyrotropin-releasing hormone in thyroid disease.
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High levels of circulating thyroid hormones interfere with the releasing action of TRH; therefore this agent is not so far useful in the diagnosis of disorders associated with hyperthyroxinemia except to reveal the suppressed state of the pituitary thyrophic cell. 12 Normal men develop progressively reduced TRH responsiveness with advancing age; the differences are observed after the age of 40 but are noteworthy after 60. Females show the same general TRH responses throughout their lifetimes. Such information is of great interest because the mechanism of thyroid disease in the elderly patient is not well understood and the diagnosis of thyroid disease becomes more difficult with increasing age.
Tests with Bovine TSH The oral effectiveness of TRH49 and its freedom from side effects may make this the stimulating agent of choice in thyroid testing, since it increases circulating TSH and also circulating T3 and T4 if given in a single large dose. However, since TRH is not yet widely available, bovine TSH remains temporarily the standard agent for testing the capacity of the thyroid to respond to stimulation. 9 Species-specificity is probably important in relation to all pituitary hormones, therefore improvement in the safety and the specificity of TSH testing may be forthcoming when the human material becomes available.
Thyroid Antibody Tests Thyroglobulin antibodies as detected by the sensitive tanned red cell agglutination method (TRC) have been found in low titers (less than 1: 1000) in patients with a variety of other thyroid disorders such as Graves' disease, thyroid cancer, or acute thyroiditis. On the other hand, high thyroglobulin antibodies titers (above 1: 10,000) are seen in over 90 per cent of patients with autoimmune (Hashimoto's) thyroiditis. 4 In our experience the majority of patients with autoimmune thyroiditis have exceedingly high titers in dilutions as high as one to several million. There is good correlation between the antibody data and a positive thyroid biopsy.2 Other methods for demonstrating thyroglobulin antibodies are less sensitive than the TRC test. There is a slight diagnostic advantage in measuring anti-microsomal antibodies, as determined by the complement fixation test. Titers of over 1 :64 support the diagnosis of autoimmune thyroiditis. Thyroglobulin and/or microsomal antibodies are found in approximately 98 per cent of patients with autoimmune thyroiditis. 52
TREATMENT OF THYROID DISEASE Efficient methods of treatment are available for most forms of thyroid disease. Certain problems persist and others remain highly controversial. Our own methods of treatment are described and their limitations delineated. Principles of management of thyroid disease may vary according to particular geographic location (e.g., in regions of endemic
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goiter), where populations may exhibit special trends in the incidence and evolution of thyroid disorders. Thyroid preparations are used for two major purposes: (1) to provide substitution therapy in managing hypothyroidism, and (2) as suppressive therapy (via TSH suppression) in cases of autoimmune thyroiditis, thyroid cancer, or goiter due to defects in hormonogenesis or iodine deficiency. Sodium-L-thyroxin':' or combinations of sodium-L-thyroxin with sodium-L-triiodothyronine':'" have been uniformly effective in all the above mentioned instances, and has been correlated with consistent biochemical response. For some years we have observed that patients appear more physiologically controlled with doses ranging between 1.5 to 2.5 "grain equivalents" of hormone. This is a somewhat smaller dose than has been recommended in the past, but appears to be substantiated by recent investigations involving TRH administration and TSH measurements of patients on various modes of substitution therapy. 12 In contrast with results obtained with synthetic hormones, we have observed markedly discrepant clinical responses to desiccated thyroid. In spite of known deterioration of this preparation on the pharmacy shelf, poor batches of dry gland with satisfactory iodine content but low biologic potency, known variability of potency dependent on seasonal and geographic factors, and known contamination with substances such as radium,62 desiccated thyroid continues to be used in many medical centers. Synthetic T4 and T3 have none ofthe disadvantages of desiccated thyroid and are not significantly more expensive. They are pure, are uniformly potent, have a brisk onset of action, and achieve reliable TSH suppression.
Coronary Artery Disease and Hypothyroidism It is very difficult to provide adequate substitution therapy for patients with advanced coronary atherosclerosis and hypercholesterolemia, frequently seen in untreated hypothyroidism of long standing. Recently, somewhat more satisfactory management has been possible through the use of T3 in very small doses accompanied by small doses of propranolol (Inderal), a beta-adrenergic blocking agent. Gradually increasing doses of both of these agents may allow correction of some aspects of hypothyroidism while decreasing the risk of arrhythmia, angina, or even myocardial infarction.24 T3 is recommended in such cases because its shorter duration of action allows more rapid subsidence of its effects after withdrawal, which may become necessary if treatment is associated with increasing or new cardiac symptoms. Myxedema Coma Myxedema coma is characteristically seen in female patients over the age of 50 who present with bradycardia, slowed deep tendon reflexes, head and eyebrow hair loss, dry hyperkeratotic skin, and hypothermia. A previous history of 1311 therapy or a surgical scar of the neck may help to ·Synthroid (Flint Laboratories); Letter (Armour Pharmaceuticals) "'*Thyrolar (Armour Pharmaceuticals); Euthroid (Warner·Chilcott Laboratories)
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suggest the diagnosis. The electrocardiogram may reveal low voltage, prolonged QT interval, and sinus bradycardia. The cause of the coma will be objectively established by identifying low serum levels of T. and T3 and high serum levels of TSH. Myxedema coma necessitates prompt treatment of the hypothyroid state and associated complications as soon as the appropriate laboratory studies are obtained. Baseline blood gases should be determined and cardiac monitoring initiated. If present, alveolar hypoventilation with hypoxemia and hypercapnia, inappropriate secretion of antidiuretic hormone (ADH), hypothermia, cardiac disease and relative adrenal insufficiency must be treated promptly and vigorously. Precipitating causes such as infection or central nervous depressant drugs must be considered. 66 It has been customary to institute treatment with low doses of thyroid hormones; however, there are reports that prompt intravenous administration of large doses of T. and T3 (500 f,Lg of T. or 50 f,Lg of T 3) may reduce mortality. Patients with known coronary artery disease or congestive failure should receive smaller doses. Treatment should be guided by clinical response, cardiac monitoring, and frequent blood gas determination. We have used lower initial doses (0.1 mg. of T. i.v.) followed by oral replacement with T. or T3 in small amounts (50 f,Lg of T. daily or 5 f,Lg of T3 every 6 to 12 hours) with good results. Doses are increased slowly until full replacement achieves optimal clinical response. Various dose schedules have recently been reviewed. 22 Hydrocortisone, 50 to 100 mg. every 6 hours intravenously, is recommended. If infection is present antibiotic treatment is initiated. Inappropriate ADH secretion, if documented by determination of serum and urine sodium and osmolality, should be treated with fluid restriction. We do not recommend rapid warming of the patient. Respiratory assistance with intubation or tracheostomy has decreased mortality in patients with the respiratory complications of myxedema coma. 65
Thyroiditis We are inclined to avoid the use of steroids in treating acute and subacute thyroiditis, and recommend conservative measures such as rest and aspirin for pain. However, short courses of steroids (prednisone 40 mg. per day for 5 to 7 days) may be required for some progressive or persistent forms of this disorder. If goiter or nodularity of the thyroid gland is evident because of subacute or chronic thyroiditis, we use suppressive treatment with T. and/or T3 whether or not hypothyroidism is present. Surgery is assiduously avoided except for limited biopsy of suspicious masses. The incidence of surgical complications is markedly increased if thyroiditis is present, possibly because inflammation and fibrosis make clean dissection much more difficult. Obviously, if cancer is present with thyroiditis, there is no alternative to surgical management.
Thyroid Nodules Controversy concerning the subject of thyroid nodules and thyroid cancer does not appear to lend itself to resolution at the present time.
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This may derive from conflicting criteria for pathologic diagnosis, particularly of thyroid cancer, and divergent clinical experience stemming from marked regional differences in attack rate, severity, and natural history of thyroid disease. 66 In keeping with the opinion of many groups13 but diverging from that of others, we do not perform radical neck dissection if follicular or papillary cancer is limited to the thyroid gland at the time of initial surgery. We treat all such patients with lobectomy, followed by suppressive T4 and/or T 3. Lymph node involvement is treated with conservative surgery unless there is diffuse local spread, in which case radical neck surgery is performed and followed by ablative 1311 treatment. 50 If distant metastases appear, measures to increase their uptake of 1311 are instituted, including cessation of exogenous T3 or T 4, induction of iodine deficiency through chloride diuresis, bovine TSH treatment, and possibly TRH administration. Provided the lesions can be induced to function, therapeutic doses of 1311 are administered. In the case of a nonmalignant solitary nodule, provided that the patient is a good risk, we perform lobectomy followed by suppressive hormone therapy with T4 or T 3, reasoning that the process which allowed the nodule to form in the first place is still operative and that suppression may be beneficial. Autonomous, hyperfunctioning solitary nodules producing hyperthyroidism are treated surgically after euthyroidism has been established with medical treatment. When poor risk is a factor, ablative 131 1 therapy is effective. 42 Most examples of multinodular toxic goiter are found in older individuals; in such patients, 1311 therapy is the treatment of choice. Hyperthyroidism We prefer medical therapy, with propylthiouracil (PTU) or tapazole for young persons provided the drugs are well tolerated and the patient can . be relied upon to report. side effects. Possible side effects are thoroughly described in advance to the patient and he is warned to stop the drug and communicate with the physician if side effects appear. For older patients (over 40 years) 131 I therapy is the treatment of choice. Since it may take 6 to 12 weeks for therapeutic doses of 1311 to control hyperthyroidism, medical antithyroid therapy (iodides, Tapazole or PTU) may be required for interim control of hyperthyroid symptoms. Tapazole or PTU and/or iodides may be started 3 to 7 days after administration of therapeutic doses of 1311. If the patient is markedly toxic, iodides and Tapazole or PTU plus other supportive measures may be required immediately; after establishment of reasonable control, these agents may be withdrawn and 1 week later 1311 treatment may be administered. Beta-adrenergic blocking agents are useful in treating hyperthyroidism.64 We choose propranolol for this purpose because it is potent, appears to be safe even in the presence of high output failure, and has few unpleasant side effects.54 Propranolol is useful in rapid control of tremor, agitation, sleeplessness, and severe tachycardia or cardiac arrhythmia. It may be used together with Tapazole or PTU in the initial phases of medical treatment of Graves' disease. However, it must be discontinued well before overtreatment is a possibility, since the combination of hypo-
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thyroidism and beta-adrenergic blockade are very poorly tolerated by formerly hyperthyroid patients. To be effective, adrenergic blocking agents must be given in adequate doses, e.g., 40 mg. of propranolol, four times a day for severe toxicity.32 The dose may be adjusted downward or up as required, the duration of each dose being reasonably short. Many side effects of propranolol have been described in euthyroid individuals, but in hyperthyroidism large doses of the drug are required and are well tolerated.
