9.6 COURSE OF THE DISEASE

Although technologically dated, one of the most charming and clear descriptions of a typical case of myxedema is that given by William M. Ord ¹ in Allbutt's System of Medicine, published first in 1897. It is as follows:

THE PICTURE OF THE DISEASE

"Thirty years ago the writer of this article had occasion to investigate the case of a lady suffering from myxedema in a most definite form, and therefore offering complete opportunity of studying the symptoms and the relations of the disease. The patient, a lady of thirty-five, who had several children, presented an appearance suggestive of Bright's disease, yet, although she was greatly swollen on the whole of her body, on careful examination the swelling did not appear to be due to an ordinary dropsy. There was nowhere any pitting on pressure, and there was no albuminuria in the slightest amount. The diagnosis of chronic Bright's disease without albuminuria at first suggested itself, but on further examination many symptoms not known to be related with Bright's disease came under the eye. The face, very much swollen in all parts, was particularly swollen in the eyelids, upper and lower, in the lips, and in the alae nasi. There was a flush, very limited, over the malar bones, contrasting with a complete pallor over the orbital regions. The eyebrows were greatly raised by the effort to keep the lids apart. The skin of the face, and indeed of the whole body, was completely dry, rough and harsh to the touch; not exactly doughy, but giving a sensation of the loss of all elasticity or resilience. The hair was scanty, had no proper gloss, and was much broken. In the absence of all signs of visceral disease the condition of the nervous system was such as to attract much attention. The physiognomy was singularly placid at most times, less frequently heavy, with signs of somnolence, very rarely alert. In interviews the patient was imperturbably garrulous to a degree that could not fail to attract attention. For many minutes she would talk without cessation until obliged to stop and take a good breath. What she said was not altogether relevant, but it had to be said. All interrupting questions were disregarded. If, at the end of a small pause, she was asked to put her tongue, she ignored the request, but at the end of a varying time, when her breath became short, she would put out her tongue for a long time. She dealt in the same way with questions put to her in respect of the points raised by her statements. Her letters were frequent, voluminous, and, as regarded handwriting, very good. Her speech was slow and laboured. There was some difficulty in it, evidently due to the swelling of the lips, but was more than this: the words hung in a way that indicated nervous as well as physical difficulty, and inflexions of the voice were wanting. The tones of the voice were leathery, and suggested rather those of an automaton. The proper timbre was quite lost. Doubtless this was in part, again, due to obvious thickenings in the fauces and the larynx; but it did not in any way resemble the character of voice observed in ordinary swellings of those parts. Her temper was singularly equable, she was the most tender and solicitous of mothers, and in a long course of years during which she was under the writer's observation no word of unkindness or suspicion fell from her lips. Lethargy was an impressive part of her mental condition. Memory was slow, but correct. She thought slowly, performed all movements slowly, and was slow in receiving impressions. Her toilet, and she was no fashionable person, occupied hours. Her household duties could never be overtaken, and she had to seek assistance. Her gait presented a distinct ataxic quality. As her bulky body moved across a room, there occurred at each step forward a quiver running from the legs upwards, such as may be seen in people under the influence of great emotion, as in Lady Macbeth. This appeared to be due to a want of complete concert in the action of the flexors and extensors of the body, the flexors acting for the most part in advance. The interval between the action of the two sets of muscles was at some times extreme enough to determine falls, not in any way produced by obstacles. She fell forward on her knees, and, as a result, she sustained fracture of the patella on one side, and the patellar tendon on the other. Similar conditions existing in the head and neck produced excessive distress. From time to time the head would fall forward in spite of all voluntary effort to prevent it. The chin would then rest on the upper part of the sternum, as is seen in cretins. Sometimes by prolonged exertion of the will, sometimes with the assistance of the hands, the head would be raised, not always to good effect; for unless great care were exercised the head would fall backwards with a suddenness that was alarming. There was no obvious defect of the sense of touch, but it must be admitted that the speed of the reception of tactile sensations was not noted. After the establishment of the disease she bore two children; on both occasions severe postpartum haemorrhage occurred. She had no other haemorrhages. The first impression was, as I said above, that the case was one of Bright's disease without albuminuria. The urine was examined regularly for years without detection of albumin, and there were no such changes in the heart and arteries as belong to Bright's disease. After ten years, however, albumin appeared in the urine, and the patient died ultimately with symptoms of contracting granular kidney. A postmortem examination could not be obtained, and therefore the condition of the thyroid gland and of the kidneys cannot be recorded."

