The Thyroid and its Diseases
	Chapter 9                                                    HOME Adult Hypothyroidism Revised by  W.M. Wiersinga, March 4, 2004 TO OBTAIN A DOWNLOAD OF THIS CHAPTER IN PDF OR WORD,  CLICK HERE

9.1 HISTORY

9.2 DEFINITION AND EPIDEMIOLOGY OF HYPOTHYROIDISM

The full-blown expression of hypothyroidism is known as myxedema. Adult myxedema escaped serious attention until Gull described it in 1874 ¹. That it was a state resembling the familiar endemic cretinism, but coming on in adult life, was what chiefly impressed Gull. Ord ² invented the term myxedema in 1873. The disorder arising from surgical removal of the thyroid gland (cachexia strumipriva) was described in 1882 by Reverdin ³ of Geneva and in 1883 by Kocher of Berne ⁴. After Gull's description, myxedma aroused enormous interest, and in 1883 the Clinical Society of London appointed a committee to study the disease and report its findings ⁵. The committee's report, published in 1888, contains a significant portion of what is known today about the clinical and pathologic aspects of myxedema. It is referred to in the following discussion as the Report on Myxedema. The final conclusion of the 200-page volume are penetrating. They are as follows:

1. That myxedema is a well-defined disease.

2. That the disease affects women much more frequently than men, and that the subjects are for the most part of middle age.

3. That clinical and pathological observations, respectively, indicate in a decisive way that the one condition common to all cases is destructive change of the thyroid gland.

4. That the most common form of destructive change of the thyroid gland consists in the substitution of a delicate fibrous tissue for the proper glandular structure.

5. That the interstitial development of fibrous tissue is also observed very frequently in the skin, and, with much less frequency, in the viscera, the appearances presented by this tissue being suggestive of an irritative or inflammatory process.

6. That pathological observation, while showing cause for the changes in the skin observed during life, for the falling off the hair, and the loss of the teeth, for the increased bulk of body, as due to the excess of subcutaneous fat, affords no explanation of the affections of speech, movement, sensation, consciousness, and intellect, which form a large part of the symptoms of the disease.

7. That chemical examination of the comparatively few available cases fails to show the general existence of an excess of mucin in the tissues adequately corresponding to the amount recorded in the first observation, but that this discrepancy may be, in part, attributed to the fact that tumefaction of the integuments, although generally characteristic of myxedema, varies considerably throughout the course of the disease, and often disappears shortly before death.

8. That in experiments made upon animals, particularly on monkeys, symptoms resembling in a very close and remarkable way those of myxedema have followed complete removal of the thyroid gland, performed under antiseptic precautions, and with, as far as could be ascertained, no injury to the adjacent nerves or to the trachea.

9. That in such experimental cases a large excess of mucin has been found to be present in the skin, fibrous tissues, blood, and salivary glands; in particular the parotid gland, normally containing no mucin, has presented that substance in quantities corresponding to what would be ordinarily found in the submaxillary gland.

10. That following removal of the thyroid gland in man in an important proportion of the cases, symptoms exactly corresponding with those of myxedema subsequently develop.

11. That in a considerable number of cases the operation has not been known to have been followed by such symptoms, the apparent immunity being in many cases probably due to the presence and subsequent development of accessory thyroid glands, or to accidentally incomplete removal, or to insufficiently long observation of the patients after operation.

12. That, whereas injury to the trachea, atrophy of the trachea, injury of the recurrent laryngeal nerves, injury of the cervical sympathetic, and endemic influences, have been by various observers supposed to be the true cases of experimental or of operative myxedema (cachexia strumipriva), there is, in the first place, no evidence to show that, of the numerous and various surgical operations performed on the neck and throat, involving various organs and tissues, any, save those in which the thyroid gland has been removed, have been followed by the symptoms under consideration; that in many of the operations on man, and in most, if not all, of the experimental operations made by Professor Horsley on monkeys and other animals, this procedure avoided all injury of surrounding parts, and was perfectly antiseptic; that myxedema has followed removal of the thyroid gland in persons neither living in nor having lived in localities the seat of endemic cretinism; that, therefore, the positive evidence on this point vastly outweighs the negative; and that it appears strongly proved that myxedema is frequently produced by the removal, as well as by the pathological destruction, of the thyroid gland.

13. That whereas, according to Clause 2, in myxedema women are much more numerously affected than men, in the operative form of myxedema no important numerical difference is observed.

14. That a general review of symptoms and pathology leads to the belief that the disease described under the name of myxedema, as observed in adults, is practically the same disease as that named sporadic cretinism when affecting children; that myxedema is probably identical with cachexia strumipriva; and that a very close affinity exists between myxedema and endemic cretinism.