Thyroid Storm There is no definite point which separates patients with severe thyrotoxicosis from those in storm. However, except in rare cases of apathetic hyperthyroidism, storm is clearly signaled by a history of rapid worsening of preexisting symptoms of thyrotoxicosis plus fever and prostration. Immediate supportive measures include oxygen, digitalis if cardiac failure is evident, sedation in the form of intramuscular phenobarbital (100 mg. repeated every 4 to 6 hours if necessary), and measures to control the hyperpyrexia such as aspirin and hypothermic blankets. Although fever may reflect the temperature-regulating aberrations of the underlying disorder, it may be a result of underlying infection which itself may have precipitated the acute worsening of thyrotoxic symptoms. Therefore a systematic search for infection based on history, physical examination, special x-ray studies, and throat, urine, and blood cultures, and prompt treatment based on specific bacteriologic diagnosis, are of great importance in management. Once diagnostic studies, including complete blood count, T 4, T3 or T3 resin uptake are drawn, the needle may be left in place to start intravenous glucose containing potassium iodide; and cautiously, if serum sodium is low, half normal saline. In addition to iodide, antithyroid therapy with Tapazole or PTU should be instituted immediately. Doses are 30 to 40 mg. every 6 hours for Tapazole, and as much as 10 times this amount for PTU. Although thyroid hormone production may be significantly reduced as a result of massive treatment with antithyroid drugs, blood and tissue levels of hormones may remain elevated for several days, and therefore symptoms will continue. During this period, and for several days thereafter, many of the acute peripheral manifestations of toxicity, especially those related to the heart, may be reduced to a considerable degree with intravenous or oral propranolol. We prefer 20 to 40 mg. doses administered orally every 6 hours, a regimen which is usually effective and well tolerated. Continued treatment with propranolol should be adjusted according to the response of the patient, but is usually not required after clinical improvement is clearly manifest and blood levels of T3 and T4 start to decline. Although there is usually no specific rationale for their use, steroid hormones are usually without deleterious effect, and may be beneficial especially for fever, if given in limited amounts (lOO to 300 mg. of hydrocortisone per day intravenously) during the first few days of treat-
EVOLVING CONCEPTS OF THYROID FUNCTION
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ment of the exhausted, restless individual in storm. Glucocorticoids acutely reduce thyroidal release of Ta and T4 in normal individuals,55 but it is questionable whether this effect would be additive to the action of iodides. Protracted treatment with high doses of steroids will cause the usual untoward reactions and may be dangerous in the presence of intercurrent infections. Patients in storm should be admitted to the medical intensive care unit when such facilities are available. Under circumstances of constant supervision and specific therapy, death is rare; otherwise mortality may be high.
Hyperthyroidism in Pregnancy Controversy concerning treatment of hyperthyroidism in pregnancy continues. 29 Our position is that Ta and T4 are not well transported across the placental barrier and therefore maternal hyperthyroidism is unlikely to damage the fetus. Antithyroid agents including Tapazole, PTU, or iodides freely cross the placenta and may severely damage the fetal thyroid and produce fetal hypothyroidism. Therefore we recommend that the smallest possible dose of antithyroid therapy which is compatible with the safety of the mother be adIninistered for control of maternal hyperthyroidism. Serial tests of serum TSH by radioimmunoassay alerts to the development of maternal hypothyroidism and helps prevent excessive antithyroid therapy. We do not recommend concurrent use of exogenous Ta since it is assumed that the treatment described above will be associated with maternal hyperthyroxinemia; excess endogenous hormone therefore will be available to the fetus by way of the limited placental transport mechanism. It may be falsely reassuring to the physician to administer thyroid hormones to protect the fetus; the emphasis should be on adIninistration of minimum doses of antithyroid drugs.
Ophthalmopathy Graves' ophthalmopathy is usually controlled by measures which control hyperthyroidism. However, progressive infiltrative ophthalmopathy appears to pursue a course not necessarily related to the hyperthyroid state, and methods of management are generally poor. There is no conclusion concerning the value of orbital decompression, immunosuppressive drugs, pituitary irradiation, or any other form of treatment. We have found large doses of prednisone (120 mg. per day) to be uniformly helpful to the eyes but toxic side effects are significant. Individuals with Graves' disease tolerate prolonged and excessive amounts of steroid hormones poorly; myopathy is additive from both steroids and thyrotoxicosis, and other side effects are prominent, severely liIniting the value of this treatment. Most patients will be reasonably well maintained on a regimen of close supervision, reassurance, local measures designed to keep the eyeball moist, occlusive light-shielding glasses, diuretics as tolerated, sitting posture during sleep, salt restriction, and small doses of oral steroids. The aim of treatment is to preserve sight and provide the maximum subjective comfort until stabilization or spontaneous remission.56
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MECHANISM OF ACTION OF THYROID HORMONES Concepts of the action of the thyroid hormones have developed largely from study of their effects on diverse physiologic and biochemical processes of immature and adult organisms. 33 No unifying principle has been proposed which explains all the effects of the hormones, nor has a working theory of their molecular actions emerged. Is T3 the active form of thyroid hormone? There is presently much speculation about the significance of various molecular forms of the thyroid hormones, especially T4 and T 3. A number of investigators have found evidence of significant amounts of peripheral T4 to T3 conversion, and using calculations based on the half-time of turnover and the relative potency of the two hormones, have suggested that T4 may be a prohormone and T3 the active cellular hormone. 45 T4 to T3 conversion in athyreotic individuals has been demonstrated with different techniques, including gas chromatography, paper chromatography, and radioimmunoassay. Although all questions concerning technical artifacts have not been answered, the weight of present opinion favors the possibility that T3 is generated from T4 at sites of hormone action, and that T3 may initiate most if not all of the peripheral effects of the thyroid hormones.6 , 59 However, until further information becomes available, the issue cannot be considered settled. Effects on Growth and Development Most studies of the actions of the thyroid hormones differentiate their effects on growth and development from those on metabolism. Effects on protein metabolism in general and on differentiation in particular have been attributed to the ability of the thyroid hormones to increase amino acid incorporation into protein,57 and to influence both the transcription and the translation of genetic information. However, the time course of RNA changes after T3 or T4 administration thus far observed argue against a primary effect of the hormone on either nuclear or ribosomal mechanisms. Moreover, molecular interactions of T3 and T4 with the genetic apparatus have not been demonstrated, although nuclear binding has been described. 37 Binding of thyroxin to tissue proteins has been noted in various in vitro and in vivo systems by many investigators. Covalent binding between thyroxin and protein fractions of thyroxin-sensitive tissues have been demonstrated; according to some evidence these bonds may be peptide in nature. It has been suggested that thyroxin-containing proteins may play a role in the thyroxin-dependent differentiation of immature animals. 15
Effects on Metabolism The effects of T3 and T4 on mitochondrial structure, function, and mass have been explored in many laboratories. Rapid changes in respiratory control, associated with changes in amino acid incorporation into certain mitochondrial proteins have been described. T 4-induced changes in energy transformations have been attributed also to stimulation of fat,
EVOLVING CONCEPTS OF THYROID FUNCTION
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protein and/or carbohydrate turnover, possibly related to mitochondrial enzyme alterations. 33 Changes in membrane structure and function, especially as they may effect ion transport, have been considered related to the fundamental action of iodothyronines. 37 The effects of hormones in general on the adenyl cyclase system have been documented in numerous investigations,61 including many which describe specific effects of T4 on this system.4' Interactions Among Catecholamines and Thyroid Hormones These have been postulated for many decades,1 but the exact nature of the interrelationship has not been understood. It is suggested that catecholamines are required for the expression of many thyroid hormone effects.63 A number of workers consider that the effects of norepinephrine and epinephrine are potentiated in the presence of hyperthyroidismP However, others suggest that the interaction is, at best, additive.32 The assumption that specific interactions between thyroid hormones and catecholamines do in fact exist, has led many investigators to study the mechanism of such interactions. In hyperthyroidism, blood catecholamine levels and turnover times are low, whereas in hypothyroidism they are high.39 In view of the fact that hypothyroid patients seem to have poor adrenergic nervous function and hyperthyroid individuals appear to have very active adrenergic systems, these findings are unexpected and unexplained. It is possible that cell receptors for the thyroid hormones may be functionally similar to adrenergic receptors or alternatively, that thyroid hormones may increase the sensitivity and perhaps even the number of adrenergic receptors. However, further study is required to unravel these interrelationships.