ONSET OF THE DISEASE

The onset of naturally occurring hypothyroidism is insidious. The patient is often unaware of it, as may be friends and relations. As the gland is gradually replaced by fibrous tissue, lymphocytic infiltration, or both, the serum hormone levels and metabolic rate begin slowly to fall. The first symptoms may be a decrease in sweating and dislike of cold. They may be present alone for a period of years before dramatic events occur. One of our patients gave a story of marked hypersensitivity to cold for 12 years, at the end of which time the picture of full-blown myxedema developed. Sometimes the presenting symptom may be a demand for a warmer room or more clothing. Sometimes a mere decrease in activity due to listlessness, lack of energy, or fatigue, is the first change noted. In other patients, mental dullness or drowsiness may be observed. We have also seen the opposite change, namely, nervousness and irritability, or even peevishness in the exceptional case.

Progressive constipation or increase in menstrual flow may occasionally be the first event. So, too, may any of the following: deafness, falling hair, thick speech, dizziness, puffiness of the face, headache, pallor, weight gain, or fatigue. When hypothyroidism occurs more suddenly, as after surgical thyroidectomy or RAI therapy, the symptoms may not be so insidious, and indeed may be quite upsetting to the patient. Musculoskeletal symptoms such as frequent cramps may be distressing, and acute depression or acute anxiety may appear. Thus, the clinical course may be much influenced by the cause of the hypothyroid state. Obvious symptoms and signs usually appear as the thyroxine (T4) level falls below normal. Of these symptoms, nonpitting edema, from which myxedema derives its name, is pathognomonic. It is a specific thyroprival sign, and when it develops, the disease is in the full-blown state. There may be little apparent change in the patient's appearance or condition for several years. During such a period the patient may be well off subjectively. The increased sensitivity to cold can be met by maintaining the living area at an unduly warm temperature. The decreased energy makes the person content to do little or nothing. The myxedematous state is characterized by an amazing placidity. The terminal stage may be called myxedematous cachexia.

MYXEDEMATOUS CACHEXIA

Myxedematous cachexia is characterized by an intensification of all symptoms and signs. There is great thickening of the tongue, thickness, dryness and coarseness of the skin, thickening and brittleness of the nails, falling and brittleness of the hair, progressive decrease in activity and responsiveness, and a closer and closer approach to a purely vegetative existence. Although the mucous edema persists - and indeed tends to increase - body fat may disappear, so that actual wasting takes place. After this stage has persisted for an indefinite period of months or even years, death takes place because of intercurrent infection, congestive heart failure, or both. The final symptom is coma, which may last for days. In the untreated patient, the length of time between the first symptoms and death may be as long as 15 years. It is, fortunately, seldom nowadays that one witnesses the natural termination of the disease. It is seen only when the patient is already moribund when he or she comes to the physician, the diagnosis previously having been overlooked or where severe myxedema is present in association with another serious illness. In the Report on Myxoedema, which was published before the discovery of the cure of the disease, the duration is given as 10 years or more. The evolution of the symptoms of myxedema is slowly progressive. If one compares patients with myxedema of 3, 6 or 12 years' duration, although all may have classic symptoms and identical thyroid function test results, the clinical picture will be more intense at 6 years than at 3 and still more at 12. The mental manifestations, and the integumentary changes in particular, intensify as the years pass. Such severe manifestations of hypothyroidism are rarely seen in the current era. Patients and their friends and relatives are often strangely unaware of evidence of myxedema. Often patients are identified during treatment for some entirely unrelated disorder. Myxedema has been called a "consultant's diagnosis", because the changes that appear as the disease develops are so subtle and gradual that they are often overlooked by the patient's family physician. This fact is becoming less true with the ready availability of objective diagnostic tests.

9.7 DIAGNOSIS OF HYPOTHYROIDISM

Evaluation of a patient suspected of hypothyroidism starts with obtaining conclusive evidence that thyroid hormone deficiency is absent or present. Clinical examination suffices to provide a definitive answer in very severe cases of thyroid hormone deficiency, but is less accurate in mild cases. Biochemical proof of thyroid hormone deficiency is thus required in the vast majority of patients. If hypothyroidism is demonstrated, the next question to be answered is which disease entity has caused the hypothyroid state (nosological diagnosis). Delineation of the cause of hypothyroidism is relevant for identification of patients with potentially reversible hypothyroidism; it migh also give a clue for the existence of other conditions associated with a specific cause. The diagnostic process is schematically represented in Table 9-9.

Table 9-9. Schematic approach of the patient suspected of hypothyroidism.