15. That while these several conditions appear, in the main, to depend on, or to be associated with, destruction or loss of the function of the thyroid gland, the ultimate cause of such destruction or loss is at present not evident.

Hypothyroidism is traditionally defined as deficient thyroidal production of thyroid hormone. The term primary hypothyroidism indicates decreased thyroidal secretion of thyroid hormone by factors affecting the thyroid gland itself; the fall in serum concentrations of thyroid hormone causes an increased secretion of TSH resulting in elevated serum TSH concentrations. Decreased thyroidal secretion of thyroid hormone can also be caused by insufficient stimulation of the thyroid gland by TSH, due to factors directly interfering with pituitary TSH release (secondary hypothyroidism) or indirectly by diminishing hypothalamic TRH release (tertiary hypothyroidism); in clinical practice it is not always possible to discriminate between secondary and tertiary hypothyroidism, which are consequently often referred to as central hypothyroidism. In rare cases, symptoms and signs of thyroid hormone deficiency are caused by the inability of tissues to respond to thyroid hormone by mutations in the nuclear thyroid hormone receptor TRß; this condition, known as thyroid hormone resistance (see Ch. 16), is associated with an increased thyroidal secretion of thyroid hormones and increased thyroid hormone concentrations in serum in an attempt of the body to overcome the resistance to thyroid hormone. It thus seems more appropriate to define hypothyroidism as thyroid hormone deficiency in target tissues, irrespective of its cause.

GRADES OF HYPOTHYROIDISM

Hypothyroidism is a graded phenomenon, ranging from very mild cases in which biochemical abnormalities are present but the individual hardly notices symptoms and signs of thyroid hormone deficiency, to very severe cases in which the danger exists to slide down into a life-threatening myxedema coma. In the development of primary hypothyroidism, the transition from the euthyroid to the hypothyroid state is first detected by a slightly elevated serum TSH, caused by a minor decrease in thyroidal secretion of T4 which doesn't give rise to subnormal serum T4 concentrations. The reason for maintaining T4 values within the reference range is the exquisite sensitivity of the pituitary thyrotroph for even very small decreases of serum T4, as exemplified by the log-linear relationship between serum TSH and serum FT4 ¹. A further decline in T4 secretion results in serum T4 values below the lower normal limit and even higher TSH values, but serum T3 concentrations remain within the reference range. It is only in the last stage that subnormal serum T3 concentrations are found, when serum T4 has fallen to really very low values associated with markedly elevated serum TSH concentrations (Figure 9-1). Hypothyroidism is thus a graded phenomenon, in which the first stage of subclinical hypothyroidism may progress via mild hypothyroidism towards overt hypothyroidism (Table 9-1)³.

Figure 9-1. Individual and median values of thyroid function tests in patients with various grades of hypothyroidism.  Discontinuous horizontal lines represent upper limit (TSH) and lower limit (FT4,T3) of the normal reference ranges. (Reproduced with permission) (2)

Table 9-1. Grades of hypothyroidism

Maintenance of a normal serum T3 concentration until a relatively late stage in the development of hypothyroidism obviously serves as an appropriate mechanism of the body to counteract the impact of diminishing production of T4. It is accomplished by a preferential thyroidal secretion of T3: the increased secretion of TSH enhances the synthesis of T3 more than that of T4 and stimulates thyroidal 5'-monodeiodination of T4 into T3 ^4,5. It explains why sometimes a slightly elevated serum T3 is found in the early stage of development of hypothyroidism. About 80% of the daily production rate of T3 is generated in extrathyroidal tissues via the conversion of T4 into T3. The peripheral tissues also have a defense mechanism against developing hypothyroidism by increasing the overall fractional conversion rate of T4 into T3 ⁶.

EPIDEMIOLOGY OF HYPOTHYROIDISM

Thyroid hormone resistance syndromes are seldom the cause of hypothyroidism; the number of registered patients approximates one thousand (see Ch. 16). Central hypothyroidism is also rare; its precise prevalence is unknown, but has been estimated as 0.005% in the general population ⁷. Primary hypothyroidism, in contrast, is a very prevalent disease worldwide. It can be endemic in iodine-deficient regions (see Ch. 20), but it is also a common disease in iodine-replete areas as evident from prevalence and incidence figures reported in a number of population-based studies ^8-14. The most extensive data has been obtained from the Whickham Survey, a study of 2779 adults randomly selected of the general population in Great Britain who were evaluated between 1972 and 1974 and again twenty years later ^8,9. Most striking are the high prevalence of thyroid microsomal (peroxidase) antibodies and of (subclinical) hypothyroidism, and the marked female preponderance (Table 9-2).