REFERENCES 1. Barker, S. B., Humphrey, M. J., and Soley, M. H.: Clinical determination of protein-bound iodine. J. Clin. Invest., 30:55-62, 1951. 2. Beahrs, O. H., Woolner, L. B., Engel, S., et al.: Needle biopsy ofthe thyroid gland and management of lymphocytic thyroiditis. Surg. Gynec. Obstet., 114:636-639, 1962. 3. Berson, S. A., and Yallow, R. S.: Immunoassay of plasma insulin. CIBA Foundation Colloquia XIV, 1962, pp. 182-201. 4. Blizzard, R. M., Hamwi, G. J., Skillman, T. G., et al.: Thyroglobulin antibodies in multiple thyroid diseases. New Eng. J. Med., 260:112-116,1959. 5. Boler, J., Enzmann, F., Folkers, C., et al.: The identity of chemical and hormonal properties of the thyrotropin releasing hormone and pyroglutamyl-histidyl-proline amide. Biochem. Biophys. Res. Commun., 37:705-710,1969. 6. Braverman, L. E., Ingbar, S. H., and Sterling, K.: Conversion of thyroxine (T4) to triiodothyronine in athyreotic human subjects. J. Clin. Invest., 49:855-864,1970. 7. Brodie, B. B., Davies, J. I., Hynie, S., et al.: Interrelationships of catecholamines with other endocrine systems. Pharmacol. Rev., 18:273-289, 1966. 8. Burke, G.: The triiodothyronine suppression test. Amer. J. Med., 42:600-608, 1967. 9. Burke, G.: The thyrotropin-stimulation test. Ann. Intern. Med., 69:1127-1139, 1968. 10. Burke, G., Halko, A., Silverstein, G. E., et al.: Comparative thyroid uptake studies with 131 1 and T c 0 499m -. J. Clin. Endocrinol. Metab., 34:630-637, 1972. 11. Chopra, I. J.: A radioimmunoassay for measurement of thyroxines in unextracted serum. J. Clin. Endocrinol. Metab., 34:938-947, 1972. 12. Cotton, G. E., Gorman, C. A., and Mayberry, W. E.: Suppression of thyrotropin (H-TSH) in serums of patients with myxedema of varying etiology treated with thyroid hormones. New Eng. J. Med., 285:529-533, 1971. 13. Crile, G., Jr.: Endocrine dependency of papillary carcinoma of the thyroid. J.A.M.A., 195:721-724,1966.
er,)
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14. DeGroot, L. J.: Kinetic analysis of iodine metabolism. J. Clin. Endocrinol., 25:149-173, 1966. 15. Dratman, M. B., Richter, M. E., and Lynch, H. A.: Incorporation of thyroxin carbon in protein fractions of Rana catsbiana tadpole nervous system, liver and tail. Endocrinology, 85:217-224, 1970. 16. Emerson, C., and Utiger, R. D.: Hyperthyroidism and excessive thyrotropin secretion. New Eng. J. Med., 287:328-333,1972. 17. Fisher, D. A., and Odell, W. D.: Acute release of thyrotropin in the newborn. J. Clin. Invest., 48:1670-1677,1969. 18. Ghahremani, G. G., Hoffer, P. B., Oppenheim, B. E., et al.: New normal values for thyroid uptake of radioactive iodine. J.A.M.A., 217:337-339,1971. 19. Gharib, H., and Wahner, H. W.: Clinical experience with assays for triodothyronine. MED. CLIN. N. AMER., 56:861-869,1972. 20. Guillemin, R.: Hypothalamic control of the secretion of adenohypophysial hormones. Advances Metabol. Disorders, 5:16-26,1971. 21. Gorman, C. A.: Some problems in thyroid diagnosis. MED. CLIN. N. AMER., 56:841-848, 1972. 22. Green, W. L.: Guidelines for the treatment of myxedema. MED. CLIN. N. AMER., 52:431450,1968. 23. Hall, R. J., Amos, J., Garry, R., et al.: Thyroid stimulating hormones response to synthetic thyrotropin releasing hormone in man. Brit. Med. J., 2:274-277, 1970. 24. Hall, R., and Evered, D.: Hypothyroidism. Brit. Med. J., 1 :290-293,1972. 25. Hamburger, J. I.: Application of the radioiodine uptake to the clinical evaluation of thyroid disease. Seminars Nucl. Med., 1 :287-300, 1971. 26. Hamilton, C. R., Adams, L. C., and Maloof, F.: Hyperthyroidism due to thyrotropin-producing pituitary chromophobe adenoma. New Eng. J. Med., 283:1077-1080,1970. 27. Harrison, T. S.: Adrenal medullary and thyroid relationships. Physiol. Rev., 44:161-185, 1964. 28. Hayles, A. B., and Cloutier, M. D.: Clinical hypothyroidism in the young. A second look. MED. CLIN. N. AMER., 56:871-884, 1972. 29. Herbst, A. L., and Selenkow, H. A.: Hyperthyroidism during pregnancy. New Eng. J. Med., 273:627-632, 1965. 30. Hershman, J. M., and Pittman, J. A.: Utility of the radioimmunoassay of serum thyrotropin in man. Ann. Intern. Med., 74:481-490, 1971. 31. Hershman, J. M., and Pittman, J. A.: Control ofthyrotropin secretion in man. New Eng. J. Med., 285:997-1006, 1971. 32. Hess, M. E., and Shanfeld, J.: Cardiovascular and metabolic interrelationships between thyroxine and the sympathetic nervous system. J. Pharmacol. Exper. Therap., 148:290297,1965. 33. Hoch, F. L.: Energy transformations in animals: regulatory mechanisms. In Masaro, E. J., ed., Physiological Chemistry. Philadelphia, W. B. Saunders Co., 1971, pp. 109-210. 34. Hollander, C. S.: On the nature of the circulating thyroid hormone: clinical studies of triiodothyronine and thyroxine in serum using gas chromatographic methods. Trans. Assoc. Amer. Physicians, 81 :76-91, 1968. 35. Hollander, C. S.: Newer aspects of hyperthyroidism. Hosp. Pract., 87-96, May, 1972. 36. Howarth, P. J. N., and MacIagan, N. F.: Clinical application of serum total-thyroxine estimation, resin uptake and free-thyroxine index. Lancet, 1 :224-228, 1969. 37. Ismail-Beigi, F., and Edelman, I. S.: Ne mechanism of the calorogenic action of thyroid hormone. J. Gen. Physiol., 57:710-722,1971. 38. Koener, D., Schwartz, H. L., Surks, M. I., et al.: Nuclear binding of T3: comparison between in vivo and in vitro interactions. (Abstract) Procedures of the American Thyroid Association, 48th Meeting, 1972. 39. Lansberg, L., and Axelrod, J.: Influence of pituitary, thyroid, and adrenal hormones on norepinephrine turnover and metabolism in the rat heart. J. Circ. Res., 22:559-571, 1968. 40. Levy, R. P., Marshall, J. S., and Velayo, N. L.: Radioimmunoassay of human thyroxinebinding globulin (TB G). J. Clin. Endocrinol. Metab., 32:372-381, 1971. 41. Levey, G. S., and Epstein, S. E.: Myocardial adenyl cyclase: activation by thyroid hormones and evidence for two adenyl cyclase systems. J. Clin. Invest., 48:1663-1669,1969. 42. McKenzie, J. M., and Murphy, S. S.: Treatment of the thyroid nodule in Adv. Intern. Med., 17:215-236, 1971. , 43. Mitchell, M. H., Harden, A. B., and O'Rourke, M. E.: The in vitro resin sponge uptake of triiodothyronine- 131 I from serum in thyroid disease and in pregnancy. J. Clin. Endocrinol. Metab., 20:1474-1483,1960. 44. Murphy, B. E. P., and Pattee, C. J.: Determination of thyroxine utilizing the property of protein-binding. J. Clin. Endocrinol., 24:187-196,1964.
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45. Nicoloff, J. T., Low, J. C., Dussault, J. H., et al.: Simultaneous measurement of thyroxine and triiodothyronine peripheral turnover kinetics in man. J. Clin. Invest., 51:473-483, 1972. 46. Odell, W. D., Wilber, J. F., and Vtiger, R D.: Studies of thyrotropin physiology by means of radioimmunoassay. Recent Progr. Horm. Res., 23:47-85, 1967. 47. Oppenheimer, J. H.: Role of plasma proteins in the binding, distribution, and metabolism of the thyroid hormones. New Eng. J. Med., 278:1153-1162, 1968. 48. Pileggi, V. J., Lee, N. D., Golub, O. J., et al.: Determination of iodine compounds in serum. J. Clin. Endocrinol., 21 :1272-1279,1961. 49. Pittman, J. A., Haigler, E. D., Jr., Hershman, J. M., et al.: Hypothalamichypothyroidism. New Eng. J. Med., 285:844-845, 1971. 50. Pochin, E. E.: Radioactive therapy for thyroid cancer. Sem. Nucl. Med., 4:503-515, 1971. 51. Robbins, J.: Reverse-flow zone electrophoresis: a method for determining the thyroxinebinding capacity of serum protein. Arch. Biochem., 63:461-469, 1956. 52. Roitt, I. M., and Doniach, D.: Human auto-immune thyroiditis: serological studies. Lancet, 2:lO27-1033,1958. 53. Senior, R M., and Birge, S. J.: The recognition and management of myxedema coma. J.A.M.A., 217:61-65,1971. 54. Shanks, R G., Hadden, D. R, Lowe, D. C., et al.: Controlled trial of propranolol in thyrotoxicosis. Lancet, 1 :993-994, 1969. 55. Singer, P. A., and Nicoloff, J. T.: Estimation of the triiodothyronine secretion rate in euthyroid man. J. Clin. Endocrinol. Metab., 35:82-89, 1972. 56. Snyder, J. P., and Vtiger, D. R: Response to thyrotropin releasing hormone (TRH) in normal man. J. Clin. Endocrinol. Metab., 34:380-385, 1972. 57. Sokoloff, L., Roberts, P. A., Januska, M. M., et al.: Mechanisms of stimulation of protein synthesis by thyroid hormones in vivo. Proc. Acad. Nat. Sci., V.S., 60:652-659, 1968. 58. Solomon, D. H., Benotti, J., DeGroot, L. J., et al.: A nomenclature for tests of thyroid hormones in serum: report of a committee of the American Thyroid Association. J. Clin. Endocrinol. Metab., 34:884-890, 1972. 59. Sterling, K.: The significance of circulating triiodothyronine. Recent Prog. Hormone Res., 25:249-286, 1970. 60. Sterling, K., Refetoff, S., and Selenkow, H. A.: Ta thyrotoxicosis: thyrotoxicosis due to elevated serum triiodothyronine levels. J.A.M.A., 213:571-575, 1970. 61. Sutherland, E. W., Oye, I., and Butcher, R. W.: The action of epinephrine and the role of the adenyl cyclase system in hormone action. Recent Prog. Hormone Res., 21 :623-646, 1965. 62. VanMiddleworth, L.: Radium bodies in bovine thyroids. American Thyroid Association Fourth Meeting (abstract) 1971, p. 70. 63. Waldstein, S. S.: Thyroid-catecholamine interrelations. Ann. Rev. Med., 17:123-132, 1966. 64. Wiener, L., Stout, B. D., and Cox, J. W.: Influence of beta sympathetic blockade (propranolol) on the hemodynamics of hyperthyroidism Amer. J. Med., 46:227-233, 1969. 65. Werner, S. C.: Treatment: Myxedema coma. In Werner, S. C., and Ingbar, S. H., eds.: The Thyroid. New York, Harper and Row, 1971, pp. 832-841. 66. Werner, S. C.: Prednisone in emergency treatment of malignant exophthalmos. Lancet, 1:1004-1007,1966. 67. Wollner, L. B., Beahrs, O. H., Black, B. M., et al.: Classification and prognosis of thyroid carcinoma. A study of 885 cases observed in a 30 year period. Amer. J. Surg., 102:354386, 1961.