9.7.1 CLINICAL EVALUATION (STAGE 1A)

Table 9-10 lists the relative frequency of symptoms and signs accumulated by Lerman in a study of 77 myxedematous patients in one thyroid clinic and by Murray in a study of 100 patients with primary hypothyroidism, 15 pituitary patients, and 100 normal control subjects. This analysis identifies the cardinal manifestations of the disease. It also discloses that a certain number of manifestations are occasionally found in overt myxedema that are somewhat more suggestive of hyperthyroidism than of hypothyroidism. Under this heading may be listed dyspnea, nervousness, palpitations, precordial pain, loss of weight, and emotional instability. These symptoms are also found in normal control subjects in nearly the same frequency.

Many symptoms typical of primary hypothyroidism are not commonly found in pituitary hypothyroidism - for example, coarse skin, thick tongue, coarseness of hair, peripheral edema, hoarseness, and paresthesias.

The diagnosis of severe hypothyroidism is relatively straightforward on clinical grounds. All of the manifestations mentioned in the above discussion are present, and laboratory testing merely confirms the high index of clinical suspicion. However, severe hypothyroidism has become increasingly rare due to physicians' raised level of consciousness about the relatively high prevalence of this disease in women and the ease of making a laboratory diagnosis. Rather it is the more sublte or unusual presentations of hypothyroidism that may present difficulties ¹. Since laboratory confirmation of hypothyroidism is straightforward, the critical factor in successful diagnosis is maintaining a high degree of suspicion. If the diagnosis is not suspected in a patient with some of the typical manifestations of hypothyroidism at the first encounter, it may be several months before the physician reconsiders this explanation for the patient's complaints. Thus, hypothyroidism may be more readily diagnosed by a consultant who has not seen the patient before, since both the patient and the regular physician may have assumed that the many nonspecific symptoms are insignificant or at least unrelated to a specific organic disease.

There are certain symptoms or signs that should, irrespective of other factors, lead to a biochemical evaluation for possible hypothyroidism. In the child or adolescent, growth retardation is one of these. The presence of an enlarged thyroid should trigger a similar response. However, more subtle, less specific complaints, including depression or other organic mental syndromes, muscle cramps, paresthesias, carpal tunnel syndrome, hoarse voice, elevated cholesterol, pericardial effusion, arthritis, yellow skin (carotenemia), hyperkeratosis of the palms or soles, or menorraghia, can be manifestations of hypothyroidism. In addition, certain constellations of autoimmune disease occur in concert with hypothyroidism, including primary adrenal insufficiency, type I diabetes, and pernicious anemia. The presence of any of these should lead to search for primary thyroid dysfunction.

Statistical methods have been applied to the clinical diagnosis of hypothyroidism, based on the frequency of symptoms and signs in patients and controls. Well-known is the Billewicz score, composed of points given in a weighted manner for the presence or absence of 17 symptoms and signs ². Application of this score increases the pretest likelihood of hypothyroidism by 15-19% ³. A newly developed clinical score is, however, easier to perform and more sensitive ⁴ (Table 9-11).

The positive predictive value of this new score for hypothyroidism is 96.9% at a score of 6 points or more; the negative predictive value for the exclusion of hypothyroidism is 94.2% at a score of 2 points or less. 62% of all overt hypothyroid and 24% of subclinical hypothyroid patients are classified as clinically hypothyroid by the new score, as opposed to 42% and 6% respectively by the Billewicz score Figure 9-4.

Figure 9-4. Assessment of hypothyroidism by a clinical score, composed of 12 symptoms and signs as listed in Table 3 (Reproduced with persmission(4)).

Age and smoking have been recognized as modifiers of the clinical expression of thyroid hormone deficiency. Elderly patients have a smaller number of clinical signs than younger patients ⁵. Smokers have more severe manifestations of hypothyroidism than nonsmokers ⁶.

9.7.2 LABORATORY EVALUATION (STAGE 1B)

The assay of TSH in serum has proven to be the best single test for the exclusion or detection of hypothyroidism. Using the flow-chart of Figure 9-2, the following results can be obtained:

Figure 9-2. Logit probability (log odds) for the development of hypothyroidism as a function of TSH values at first survey during a 20-year follow-up of 912 women in the Whickham Survey. (Reproduced with permission)(9).

Figure 9-5. Flow-diagram for the biochemical diagnosis of hypothyroidism.

(Figure 9-5). Flow-diagram for the biochemical diagnosis of hypothyroidism.