Medical College of Pennsylvania Philadelphia, Pennsylvania 19129
Evolving Concepts of Thyroid Function Doris G. Bartuska, MD.,* and Mary B. Dratman, MD.**
Thyroid hormones are essential for normal brain and body development, normal reproduction, lifelong metabolic functions, and defense against some aspects of the aging process. Investigators in many disciplines are actively studying fundamental questions relevant to the biology of these hormones. Their discoveries have led to progressive improvement in methods of diagnosis and management of patients with thyroid disorders.
DIAGNOSIS OF THYROID DISEASE Parameters ,elated to levels of circulating thyroid hormones have been measured for several decades, with iodine serving as the marker for these measurements. From originally poorly informative data derived from analysis of unfractionated blood iodine,t4 methods have been progressively refined to permit estimation of protein bound iodine (PBI),t serum thyroxin (T4) as measured after separation of iodocompounds on ion exchange columns (T4 by column),48 T4 measured by displacement techniques (especially Murphy-Pattee),44 and both T4 and triiodothyronine (T3) as measured by gas chromatography34 and finally by radioimmunoassay.11. 19. 46 According to recent reports, 11.46 radioimmunoassay techniques for these substances are accurate, reproducible, and sensitive, are not altered by iodine contamination (this is also true of the Murphy-Pattee and gas chromatographic techniques), and, because of their relative ease of performance, may become increasingly available. t
tThe radioimmunoassay method, discovered and pioneered by Berson and Yallow has permitted great advances in biologic research and clinical medicine. Its impact on thyroidology has been highly significant.' *Associate Professor of Medicine, Assistant Professor of Clinical Pathology, Medical College
of Pennsylvania; Attending Physician, Veterans Administration Hospital, Philadelphia, Pennsylvania ':,* Associate Professor of Medicine, Medical College of Pennsylvania; Medical Investigator, Veterans Administration Hospital, Philadelphia, Pennsylvania
Medical Clinics of North America- Vo!. 57, No. 4, July 1973
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Protein-Binding of Thyroid Hormones Unfortunately, even precise knowledge of levels of circulating hormones does not alone rule out or indicate the presence of disorders of endocrine function. The very precision of available T3 and T4 measurements has made estimation of serum hormone binding capacity increasingly important. T4 is transported by three major protein fractions: thyroxinbinding globulin (TBG), thyroxin-binding prealbumin (TBP A) and thyroxin-binding albumin (TBA).47 The small fraction of hormone which is not bound to protein is called the free fraction and is presumably the metabolically active hormone. Protein-bound hormone may vary within wide limits without necessarily reflecting alterations of free hormone. Accordingly, total circulating hormones may be high, low, or normal, but these values will be correlated with their corresponding states of thyroid function only if the T. binding capacities are normal. T~
Resin Uptake*
Competitive resin binding techniques 43 have proved useful for estimating residual T3 and T. serum binding activity. In patients without binding abnormalities, the results also indicate the level of circulating hormone. Thus a low resin value indicates high binding activity of the serum (unfilled binding sites), and is ordinarily correlated with hypothyroidism, whereas a high resin value indicates low serum binding activity (binding sites filled up) and is correlated with hyperthyroidism. However, when the clinical picture and the total levels of circulating hormones are at odds with the T3 resin test, then disorders of binding capacity should be suspected, and should be assessed. This is often made possible by identifying a cause for thyroxin binding change (See Table 1) and making a rough correlation of degree of resin-binding abnormality and degree and direction of serum T. abnormality. Table 2 provides examples of frequently observed related changes in serum T3 and T4 levels and T3 resin uptake and the nature of the thyroid diagnosis which may be derived from correlating these changes. 21 ':'The T3 resin uptake test (sometimes called the T3 test) measures the residual T4 and Ta binding capacities of the serum proteins and is not specific for T 3; therefore its name is misleading. Since the advent of T3 measurement by radioimmunoassay, confusion about nomenclature has increased even further. A more explicit shorthand is required.'8
Table 1.
Conditions Associated with Altered Thyroid Hormone Binding Capacity of Serum Proteins
DECREASED BINDING CAPACITY
INCREASED BINDING CAPACITY
Hereditary decreased TBG Protein-losing states Cirrhosis Major physical stress (surgery, acute illness) Corticosteroid therapy Dilantin therapy Androgen therapy
Hereditary increased TBG Pregnancy Infectious hepatitis Porphyria Estrogen therapy including most oral contraceptives
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Table 2.
Thyroid Hormone Levels and Serum Binding Proteins: Correlated Changes in Ta Resin Uptake
THYROID STATE
Euthyroid with normal binding capacity Euthyroid with decreased binding capacity Euthyroid with increased binding capacity Hypothyroid with normal binding capacity Hypothyroid with decreased binding capacity Hyperthyroid with normal binding capacity Hyperthyroid with increased binding capacity T 3 toxicosis
T3
T.
T3
RADIOIMMUNOASSAY
(MURPHY-PATTEE)
RESIN UPTAKE
normal
normal
normal
low
low
high
borderline high or high low
borderline high or high low
low
very low
very low
high
high
high normal or slightly increased high
high
high
very high
normal or low
low
normal or slightly decreased normal
Ta is much less tightly bound to plasma proteins than T 4, but binding is nevertheless a significant factor in determining circulating levels of this potent thyroid hormone. Abnormalities of binding capacity are reflected in quantitative alterations of T3 as measured by radioimmunoassay, similar to those found in the T4 fraction. However, there may be relatively rare but extremely important independent variations in blood levels of these two thyroid hormones, the most notable of which is "Tatoxicosis." In the latter condition, T4 levels and T4 binding capacity as measured by the T3 resin uptake are normal. Therefore, in patients who present with signs and symptoms suggestive of but not conclusive for thyrotoxicosis, with normal serum T 4 levels and normal Ta resin uptake tests, the measurement of Ta by radioimmunoassay may establish the diagnosis of this rare form of hyperthyroidism. a5, 60 Other Tests of Binding Capacity More direct estimation of serum binding is possible through the use of physical separation procedures (especially reverse flow electrophoresis) which indicate the extent of protein binding of radioactive hormone added to serum. 51 This test has a number of inherent sources of error, but it succeeds nevertheless in establishing an independent measure of binding capacity and is therefore of particular value in determining the state of thyroid function in individuals and families with major variations of thyroxin-binding proteins. Most recently, radioimmunoassay has provided precise information concerning the most important serum binding protein, namely, TBG.40 Already, this test has provided new insights into the relationship between TBG levels and systemic disease (liver disease, nephrosis), not necessarily related to primary functional thyroid abnormalities. Perhaps clinical
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information to be derived from this test will be limited by its specificity for a single binding protein. However, further investigation may make available precise tests for TBP A and TBA. If so, the direct measure of these extremely important protein fractions, yielding information about total serum binding capacity, may become standard procedure in assaying human thyroid function. Some physicians have found it useful to have available the T3 x T4 index - sometimes called the free thyroxin index or "T/'.36 This value establishes a relationship between T 4 levels and hormone binding capacity as measured by the T3 resin test. The free thyroxin index may be useful as part of the battery of screening procedures which are becoming increasingly helpful in medical diagnosis.
Thyroidal Uptake of 131 1 This test of the capacity of the thyroid gland to transport and retain iodide is of value in the diagnosis of hyperthyroidism. 25 Rarely, the thyroid may be so active that at 24 hours it may already have discharged a high percentage of its incorporated 131J into the circulation in the form of 1311_T4 and 1311_T3. Under these circumstances the per cent retained in the thyroid may fall within normal limits. In such instances, the 2 hour uptake will be helpful in identifying increased thyroidal iodine metabolism. If both 2 hour and 24 hour 131 1 uptake studies are borderline, but the clinical picture suggests hyperthyroidism, demonstration of nonsuppressibility of 131 1 uptake will be helpful in diagnosis. One week of treatment with 75 micro grams of T3 (Cytomel) daily, reduces the uptake of a normal thyroid to almost background. Hyperthyroid glands and autonomously functioning hot nodules do not change their concentration and retention of iodide under these circumstances. 8 Increased 1311 uptake does not always mean hyperthyroidism. Iodine deficiency, inborn or acquired biosynthetic defects of thyroid gland fun~ tion, and certain phases of thyroiditis are associated with high uptakes. However, these rarely lead to a mistaken diagnosis of hyperthyroidism since in most cases the patient is not toxic clinically and may in fact be hypothyroid. The exceptions relate to certain phases of thyroiditis when the patient may appear somewhat toxic and have an increased thyroidal uptake of 1311. Tenderness over the thyroid and the transient nature of the "toxic" state (weeks) often followed by signs of hypothyroidism are helpful in differentiating between Graves' disease and thyroiditis. However, prolongation of the so-called toxic phase of Hashimoto's thyroiditis has ied to its identification as a specific entity sometimes called "Hashi-toxicosis." It is reported that patients with "T3-toxicosis" may have normal 131J uptake values, but their thyroids as in most cases of Graves' disease are autonomous, i.e., nonsuppressible. In geographic areas of high iodine intake, normal 131 1 uptake levels are lower than in regions of lesser iodine availability. As the years pass and more iodine is ingested, normal values are revised downward,18 and are now in a range too low to allow them to be differentiated from those in hypothyroidism. The 131 1 uptake is decreased in all instances of
EVOLVING CONCEPTS OF THYROID FUNCTION
1121
iodine contamination of body fluids, as seen following use of iodinated radioopaque diagnostic materials.
Thyroid Scans The thyroid gland varies in size and shape from one individual to another, and distribution of functioning tissue changes not only with disease of the gland but also with age and with availability of iodine. Therefore the thyroid scan must be correlated with independent criteria of disease in order to be properly interpreted. Irregular uptake may indicate the presence of thyroiditis or multinodularity, but only if related to other evidence of these disorders. The interpretation of hot or cold areas must depend on history and physical findings, including the presence of palpable nodules. Conversely, a normal scan does not rule out the presence of significant thyroid disease since a critical mass is required fur a variant area to be visible in the scan. Thyroid scanning may be performed either with 131 1, 1231, or with technetium}O Since uptake studies are usually requested at the time of scanning procedures, it is reasonable that most scans be done with 131 I or 1231. However, in cases of low 131 1 uptakes incompatible with satisfactory scans, it may be better (because ofless radiation exposure) to use technetium rather than larger doses of the iodine isotope. Radioimmunoassay of TSH In spite of increasing precision of serum iodocompound measurement and of serum protein-binding capacity, some cases of hypothyroidism cannot be diagnosed early in the course of disease by either clinical or the above described laboratory methods. Thyrotropin (TSH) measurement by radioimmunoassay is now widely available and has sustained its initial promise of providing precise information concerning the presence of early hypothyroidism due to disease of the thyroid gland. 30 Although the exact mechanisms are not fully understood, it is clear that the hypothalamic-pituitary system is exquisitely sensitive to changes in concentrations of circulating thyroid hormones. In the presence of a normally functioning hypo thalamus providing adequate amounts of releasing hormones, the pituitary thyrotrophic cells respond to reduction ofT3 and T4 by increasing the release ofTSH into the circulationY Because the serum TSH test is reliably elevated in hypothyroid patients with intact hypo thalamic-pituitary function, it is now possible to make the diagnosis of hypothyroidism in many cases before signs and symptoms become obvious and the disease becomes well established. This may be very important in newborn infants and young children with a positive family history of thyroid disease, or in instances of prepartum treatment of the mother with antithyroid drugs. It is also important in adults: after surgery or irradiation as with 131 1, in relation to thyroiditis; in instances of etiologically unidentified atrophic change of the gland; in inherited or acquired biosynthetic defect; and in patients with untreated, clinically evident hypothyroidism where the primacy of the defect-hypothalamus, pituitary, or thyroid-is in question. Since placental TSH
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does not cross react with pituitary TSH in the radioimmunoassay procedure, it will not interfere with the diagnosis of maternal hypothyroidism during pregnancy. High levels of circulating TSH are found during the first few hours of life; these fall to normal by the third day.17.28 Therefore, if thyroid function of the newborn is in question, TSH levels will be reliable if blood for the test is drawn on or after the third day of life. Although TSH is readily and reproducibly detected by radioimmunoassayat levels slightly above normal and beyond, it is not possible to differentiate low from normal values because of technical limitations of the test. Therefore, the serum TSH will be reported as falling within the normal range in cases of hypothyroidism from hypothalamic or pituitary disease associated with deficient production of TSH. If the patient is hypothyroid by clinical criteria, with low T 4, low T3 resin uptake, and low T3 by radioimmunoassay, the TSH should be elevated; if instead it is within the normal range, then TSH deficiency may be inferred. TSH levels are not helpful in the diagnosis of thyroid overactivity since high levels of T3 and T4 found in hyperthyroxinemia of all causes suppress radioimmunoassayable pituitary TSH, and suppressed levels cannot be differentiated from normal. However, there are at least four case reports of TSH excess causing hyperthyroidism. 16, 26 The unknown stimulator of the thyroid in Graves' disease is not detected in the TSH assay. Radioimmunoassay of TSH, however, may be helpful during and after treatment for hyperthyroidism. Although the clinical status of the patient is the best guide to adjustments of doses of antithyroid drugs, the serum TSH is the best objective guide for purposes of monitoring the patient after toxic symptoms have come under some measure of control. Elevations of TSH will occur promptly as the patient develops hypothyroidism, indicating the need for reduction or cessation of antithyroid treatment. In the case of hypothyroidism following 131 1, serial TSH testing (every year, or when suggestive symptoms develop) will allow early detection of the hypothyroid state.
Thyrotropin-Releasing Hormone Tests Neuronal cells of the hypothalamus release specific chemical substances, the releasing hormones, into the portal venous circulation supplying the pituitary. These hormones are highly specific in their action and are essential for coordinated endocrine function of the pituitary gland. Thyrotropin-releasing hormone (TRH) was the first releasing hormone to be purified and synthesized. 5 , 20 Many of its properties have been defined as a result of well controlled studies in normal persons and in patients with a variety of thyroid disorders. 56 The synthetic tripeptide, pyroglutamyl-histidyl-proline amide, in every measurable way identical to TRH isolated from hypothalamus, releases TSH from the pituitary gland and raises TSH and prolactin concentration in the systemic circulation within 30 minutes after intravenous administration. 56 TRH, also known as thyrotropin-releasing factor (TRF)2° is under active investigation in a number of clinical research centers. 23, 56 The full range of its ap-
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EVOLVING CONCEPTS OF THYROID FUNCTION
plicability for thyroid diagnosis is not yet known. However, it is safe (no LD50 can be defined), free of significant side effects, and highly potent. Patients with normal thyroid and pituitary function respond to TRF with changes in circulating TSH as illustrated in Figure 1. The response is quite different in patients with differing forms of thyroid disease. As noted in Figure 1, patients with thyroidal hyPothyroidism have elevated resting TSH levels and show hyperresponsiveness to TRH. Patients with hypothyroidism due to hypopituitarism have low basal TSH levels and they respond poorly or not at all to TRH. Individuals with low basal TSH levels due to hypo thalamic disorders (TRH failure) but with intact pituitary glands will show blunted and delayed TSH response to one injection of TRH, but will improve their responsiveness with repeated injections of the releasing hormone. Therefore, individuals with primary hypothalamic, pituitary, or thyroidal deficiency may be identified by means of their differential response to TRH.
E
...
::J
Q)
'" Q)
E ::J
(5
>
"-
::c
(/)
I-
hyperthyroidism
(c) euthyrOid
(d) hYpotha/amic h YPothyroidism
o
60
120
180
Time: min
(f) Groves' disease and/or hyperthyroxinemia Figure 1. Responses to thyrotropin-releasing hormone in thyroid disease.
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High levels of circulating thyroid hormones interfere with the releasing action of TRH; therefore this agent is not so far useful in the diagnosis of disorders associated with hyperthyroxinemia except to reveal the suppressed state of the pituitary thyrophic cell. 12 Normal men develop progressively reduced TRH responsiveness with advancing age; the differences are observed after the age of 40 but are noteworthy after 60. Females show the same general TRH responses throughout their lifetimes. Such information is of great interest because the mechanism of thyroid disease in the elderly patient is not well understood and the diagnosis of thyroid disease becomes more difficult with increasing age.
Tests with Bovine TSH The oral effectiveness of TRH49 and its freedom from side effects may make this the stimulating agent of choice in thyroid testing, since it increases circulating TSH and also circulating T3 and T4 if given in a single large dose. However, since TRH is not yet widely available, bovine TSH remains temporarily the standard agent for testing the capacity of the thyroid to respond to stimulation. 9 Species-specificity is probably important in relation to all pituitary hormones, therefore improvement in the safety and the specificity of TSH testing may be forthcoming when the human material becomes available.