1. TSH normal. Euthyroidism is almost certain, as primary hypothyroidism is excluded. The only exception is the existence of central hypothyroidism. As isolated TSH deficiency is very rare, clinical examination of the patient will usually provide sufficient clues (symptoms and signs of a pituitary mass, of hypopituitarism, or of overproduction of pituitary hormones) to warrant further evaluation by a FT4 assay.

2. TSH elevated, FT4 decreases. This classical combination of test results indicates primary hypothyroidism. Test results are sometimes due to central hypothyroidism or nonthyroidal illness when TSH is slightly elevated (5-15 mU/l).

3. TSH elevated, FT4 normal. Test results indicate most often subclinical hypothyroidism, sometimes nonthyroidal illness. 4. TSH elevated, FT4 increased. A rarely encountered combination of test results, indicating either thyroid hormone resistance or TSH producing pituitary adenoma.

5. TSH decreased, FT4 decreased. Central hypothyroidism accounts for these test results, which, however, also can be observed in severe nonthyroidal illness and after recently instituted treatment for thyrotoxicosis (131I, surgery, antithyroid drugs) or recent discontinuation of excessive thyroid hormone medication.

6. TSH decreased, FT4 increased or normal. Hypothyroidism is excluded. Results indicate overt thyrotoxicosis or subclinical hyperthyroidism respectively.

9.7.3 NOSOLOGICAL DIAGNOSIS (STAGE 2)

The cause of the hypothyroid condition is in general easily established. Most informative are a careful clinical examination and determination of TPO antibodies in serum. Particularly relevant questions in the history taking are: family history of thyroid disease? recent delivery? previous thyroid surgery or 131I therapy? use of antithyroid drugs? exposure to iodine excess? Symptoms and signs of a pituitary mass or of hypopituitarism suggest the presence of central hypothyroidism. Physical examination may reveal a goiter (like the characteristic firm rubbery' goiter in goitrous Hashimoto's hypothyroidism), but many if not most hypothyroid patients have no palpable thyroid gland. High titers of TPO antibodies indicate chronic autoimmune thyroiditis, the most prevalent cause of hypothyroidism. Although most cases of hypothyroidism are permanent and require life-long treatment with thyroxine, a substantial minority is transient in nature due to the natural course of the underlying disease entity. Elimination of the causal factor is possible only in a few patients in whom the hypothyroid state is induced by antithyroid drugs or iodine excess. Table 9-12 provides the physician with possible clues for assessing the likelihood of reversible hypothyroidism in a particular patient. In selected cases further evaluation by thyroidal radioiodine uptake studies might be useful.