Thyroid Antibody Tests Thyroglobulin antibodies as detected by the sensitive tanned red cell agglutination method (TRC) have been found in low titers (less than 1: 1000) in patients with a variety of other thyroid disorders such as Graves' disease, thyroid cancer, or acute thyroiditis. On the other hand, high thyroglobulin antibodies titers (above 1: 10,000) are seen in over 90 per cent of patients with autoimmune (Hashimoto's) thyroiditis. 4 In our experience the majority of patients with autoimmune thyroiditis have exceedingly high titers in dilutions as high as one to several million. There is good correlation between the antibody data and a positive thyroid biopsy.2 Other methods for demonstrating thyroglobulin antibodies are less sensitive than the TRC test. There is a slight diagnostic advantage in measuring anti-microsomal antibodies, as determined by the complement fixation test. Titers of over 1 :64 support the diagnosis of autoimmune thyroiditis. Thyroglobulin and/or microsomal antibodies are found in approximately 98 per cent of patients with autoimmune thyroiditis. 52
TREATMENT OF THYROID DISEASE Efficient methods of treatment are available for most forms of thyroid disease. Certain problems persist and others remain highly controversial. Our own methods of treatment are described and their limitations delineated. Principles of management of thyroid disease may vary according to particular geographic location (e.g., in regions of endemic
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goiter), where populations may exhibit special trends in the incidence and evolution of thyroid disorders. Thyroid preparations are used for two major purposes: (1) to provide substitution therapy in managing hypothyroidism, and (2) as suppressive therapy (via TSH suppression) in cases of autoimmune thyroiditis, thyroid cancer, or goiter due to defects in hormonogenesis or iodine deficiency. Sodium-L-thyroxin':' or combinations of sodium-L-thyroxin with sodium-L-triiodothyronine':'" have been uniformly effective in all the above mentioned instances, and has been correlated with consistent biochemical response. For some years we have observed that patients appear more physiologically controlled with doses ranging between 1.5 to 2.5 "grain equivalents" of hormone. This is a somewhat smaller dose than has been recommended in the past, but appears to be substantiated by recent investigations involving TRH administration and TSH measurements of patients on various modes of substitution therapy. 12 In contrast with results obtained with synthetic hormones, we have observed markedly discrepant clinical responses to desiccated thyroid. In spite of known deterioration of this preparation on the pharmacy shelf, poor batches of dry gland with satisfactory iodine content but low biologic potency, known variability of potency dependent on seasonal and geographic factors, and known contamination with substances such as radium,62 desiccated thyroid continues to be used in many medical centers. Synthetic T4 and T3 have none ofthe disadvantages of desiccated thyroid and are not significantly more expensive. They are pure, are uniformly potent, have a brisk onset of action, and achieve reliable TSH suppression.
Coronary Artery Disease and Hypothyroidism It is very difficult to provide adequate substitution therapy for patients with advanced coronary atherosclerosis and hypercholesterolemia, frequently seen in untreated hypothyroidism of long standing. Recently, somewhat more satisfactory management has been possible through the use of T3 in very small doses accompanied by small doses of propranolol (Inderal), a beta-adrenergic blocking agent. Gradually increasing doses of both of these agents may allow correction of some aspects of hypothyroidism while decreasing the risk of arrhythmia, angina, or even myocardial infarction.24 T3 is recommended in such cases because its shorter duration of action allows more rapid subsidence of its effects after withdrawal, which may become necessary if treatment is associated with increasing or new cardiac symptoms. Myxedema Coma Myxedema coma is characteristically seen in female patients over the age of 50 who present with bradycardia, slowed deep tendon reflexes, head and eyebrow hair loss, dry hyperkeratotic skin, and hypothermia. A previous history of 1311 therapy or a surgical scar of the neck may help to ·Synthroid (Flint Laboratories); Letter (Armour Pharmaceuticals) "'*Thyrolar (Armour Pharmaceuticals); Euthroid (Warner·Chilcott Laboratories)
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suggest the diagnosis. The electrocardiogram may reveal low voltage, prolonged QT interval, and sinus bradycardia. The cause of the coma will be objectively established by identifying low serum levels of T. and T3 and high serum levels of TSH. Myxedema coma necessitates prompt treatment of the hypothyroid state and associated complications as soon as the appropriate laboratory studies are obtained. Baseline blood gases should be determined and cardiac monitoring initiated. If present, alveolar hypoventilation with hypoxemia and hypercapnia, inappropriate secretion of antidiuretic hormone (ADH), hypothermia, cardiac disease and relative adrenal insufficiency must be treated promptly and vigorously. Precipitating causes such as infection or central nervous depressant drugs must be considered. 66 It has been customary to institute treatment with low doses of thyroid hormones; however, there are reports that prompt intravenous administration of large doses of T. and T3 (500 f,Lg of T. or 50 f,Lg of T 3) may reduce mortality. Patients with known coronary artery disease or congestive failure should receive smaller doses. Treatment should be guided by clinical response, cardiac monitoring, and frequent blood gas determination. We have used lower initial doses (0.1 mg. of T. i.v.) followed by oral replacement with T. or T3 in small amounts (50 f,Lg of T. daily or 5 f,Lg of T3 every 6 to 12 hours) with good results. Doses are increased slowly until full replacement achieves optimal clinical response. Various dose schedules have recently been reviewed. 22 Hydrocortisone, 50 to 100 mg. every 6 hours intravenously, is recommended. If infection is present antibiotic treatment is initiated. Inappropriate ADH secretion, if documented by determination of serum and urine sodium and osmolality, should be treated with fluid restriction. We do not recommend rapid warming of the patient. Respiratory assistance with intubation or tracheostomy has decreased mortality in patients with the respiratory complications of myxedema coma. 65
Thyroiditis We are inclined to avoid the use of steroids in treating acute and subacute thyroiditis, and recommend conservative measures such as rest and aspirin for pain. However, short courses of steroids (prednisone 40 mg. per day for 5 to 7 days) may be required for some progressive or persistent forms of this disorder. If goiter or nodularity of the thyroid gland is evident because of subacute or chronic thyroiditis, we use suppressive treatment with T. and/or T3 whether or not hypothyroidism is present. Surgery is assiduously avoided except for limited biopsy of suspicious masses. The incidence of surgical complications is markedly increased if thyroiditis is present, possibly because inflammation and fibrosis make clean dissection much more difficult. Obviously, if cancer is present with thyroiditis, there is no alternative to surgical management.
Thyroid Nodules Controversy concerning the subject of thyroid nodules and thyroid cancer does not appear to lend itself to resolution at the present time.
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This may derive from conflicting criteria for pathologic diagnosis, particularly of thyroid cancer, and divergent clinical experience stemming from marked regional differences in attack rate, severity, and natural history of thyroid disease. 66 In keeping with the opinion of many groups13 but diverging from that of others, we do not perform radical neck dissection if follicular or papillary cancer is limited to the thyroid gland at the time of initial surgery. We treat all such patients with lobectomy, followed by suppressive T4 and/or T 3. Lymph node involvement is treated with conservative surgery unless there is diffuse local spread, in which case radical neck surgery is performed and followed by ablative 1311 treatment. 50 If distant metastases appear, measures to increase their uptake of 1311 are instituted, including cessation of exogenous T3 or T 4, induction of iodine deficiency through chloride diuresis, bovine TSH treatment, and possibly TRH administration. Provided the lesions can be induced to function, therapeutic doses of 1311 are administered. In the case of a nonmalignant solitary nodule, provided that the patient is a good risk, we perform lobectomy followed by suppressive hormone therapy with T4 or T 3, reasoning that the process which allowed the nodule to form in the first place is still operative and that suppression may be beneficial. Autonomous, hyperfunctioning solitary nodules producing hyperthyroidism are treated surgically after euthyroidism has been established with medical treatment. When poor risk is a factor, ablative 131 1 therapy is effective. 42 Most examples of multinodular toxic goiter are found in older individuals; in such patients, 1311 therapy is the treatment of choice. Hyperthyroidism We prefer medical therapy, with propylthiouracil (PTU) or tapazole for young persons provided the drugs are well tolerated and the patient can . be relied upon to report. side effects. Possible side effects are thoroughly described in advance to the patient and he is warned to stop the drug and communicate with the physician if side effects appear. For older patients (over 40 years) 131 I therapy is the treatment of choice. Since it may take 6 to 12 weeks for therapeutic doses of 1311 to control hyperthyroidism, medical antithyroid therapy (iodides, Tapazole or PTU) may be required for interim control of hyperthyroid symptoms. Tapazole or PTU and/or iodides may be started 3 to 7 days after administration of therapeutic doses of 1311. If the patient is markedly toxic, iodides and Tapazole or PTU plus other supportive measures may be required immediately; after establishment of reasonable control, these agents may be withdrawn and 1 week later 1311 treatment may be administered. Beta-adrenergic blocking agents are useful in treating hyperthyroidism.64 We choose propranolol for this purpose because it is potent, appears to be safe even in the presence of high output failure, and has few unpleasant side effects.54 Propranolol is useful in rapid control of tremor, agitation, sleeplessness, and severe tachycardia or cardiac arrhythmia. It may be used together with Tapazole or PTU in the initial phases of medical treatment of Graves' disease. However, it must be discontinued well before overtreatment is a possibility, since the combination of hypo-
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thyroidism and beta-adrenergic blockade are very poorly tolerated by formerly hyperthyroid patients. To be effective, adrenergic blocking agents must be given in adequate doses, e.g., 40 mg. of propranolol, four times a day for severe toxicity.32 The dose may be adjusted downward or up as required, the duration of each dose being reasonably short. Many side effects of propranolol have been described in euthyroid individuals, but in hyperthyroidism large doses of the drug are required and are well tolerated.