9.8 TREATMENT OF HYPOTHYROIDISM

9.8.1 PHARMACOLOGY OF THYROID HORMONE REPLACEMENT PREPARATIONS

Levothyroxine. L-thyroxine is prescribed as the sodium salt in order to enhance its absorption, which occurs along the entire small intestine ^1,2. Intestinal absorption of oral T4 is on average 80% ³, and is greater in the fasting than in the fed state Absorption is apparrently more complete and less eratic if the daily dose is taken in the fasting state ( Bach-Huynh TG, Nayak B, Loh J, Soldin S, Jonklaas J J Clin Endocrinol Metab. 2009 Oct;94(10):3905-12 Timing of levothyroxine administration affects serum thyrotropin concentration). Generic and brand-name levothyroxine preparations are mostly bioequivalent ⁴, but altered bioavailability has been reported due to changes in the formulation of preparations ⁵. Serum T4 concentrations peak 2 to 4 hours after an oral dose and remain above normal for approximately 6 hours in patients receiving daily replacement therapy ^6,7. The gradual conversion of T4 into T3 in various tissues increases serum T3 concentrations so slowly after thyroxine absorption that with daily levothyroxine administration, no significant changes in circulating free T3 are detectable. In North America, levothyroxine tablets are available in tablet strengths of 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200 and 300 µg. The long half-life of thyroxine of about 7 days allows treatment with a singly daily tablet. Omission of an occasional tablet is of little relevance. Liothyronine. After oral administration of L-triiodothyronine sodium (which is more readily absorbed than T4) peak levels of serum T3 are observed within 2 to 4 hours ⁸. The serum T3 concentration may reach elevated values after a single dose of 50 µg or even 25 µg, sometimes associated with cardiac symptoms like palpitations ⁹. The half-life of T3 is approximately one day. Preparations of L-T3 are useful in the management of patients with thyroid cancer to shorten the period of hypothyroidism required for diagnosis and treatment of remaining tumor tissue with 131I. Desiccated thyroid. Desiccated thyroid is prepared from porcine or bovine thyroid glands. In former days desiccated thyroid was standardized by the organic iodine content, which did not distinguish between iodotyrosines and iodothyronines ¹⁰. Current guidelines stipulate that one grain (65 mg) of desiccated thyroid contains about 44 µg T4 and 9 µg of T3; the hormones are in the form of thyroglobulin ^11,12. In our experience, the biologic potency of a 1-grain desiccated thyroid tablet is about 75 to 88 µg T4. Because of the relatively high ratio of T3 to T4 in desiccated thyroid, patients receiving an amount of this medication adequate to normalize serum TSH generally have serum T4 concentrations in the lower half of the normal range. Serum T3 concentrations will vary in such patients, depending on the interval between ingestion of the medication and the time of blood sampling. The time course of the absorption of T3 is similar whether it is contained in thyroglobulin or free in the tablet, with peak levels approximately 2 to 4 hours after oral administration ⁸. Combinations of T3 and T4. Liotrix, the only combination preparation currently available in the United States, contains 50 µg T4 and 12.5 µg T3/1 grain equivalent, but is biologically equivalent to a 65 mg (1 grain) tablet of desiccated thyroid. Recent studies in thyroidectomized rats have demonstrated that restoration of the euthyroid state in all tissues can only be restored by the combination of T4 and T3, and not by T4 alone ¹³. This finding has aroused new interest in combinations of T3 and T4. In hypothyroid patients who were euthyroid under stable thyroxine treatment, replacement of 50 µg T4 of the usual dose of T4 by 12.5 µg T3 improved mood and neuropsychological functions in a cross-over study design, without suppressing serum TSH ^{14, 16}. However, two subsequent randomized clinical trials did not demonstrate any benefit of the T4+T3 combination therapy over therapy with T4 alone^17,18. One may argue that the disappointing results obtained so far with combination therapy are caused by relatively high doses of T3 as compared to the applied dose of T4, resulting in T4 to T3 ratio?s lower than the T4 to T3 ratio of about 10 which is the physiological ratio of T4 to T3 secretion by the thyroid gland. A future perspective might thus be combination preparations containing approximately 100 µg of T4 and 10 µg of T3 with the triiodothyronine in slow-release form to avoid adverse cardiac effects ¹⁵. Such preparations are not yet available for clinical validation studies. It remains to be established whether combination therapy with T4 and T3 in doses mimicking their thyroidal secretion rates might improve the impaired psychological well-being which has been observed in a subset of hypothyroid patients despite adequate doses of levothyroxine¹⁹.

9.8.2 REPLACEMENT WITH THYROXINE (SYNTHROID)

Of the available thyroid hormone replacement preparations, thyroxine is presently recommended as the drug of choice in view of its long half-life ready quantitation in the blood, ease of absorption, and the availability of multiple tablet strenghts ^1-4. Institution of therapy. The rapidity with which normal thyroid hormone levels should be restored depends on a number of factors, including the age of patient, the duration and severity of the hypothyroidism, and the presence or absence of other disorders, particularly those of the cardiovascular system. Most patients under the age of 60 can immediately begin a complete replacement dose of 1.6 to 1.8 µg levothyroxine/kg ideal body weight (about 0.7 to 0.8 µg/1b). Requirements for children and infants are discussed separately and are higher than those for adults between the ages of 20 and 70. The cause of hypothyroidism also influences replacement in that patients with total thyroidectomy or severe primary hypothyroidism have slightly higher requirements than do patients who become hypothyroid after radioiodine or surgical treatment for Graves' disease ⁵. The latter group may have some residual thyroid function that is autonomous, and thus a complete replacement dose is excessive. For most women, a complete replacement dose will be between 100 and 150 µg per day and, for most men, between 125 and 200 µg per day. Pretreatment serum TSH predicts to a certain extent the daily maintenance dose of levothyroxine in patients with primary hypothyroidism (Figure 9-6) ⁶.

Individual l-T(4) requirements are dependent on lean body mass. Age- and gender-related differences in l-T(4) needs reflect different proportions of lean mass over the total body weight. An estimate of lean mass may be helpful to shorten the time  required to attain a stable dose of l-T(4), particularly in subjects with high body mass index values that may be due either to increased muscular mass or to obesity.  (J Clin Endocrinol Metab. 2005 Jan;90(1):124-7. Lean body mass is a major determinant of levothyroxine dosage in the treatment of thyroid diseases. Santini F, Pinchera A, Marsili A, Ceccarini G, Castagna MG, Valeriano R, Giannetti M, Taddei D, Centoni R, Scartabelli G, Rago T, Mammoli C, Elisei R,Vitti P.)