Thyroid Storm There is no definite point which separates patients with severe thyrotoxicosis from those in storm. However, except in rare cases of apathetic hyperthyroidism, storm is clearly signaled by a history of rapid worsening of preexisting symptoms of thyrotoxicosis plus fever and prostration. Immediate supportive measures include oxygen, digitalis if cardiac failure is evident, sedation in the form of intramuscular phenobarbital (100 mg. repeated every 4 to 6 hours if necessary), and measures to control the hyperpyrexia such as aspirin and hypothermic blankets. Although fever may reflect the temperature-regulating aberrations of the underlying disorder, it may be a result of underlying infection which itself may have precipitated the acute worsening of thyrotoxic symptoms. Therefore a systematic search for infection based on history, physical examination, special x-ray studies, and throat, urine, and blood cultures, and prompt treatment based on specific bacteriologic diagnosis, are of great importance in management. Once diagnostic studies, including complete blood count, T 4, T3 or T3 resin uptake are drawn, the needle may be left in place to start intravenous glucose containing potassium iodide; and cautiously, if serum sodium is low, half normal saline. In addition to iodide, antithyroid therapy with Tapazole or PTU should be instituted immediately. Doses are 30 to 40 mg. every 6 hours for Tapazole, and as much as 10 times this amount for PTU. Although thyroid hormone production may be significantly reduced as a result of massive treatment with antithyroid drugs, blood and tissue levels of hormones may remain elevated for several days, and therefore symptoms will continue. During this period, and for several days thereafter, many of the acute peripheral manifestations of toxicity, especially those related to the heart, may be reduced to a considerable degree with intravenous or oral propranolol. We prefer 20 to 40 mg. doses administered orally every 6 hours, a regimen which is usually effective and well tolerated. Continued treatment with propranolol should be adjusted according to the response of the patient, but is usually not required after clinical improvement is clearly manifest and blood levels of T3 and T4 start to decline. Although there is usually no specific rationale for their use, steroid hormones are usually without deleterious effect, and may be beneficial especially for fever, if given in limited amounts (lOO to 300 mg. of hydrocortisone per day intravenously) during the first few days of treat-
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ment of the exhausted, restless individual in storm. Glucocorticoids acutely reduce thyroidal release of Ta and T4 in normal individuals,55 but it is questionable whether this effect would be additive to the action of iodides. Protracted treatment with high doses of steroids will cause the usual untoward reactions and may be dangerous in the presence of intercurrent infections. Patients in storm should be admitted to the medical intensive care unit when such facilities are available. Under circumstances of constant supervision and specific therapy, death is rare; otherwise mortality may be high.
Hyperthyroidism in Pregnancy Controversy concerning treatment of hyperthyroidism in pregnancy continues. 29 Our position is that Ta and T4 are not well transported across the placental barrier and therefore maternal hyperthyroidism is unlikely to damage the fetus. Antithyroid agents including Tapazole, PTU, or iodides freely cross the placenta and may severely damage the fetal thyroid and produce fetal hypothyroidism. Therefore we recommend that the smallest possible dose of antithyroid therapy which is compatible with the safety of the mother be adIninistered for control of maternal hyperthyroidism. Serial tests of serum TSH by radioimmunoassay alerts to the development of maternal hypothyroidism and helps prevent excessive antithyroid therapy. We do not recommend concurrent use of exogenous Ta since it is assumed that the treatment described above will be associated with maternal hyperthyroxinemia; excess endogenous hormone therefore will be available to the fetus by way of the limited placental transport mechanism. It may be falsely reassuring to the physician to administer thyroid hormones to protect the fetus; the emphasis should be on adIninistration of minimum doses of antithyroid drugs.
Ophthalmopathy Graves' ophthalmopathy is usually controlled by measures which control hyperthyroidism. However, progressive infiltrative ophthalmopathy appears to pursue a course not necessarily related to the hyperthyroid state, and methods of management are generally poor. There is no conclusion concerning the value of orbital decompression, immunosuppressive drugs, pituitary irradiation, or any other form of treatment. We have found large doses of prednisone (120 mg. per day) to be uniformly helpful to the eyes but toxic side effects are significant. Individuals with Graves' disease tolerate prolonged and excessive amounts of steroid hormones poorly; myopathy is additive from both steroids and thyrotoxicosis, and other side effects are prominent, severely liIniting the value of this treatment. Most patients will be reasonably well maintained on a regimen of close supervision, reassurance, local measures designed to keep the eyeball moist, occlusive light-shielding glasses, diuretics as tolerated, sitting posture during sleep, salt restriction, and small doses of oral steroids. The aim of treatment is to preserve sight and provide the maximum subjective comfort until stabilization or spontaneous remission.56
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MECHANISM OF ACTION OF THYROID HORMONES Concepts of the action of the thyroid hormones have developed largely from study of their effects on diverse physiologic and biochemical processes of immature and adult organisms. 33 No unifying principle has been proposed which explains all the effects of the hormones, nor has a working theory of their molecular actions emerged. Is T3 the active form of thyroid hormone? There is presently much speculation about the significance of various molecular forms of the thyroid hormones, especially T4 and T 3. A number of investigators have found evidence of significant amounts of peripheral T4 to T3 conversion, and using calculations based on the half-time of turnover and the relative potency of the two hormones, have suggested that T4 may be a prohormone and T3 the active cellular hormone. 45 T4 to T3 conversion in athyreotic individuals has been demonstrated with different techniques, including gas chromatography, paper chromatography, and radioimmunoassay. Although all questions concerning technical artifacts have not been answered, the weight of present opinion favors the possibility that T3 is generated from T4 at sites of hormone action, and that T3 may initiate most if not all of the peripheral effects of the thyroid hormones.6 , 59 However, until further information becomes available, the issue cannot be considered settled. Effects on Growth and Development Most studies of the actions of the thyroid hormones differentiate their effects on growth and development from those on metabolism. Effects on protein metabolism in general and on differentiation in particular have been attributed to the ability of the thyroid hormones to increase amino acid incorporation into protein,57 and to influence both the transcription and the translation of genetic information. However, the time course of RNA changes after T3 or T4 administration thus far observed argue against a primary effect of the hormone on either nuclear or ribosomal mechanisms. Moreover, molecular interactions of T3 and T4 with the genetic apparatus have not been demonstrated, although nuclear binding has been described. 37 Binding of thyroxin to tissue proteins has been noted in various in vitro and in vivo systems by many investigators. Covalent binding between thyroxin and protein fractions of thyroxin-sensitive tissues have been demonstrated; according to some evidence these bonds may be peptide in nature. It has been suggested that thyroxin-containing proteins may play a role in the thyroxin-dependent differentiation of immature animals. 15
Effects on Metabolism The effects of T3 and T4 on mitochondrial structure, function, and mass have been explored in many laboratories. Rapid changes in respiratory control, associated with changes in amino acid incorporation into certain mitochondrial proteins have been described. T 4-induced changes in energy transformations have been attributed also to stimulation of fat,
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protein and/or carbohydrate turnover, possibly related to mitochondrial enzyme alterations. 33 Changes in membrane structure and function, especially as they may effect ion transport, have been considered related to the fundamental action of iodothyronines. 37 The effects of hormones in general on the adenyl cyclase system have been documented in numerous investigations,61 including many which describe specific effects of T4 on this system.4' Interactions Among Catecholamines and Thyroid Hormones These have been postulated for many decades,1 but the exact nature of the interrelationship has not been understood. It is suggested that catecholamines are required for the expression of many thyroid hormone effects.63 A number of workers consider that the effects of norepinephrine and epinephrine are potentiated in the presence of hyperthyroidismP However, others suggest that the interaction is, at best, additive.32 The assumption that specific interactions between thyroid hormones and catecholamines do in fact exist, has led many investigators to study the mechanism of such interactions. In hyperthyroidism, blood catecholamine levels and turnover times are low, whereas in hypothyroidism they are high.39 In view of the fact that hypothyroid patients seem to have poor adrenergic nervous function and hyperthyroid individuals appear to have very active adrenergic systems, these findings are unexpected and unexplained. It is possible that cell receptors for the thyroid hormones may be functionally similar to adrenergic receptors or alternatively, that thyroid hormones may increase the sensitivity and perhaps even the number of adrenergic receptors. However, further study is required to unravel these interrelationships.
REFERENCES 1. Barker, S. B., Humphrey, M. J., and Soley, M. H.: Clinical determination of protein-bound iodine. J. Clin. Invest., 30:55-62, 1951. 2. Beahrs, O. H., Woolner, L. B., Engel, S., et al.: Needle biopsy ofthe thyroid gland and management of lymphocytic thyroiditis. Surg. Gynec. Obstet., 114:636-639, 1962. 3. Berson, S. A., and Yallow, R. S.: Immunoassay of plasma insulin. CIBA Foundation Colloquia XIV, 1962, pp. 182-201. 4. Blizzard, R. M., Hamwi, G. J., Skillman, T. G., et al.: Thyroglobulin antibodies in multiple thyroid diseases. New Eng. J. Med., 260:112-116,1959. 5. Boler, J., Enzmann, F., Folkers, C., et al.: The identity of chemical and hormonal properties of the thyrotropin releasing hormone and pyroglutamyl-histidyl-proline amide. Biochem. Biophys. Res. Commun., 37:705-710,1969. 6. Braverman, L. E., Ingbar, S. H., and Sterling, K.: Conversion of thyroxine (T4) to triiodothyronine in athyreotic human subjects. J. Clin. Invest., 49:855-864,1970. 7. Brodie, B. B., Davies, J. I., Hynie, S., et al.: Interrelationships of catecholamines with other endocrine systems. Pharmacol. Rev., 18:273-289, 1966. 8. Burke, G.: The triiodothyronine suppression test. Amer. J. Med., 42:600-608, 1967. 9. Burke, G.: The thyrotropin-stimulation test. Ann. Intern. Med., 69:1127-1139, 1968. 10. Burke, G., Halko, A., Silverstein, G. E., et al.: Comparative thyroid uptake studies with 131 1 and T c 0 499m -. J. Clin. Endocrinol. Metab., 34:630-637, 1972. 11. Chopra, I. J.: A radioimmunoassay for measurement of thyroxines in unextracted serum. J. Clin. Endocrinol. Metab., 34:938-947, 1972. 12. Cotton, G. E., Gorman, C. A., and Mayberry, W. E.: Suppression of thyrotropin (H-TSH) in serums of patients with myxedema of varying etiology treated with thyroid hormones. New Eng. J. Med., 285:529-533, 1971. 13. Crile, G., Jr.: Endocrine dependency of papillary carcinoma of the thyroid. J.A.M.A., 195:721-724,1966.