Figure 9-6. Relationship between the optimal daily dose of levothyroxine sodium and the mean pretreatment serum TSH concentration in patients with primary hypothyroidism. Simple linear regressions are shown for two subgroups calculated according to the daily dose of L-T4 divided at the median dose of 125 µg; the intercept of these two correlation lines occurs at the TSH concentration of 36 mU/l. (Reproduced with permission)6.

Figure 9-1. Relationship between the optimal daily dose of levothyroxine sodium and the mean pretreatment serum TSH concentration in patients with primary hypothyroidism. Simple linear regressions are shown for two subgroups calculated according to the daily dose of L-T4 divided at the median dose of 125 µg; the intercept of these two correlation lines occurs at the TSH concentration of 36 mU/l. (Reproduced with permission)⁶.

Full replacement doses should not be administered initially to patients over the age of 60, to patients who have a history of coronary artery disease, or to patients with long-standing severe hypothyroidism. While levothyroxine improves cardiac function in patients with hypothyroidism and increases cardiac output and decreases systemic vascular resistance and end-diastolic volume, it also increases myocardial oxygen consumption. Thus, while patients with coronary artery disease and angina may benefit from reversal of their hypothyroid state, to avoid precipitating acute myocardial ischemia, the dose should be titrated, starting with 25µg a day and increased by increments of 25 µg at 8-week-intervals until serum TSH falls to normal or symptoms of angina worsen or appear. A similar slow approach is prudent in patients with long-standing, severe hypothyroidism, also because occasionally psychosis or agitation occurs during the initial phase of replacement in such cases ^7,8,9.

In the patient given what is thought to be a complete replacement dose of levothyroxine (SYNTHROID), a TSH and free T4 index should be measured about 2 months after therapy begins to establish that the estimated dose is appropriate for the patient. At that time, serum TSH may be still elevated, indicating the need for a modest increase in dose, or TSH may be suppressed, indicating that a reduction is in order. This is usually done in 12- to 25-µg increments, depending on the patient ¹⁰. These studies should be repeated again in 2 months to titrate proper dosage. After proper dosage has been achieved, the test should be repeated yet again after the patient has been euthyroid for approximately 6 months. This is because in certain patients, normalization of thyroxine clearance may require more than 8 weeks, and a dose of levothyroxine that is adequate when the patient is metabolizing thyroxine more slowly may be inadequate when the patient is euthyroid. This dose should be continued and monitored on an annual basis. In patients with severe primary hypothyroidism, few adjustments will be required after the initial titration until the eight decade. However, patients with Graves' disease who have had radioactive iodine may require dosage adjustments up to as long as 5 to 10 years after treatment is begun. A similar course may be followed by patients who have had subtotal thyroidectomy for Graves' disease due to the slow deterioration of residual thyroid function.

Therapy should be monitored with TSH measurements (using an immunometric assay) and estimates of free T4. As the goal of levothyroxine therapy is to normalize the thyroid status of the patient, and as serum TSH provides the most sensitive and readily quantification of thyroid status in the patient with primary hypothyroidism, one aims at TSH values in the low normal range. Serum FT4 concentrations will generally be above the middle of the normal range or slightly elevated if serum TSH concentrations are normalized, but serum T3 concentrations (predominantly derived from T4-5'-monodeiodination) will be in the midnormal range ¹¹. In patients with central hypothyroidism one should rely primarily on serum FT4 and T3¹²; the required replacement dose will frequently suppress serum TSH values to below 0.1 mU/l²⁰.

Clinical response. In general, serum thyroxine normalizes before serum TSH, and both may normalize before the disappearance of all of the symptoms of hypothyroidism. In the severely hypothyroid patient with long-standing disease, a number of profound alterations may occur as the hypothyroid state is corrected. Thus, loss of weight, primarily due to mobilization of interstitial fluid as the glycosaminoglycans are degraded, is prominent. The moon facies, coarse nasal voice, puffy fingers, deafness, and sleep apnea will all diminish. Many of nonspecific symptoms, such as fatigue or cold intolerance, will eventually reverse as well. Hair and skin abnormalities take longer to improve. Despite weight loss due to fluid loss, the obese patient should not expect more than a 10-pound weight change, particularly if serum TSH values are only modestly elevated. Virtually all of the weight loss in hypothyroidism is associated with mobilization of fluid, and significant decreases in body fat rarely occur. While metabolic rate increases, in general, appetite increases as well, and a new equilibrium is established.