er,)
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14. DeGroot, L. J.: Kinetic analysis of iodine metabolism. J. Clin. Endocrinol., 25:149-173, 1966. 15. Dratman, M. B., Richter, M. E., and Lynch, H. A.: Incorporation of thyroxin carbon in protein fractions of Rana catsbiana tadpole nervous system, liver and tail. Endocrinology, 85:217-224, 1970. 16. Emerson, C., and Utiger, R. D.: Hyperthyroidism and excessive thyrotropin secretion. New Eng. J. Med., 287:328-333,1972. 17. Fisher, D. A., and Odell, W. D.: Acute release of thyrotropin in the newborn. J. Clin. Invest., 48:1670-1677,1969. 18. Ghahremani, G. G., Hoffer, P. B., Oppenheim, B. E., et al.: New normal values for thyroid uptake of radioactive iodine. J.A.M.A., 217:337-339,1971. 19. Gharib, H., and Wahner, H. W.: Clinical experience with assays for triodothyronine. MED. CLIN. N. AMER., 56:861-869,1972. 20. Guillemin, R.: Hypothalamic control of the secretion of adenohypophysial hormones. Advances Metabol. Disorders, 5:16-26,1971. 21. Gorman, C. A.: Some problems in thyroid diagnosis. MED. CLIN. N. AMER., 56:841-848, 1972. 22. Green, W. L.: Guidelines for the treatment of myxedema. MED. CLIN. N. AMER., 52:431450,1968. 23. Hall, R. J., Amos, J., Garry, R., et al.: Thyroid stimulating hormones response to synthetic thyrotropin releasing hormone in man. Brit. Med. J., 2:274-277, 1970. 24. Hall, R., and Evered, D.: Hypothyroidism. Brit. Med. J., 1 :290-293,1972. 25. Hamburger, J. I.: Application of the radioiodine uptake to the clinical evaluation of thyroid disease. Seminars Nucl. Med., 1 :287-300, 1971. 26. Hamilton, C. R., Adams, L. C., and Maloof, F.: Hyperthyroidism due to thyrotropin-producing pituitary chromophobe adenoma. New Eng. J. Med., 283:1077-1080,1970. 27. Harrison, T. S.: Adrenal medullary and thyroid relationships. Physiol. Rev., 44:161-185, 1964. 28. Hayles, A. B., and Cloutier, M. D.: Clinical hypothyroidism in the young. A second look. MED. CLIN. N. AMER., 56:871-884, 1972. 29. Herbst, A. L., and Selenkow, H. A.: Hyperthyroidism during pregnancy. New Eng. J. Med., 273:627-632, 1965. 30. Hershman, J. M., and Pittman, J. A.: Utility of the radioimmunoassay of serum thyrotropin in man. Ann. Intern. Med., 74:481-490, 1971. 31. Hershman, J. M., and Pittman, J. A.: Control ofthyrotropin secretion in man. New Eng. J. Med., 285:997-1006, 1971. 32. Hess, M. E., and Shanfeld, J.: Cardiovascular and metabolic interrelationships between thyroxine and the sympathetic nervous system. J. Pharmacol. Exper. Therap., 148:290297,1965. 33. Hoch, F. L.: Energy transformations in animals: regulatory mechanisms. In Masaro, E. J., ed., Physiological Chemistry. Philadelphia, W. B. Saunders Co., 1971, pp. 109-210. 34. Hollander, C. S.: On the nature of the circulating thyroid hormone: clinical studies of triiodothyronine and thyroxine in serum using gas chromatographic methods. Trans. Assoc. Amer. Physicians, 81 :76-91, 1968. 35. Hollander, C. S.: Newer aspects of hyperthyroidism. Hosp. Pract., 87-96, May, 1972. 36. Howarth, P. J. N., and MacIagan, N. F.: Clinical application of serum total-thyroxine estimation, resin uptake and free-thyroxine index. Lancet, 1 :224-228, 1969. 37. Ismail-Beigi, F., and Edelman, I. S.: Ne mechanism of the calorogenic action of thyroid hormone. J. Gen. Physiol., 57:710-722,1971. 38. Koener, D., Schwartz, H. L., Surks, M. I., et al.: Nuclear binding of T3: comparison between in vivo and in vitro interactions. (Abstract) Procedures of the American Thyroid Association, 48th Meeting, 1972. 39. Lansberg, L., and Axelrod, J.: Influence of pituitary, thyroid, and adrenal hormones on norepinephrine turnover and metabolism in the rat heart. J. Circ. Res., 22:559-571, 1968. 40. Levy, R. P., Marshall, J. S., and Velayo, N. L.: Radioimmunoassay of human thyroxinebinding globulin (TB G). J. Clin. Endocrinol. Metab., 32:372-381, 1971. 41. Levey, G. S., and Epstein, S. E.: Myocardial adenyl cyclase: activation by thyroid hormones and evidence for two adenyl cyclase systems. J. Clin. Invest., 48:1663-1669,1969. 42. McKenzie, J. M., and Murphy, S. S.: Treatment of the thyroid nodule in Adv. Intern. Med., 17:215-236, 1971. , 43. Mitchell, M. H., Harden, A. B., and O'Rourke, M. E.: The in vitro resin sponge uptake of triiodothyronine- 131 I from serum in thyroid disease and in pregnancy. J. Clin. Endocrinol. Metab., 20:1474-1483,1960. 44. Murphy, B. E. P., and Pattee, C. J.: Determination of thyroxine utilizing the property of protein-binding. J. Clin. Endocrinol., 24:187-196,1964.
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45. Nicoloff, J. T., Low, J. C., Dussault, J. H., et al.: Simultaneous measurement of thyroxine and triiodothyronine peripheral turnover kinetics in man. J. Clin. Invest., 51:473-483, 1972. 46. Odell, W. D., Wilber, J. F., and Vtiger, R D.: Studies of thyrotropin physiology by means of radioimmunoassay. Recent Progr. Horm. Res., 23:47-85, 1967. 47. Oppenheimer, J. H.: Role of plasma proteins in the binding, distribution, and metabolism of the thyroid hormones. New Eng. J. Med., 278:1153-1162, 1968. 48. Pileggi, V. J., Lee, N. D., Golub, O. J., et al.: Determination of iodine compounds in serum. J. Clin. Endocrinol., 21 :1272-1279,1961. 49. Pittman, J. A., Haigler, E. D., Jr., Hershman, J. M., et al.: Hypothalamichypothyroidism. New Eng. J. Med., 285:844-845, 1971. 50. Pochin, E. E.: Radioactive therapy for thyroid cancer. Sem. Nucl. Med., 4:503-515, 1971. 51. Robbins, J.: Reverse-flow zone electrophoresis: a method for determining the thyroxinebinding capacity of serum protein. Arch. Biochem., 63:461-469, 1956. 52. Roitt, I. M., and Doniach, D.: Human auto-immune thyroiditis: serological studies. Lancet, 2:lO27-1033,1958. 53. Senior, R M., and Birge, S. J.: The recognition and management of myxedema coma. J.A.M.A., 217:61-65,1971. 54. Shanks, R G., Hadden, D. R, Lowe, D. C., et al.: Controlled trial of propranolol in thyrotoxicosis. Lancet, 1 :993-994, 1969. 55. Singer, P. A., and Nicoloff, J. T.: Estimation of the triiodothyronine secretion rate in euthyroid man. J. Clin. Endocrinol. Metab., 35:82-89, 1972. 56. Snyder, J. P., and Vtiger, D. R: Response to thyrotropin releasing hormone (TRH) in normal man. J. Clin. Endocrinol. Metab., 34:380-385, 1972. 57. Sokoloff, L., Roberts, P. A., Januska, M. M., et al.: Mechanisms of stimulation of protein synthesis by thyroid hormones in vivo. Proc. Acad. Nat. Sci., V.S., 60:652-659, 1968. 58. Solomon, D. H., Benotti, J., DeGroot, L. J., et al.: A nomenclature for tests of thyroid hormones in serum: report of a committee of the American Thyroid Association. J. Clin. Endocrinol. Metab., 34:884-890, 1972. 59. Sterling, K.: The significance of circulating triiodothyronine. Recent Prog. Hormone Res., 25:249-286, 1970. 60. Sterling, K., Refetoff, S., and Selenkow, H. A.: Ta thyrotoxicosis: thyrotoxicosis due to elevated serum triiodothyronine levels. J.A.M.A., 213:571-575, 1970. 61. Sutherland, E. W., Oye, I., and Butcher, R. W.: The action of epinephrine and the role of the adenyl cyclase system in hormone action. Recent Prog. Hormone Res., 21 :623-646, 1965. 62. VanMiddleworth, L.: Radium bodies in bovine thyroids. American Thyroid Association Fourth Meeting (abstract) 1971, p. 70. 63. Waldstein, S. S.: Thyroid-catecholamine interrelations. Ann. Rev. Med., 17:123-132, 1966. 64. Wiener, L., Stout, B. D., and Cox, J. W.: Influence of beta sympathetic blockade (propranolol) on the hemodynamics of hyperthyroidism Amer. J. Med., 46:227-233, 1969. 65. Werner, S. C.: Treatment: Myxedema coma. In Werner, S. C., and Ingbar, S. H., eds.: The Thyroid. New York, Harper and Row, 1971, pp. 832-841. 66. Werner, S. C.: Prednisone in emergency treatment of malignant exophthalmos. Lancet, 1:1004-1007,1966. 67. Wollner, L. B., Beahrs, O. H., Black, B. M., et al.: Classification and prognosis of thyroid carcinoma. A study of 885 cases observed in a 30 year period. Amer. J. Surg., 102:354386, 1961.
Medical College of Pennsylvania Philadelphia, Pennsylvania 19129