Treatment failures. There are few compliant patients whose symptoms and signs do not resolve after thyroid hormone administration. Patients with thyroid hormone resistance sometimes present in this fashion. In patients whose symptoms do not improve with levothyroxine therapy, one should establish that they are taking and absorbing the medication and that it is effective in reducing TSH. The most common cause of treatment failure is poor compliance with ingestion of thyroxine tablets. Compliance might be enhanced by the (supervised) administration of thyroxine once weekly ¹³. A slightly larger dose than 7 times the normal daily dose may be required; a singly weekly gift of 1000 µg T4 orally seems to be effective and well tolerated.

Potential adverse effects of treatment. Life-long treatment with thyroxine when properly monitored, seems to be free of complications. Long-term morbidity and mortality are normal ^1-4. Thyroxine treatment in TSH-suppressive doses, however, might give reason for some concern as it has been associated with detrimental effects on the heart and the bones. A TSH value of =0.1 mU/l has been identified as a risk factor for the development of atrial fibrillation ¹⁴. Long-term levothyroxine therapy in TSH-suppressive doses may cause left ventricular hypertrophy ¹⁵, and increases the risk of ischemic heart disease in patients under the age of 65 years ¹⁶. TSH-suppressive doses of levothyroxine have been associated with bone loss in some but not all studies. A recent extensive meta-analysis concluded that indeed bone mineral density was reduced in hypothyroid patients with a suppressed TSH due to excessive levothyroxine therapy, but only in postmenopausal women ¹⁷. No or a minimal excess of bone fractures, however, has been observed in patients on levothyroxine even if TSH is suppressed ^18,19,21,22.
A recent population-based study of all patients in Tayside, Scotland  taking T(4) replacement therapy (n = 17,684) considered fatal and nonfatal endpoints for cardiovascular disease, dysrhythmias, and fractures. Patients were categorized as having a suppressed TSH (<or=0.03 mU/liter), low TSH (0.04-0.4 mU/liter), normal TSH (0.4-4.0 mU/liter), or raised TSH (>4.0 mU/liter). Cardiovascular disease, dysrhythmias, and fractures were increased in patients with a high TSH: adjusted hazards ratio, 1.95, 1.80, and 1.83, respectively; and patients with a suppressed TSH: 1.37, 1.6, and 2.02, respectively, when compared to patients with a TSH in the laboratory reference range. Patients with a low TSH did not have an increased risk of any of these outcomes. Thus it may be safe for patients treated with T(4) to have a low but not suppressed serum TSH. (Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP. J Clin Endocrinol Metab. 2010 Jan;95(1):186-93 Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy.)

9.8.3 SITUATIONS REQUIRING DOSE ADJUSTMENT

Table 9-13 lists a number of circumstances in which dosage requirements of levothyroxine may change in compliant patients. Patients who develop clinical malabsorptive disorders like gluten-induced enteropathy may require a change in dosage ^1,26. Malabsorption may also occur in patients who ingest large quantities of bran ²; the timing of the dose should be adjusted to take this into account. Levothyroxine should be administered several hours after the patient takes any of the agents listed that can block its absorption²⁷, but the dosage or preparation used may still have to be increased during therapy with some of these agents ^3-7,28. There is an increase in thyroxine requirement in pregnant patients with primary hypothyroidism, probably related to increased lean body mass and increased serum TBG ^8,9. Patients with hypothyroidism planning to become pregnant should be instructed to report to their physician when pregnancy is confirmed, and the serum TSH and/or free T4 estimate should be monitored and the levothyroxine dose adjusted upward as indicated. The mean increment in the required daily thyroxine dose is 50 µg; it may not occur until as late as the sixth month but is often apparent by the second month of gestation. In a review of four series comprising a total of 108 women, serum TSH increased in 58% and the mean L-T4 dose increased from 117 µg to 150 µg ²⁴. Timely adjustment of the thyroxine dose in early gestation might be relevant for infant development. Children of healthy women with FT4 levels below the 10th percentile (<10.4 pmol/l) at 12 weeks gestation have lower scores on a psychomotor developmental scale at 10 months of age, compared to children of mothers with higher FT4 values (mean difference 7.4, 95% CI 1.1 to 13.9)¹⁰; psychomotor development was not related to material FT4 at 32 weeks gestation. Children at the age of 7-9 years have a lower intelligence quotient if their mother was hypothyroid during pregnancy¹¹.The lowest IQ?s were observed in children whose mother was not treated for hypothyroidism during pregnancy: 19% of such children had an IQ of #85, in contrast to 5% of the children whose mothers had a normal thyroid function during pregnancy. The data raise the issue of screening pregnant women for thyroid function disorders in the first trimester. The dosage may by reinstituted at its pregestational level immediately after delivery. Estrogen therapy may increase the need for levothyroxine and it is recommended to measure serum TSH approximately 12 weeks after estrogen therapy is initiated ²⁵.

Secondary (pituitary or hypothalamic) hypothyroidism requires special consideration in therapy, since TSH can not be used for monitoring. Lack of GH is associated with reduced T4>T3 conversion, and suggests the need for maintaining fT4 at top normal levels. GH  treatment decreases FT4, increases TT3, decreases cardiac isovolumic contraction time, and increases Resting Energy Expenditure (P < 0.05). REE correlated (P < 0.05) with IGF-I (r = 0.57) and TT3 (r = 0.64). ICT correlated only with TT3 (r = -0.46). GH replacement thus improves the biological effects of T4. Serum FT4 should be targeted at the normal range in GH-deficient patients while on  GH treatment. (Martins MR, Doin FC, Komatsu WR, Barros-Neto TL, Moises VA, Abucham J. Growth hormone replacement improves thyroxine biological effects: implications for management of central hypothyroidism. J Clin Endocrinol Metab. 2007 Nov;92(11):4144-53.)

 or if endogenous GH is satisfactorySeveral drugs (e.g. carbamezepine) induce enzymes of the cytochrome P450 class, which can accelerate thyroxine clearance via pathways that do not lead to T3 production ^12-15. Under these circumstances, dosage must be increased to compensate for this. Lastly, amiodarone and, theoretically at least, selenium deficiency may also block T4 to T3 conversion ^16,17. Androgen therapy in women with breast cancer has also recently been shown to reduce levothyroxine requirements by 25 to 50 percent ²⁰. The mechanism is not known, but thyroxine-binding globulin (TBG) levels are significantly reduced. In patients over the age of 70, levothyroxine requirements are reduced about 25 percent, related to the decrease of lean body mass with age ^21,22,23. Hypothyroid patients with end-stage renal insufficiency need lower doses of T4 after renal transplantation²⁹.

9.8.4 INTERFERENCE WITH CO-EXISTENT CONDITIONS

Hypocortisolemia. The co-existence of thyroid hormone deficiency and glucocorticoid deficiency is not rare. Primary hypothyroidism due to chronic autoimmune thyroiditis is associated with primary adrenocortical insufficiency due to autoimmune adrenalitis. The very cause of central hypothyroidism in many instances will also result in ACTH deficiency and secondary adrenocortical insufficiency. If the two entities co-exist, it is important to replace glucocorticoid before starting thyroxine. For, treatment of hypothyroidism in patients with glucocorticoid deficiency may precipitate an adrenal crises because the adrenal is incapable to meet the increasing demand for cortisol induced by the rise of the metabolic rate ¹⁰.

Ischemic heart disease. Although treatment of hypothyroidism with levothyroxine will improve myocardial function and reduce peripheral vascular resistance, it will increase the need for oxygen in the myocardium ^1,2,3. In patients with an already compromised myocardial blood supply due to coronary atherosclerosis, thyroxine treatment may provoke anginal symptoms. In a large series of hypothyroid patients, new-onset angina occurred in 2% upon thyroxine treatment; pre-existent angina worsened in 16%, did not change in 46%, and improved in 38% ⁴. Patients with preexisting angina should be evaluated for obstructive coronary lesions before thyroxine therapy begins. Retrospective studies suggest that the possibility of myocardial infarction is greater than is the possibility of an adverse event during angiography or angioplasty ^5-8. However, it is quite surprising that major surgery, such as coronary artery bypass grafting, can be very easily withstood by the patient with even moderate hypothyroidism as long as attention is paid to reducing the level of analgesics, maintaining adequate ventilation, and controlling the administration of free water ⁷. In a few patients, remediable lesions will not be present or, even with bypass grafting, complete correction of the hypothyroid state will not be possible. In such patients, submaximal amounts of levothyroxine supplemented by other agents to enhance myocardial function may be helpful in allowing the reestablishment of normal thyroid function ⁹.

Drugs. The metabolism of many drugs is slowed in hypothyroidism, resulting in higher sensitivity to a loading dose and a lower maintenance dose. Marked respiratory depression can occur after a single small dose of morphine. An increase in the dose of digoxin or insulin is sometimes noticed once euthyroidism has been restored. Treatment of adult growth hormone deficiency with rhGH decreases serum FT4 sometimes into the hypothyroid range, thereby unmasking the existence of central hypothyroidism or necessitating a higher dose of already instituted levothyroxine medication¹¹.