The mean incidence of spontaneous hypothyroidism in women was 3.5/1000 survivors/year, that of hypothyroidism after destructive treatment for thyrotoxicosis 0.6/1000 survivors/year; similar figures were obtained in those who had deceased during follow-up. The hazard rate (the probability to develop hypothyroidism) increased with age; the mean age at diagnosis of hypothyroidism in women was 60 years. Studies from other countries like the USA ^10,11, Japan ¹² and Sweden ¹³ report essentially similar data.

Of particular interest are risk factors for development of hypothyroidism. In women survivors of the Whickham Survey, the risk of developing overt hypothyroidism was 4.3% per year if both raised serum TSH and thyroid antibodies were present initially, 2.6% per year if raised serum TSH was present alone, and 2.1% per year if thyroid antibodies were present alone ⁹. At the time of follow-up twenty years later, hypothyroidism had developed in these three groups in 55%, 33% and 27% respectively, but only in 4% if initial serum TSH was normal and thyroid antibodies were absent. The probability of developing hypothyroidism already increases at a rise in serum TSH above 2 mU/L as shown in Figure 9-2, in thyroid antibody positive as well as in thyroid antibody negative women; it also increases with higher titres of thyroid microsomal antibodies ^9,15.

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).

9.3 CAUSES OF HYPOTHYROIDISM

A variety of functional or structural disorders may lead to hypothyroidism, the severity of which depends on the degree and duration of thyroid hormone deprivation. A classification according to etiology appears in Table 9-3. The two principal categories of hypothyroidism are primary, or thyroprivic, caused by an inherent inability of the thyroid gland to supply a sufficient amount of the hormone, and trophoprivic hypothyroidism, due to inadequate stimulation of an intrinsically normal thyroid gland resulting from a defect at the level of the pituitary (secondary hypothyroidism) or the hypothalamus (tertiary hypothyroidism). In a third (uncommon) form of hypothyroidism, regulation and function of thyroid gland are intact. Instead, manifestations of hormone deprivation arise from a disorder in the target tissues that reduces their responsiveness to the hormone (peripheral tissue resistance to thyroid hormone) or that inactivates the hormone (in massive infantile hemangiomas).

The most common cause of hypothyroidism is destruction of the thyroid gland by disease or as a consequence of vigorous ablative therapies to control thyrotoxicosis. Primary hypothyroidism may also result from inefficient hormone synthesis caused by inherited biosynthetic defects (see Ch. 16), a deficient supply of iodine (see Ch. 20), or inhibition of hormonogenesis by various drugs and chemicals (see Ch. 5). In such instances, hypothyroidism is typically associated with thyroid gland enlargement (goitrous hypothyroidism).

9.3.1. CENTRAL HYPOTHYROIDISM

Hypothalamic disorders cause reduced TSH secretion by impairing the production or transport of TRH to the pituitary gland. Hypothyroidism may occur because the pituitary secretes TSH in insufficient quantities, or secretes TSH with an abnormal glycosylation pattern which reduces the biologic activity of TSH ^1,2,3. Treatment with oral TRH restores the biologic activity of TSH, suggesting that deficient hypothalamic TRH release induces both quantitative and qualitative abnormalities of TSH secretion. TSH molecules with reduced biologic activity may retain their immunologic reactivity in TSH immunoassays, explaining the sometimes observed slightly increased values of serum TSH (up to 10 mU/l) in central hypothyroidism^{18, 23}.

The term central hypothyroidism is preferred because it is not always possible to distinguish between hypothalamic and pituitary causes. Central hypothyroidism is also associated with a decreased nocturnal TSH surge (due to loss of the nocturnal increase in TSH pulse amplitude under preservation of the nighttime increase in TSH pulse frequency), which further hampers maintenance of a normal thyroid function ^4,5.

Central hypothyroidism is a relatively rare condition occurring about equally in both sexes. Congenital cases of central hypothyroidism are due to structural lesions like pituitary hypoplasia, midline defects and Rathke's pouch cysts, or to functional defects in TSH biosynthesis and release like loss-of-function' mutations in genes encoding for the TRH receptor ⁶, the TSH-beta subunit ^7,8, and the pituitary-specific transcription factor Pit-1 ⁹. Familial hypothyroidism due to TSH$ gene mutations follows an autosomal mode of inheritance. The $-subunit (118 aa) heterodimerizes noncovalently with the "-subunit through a segment called ?seat-belt? (aa 88-105). The described mutations of the TSH$ gene hamper dimerization with the "-subunit and thereby the correct secretion of the mature TSH heterodimer: Q42X and Q29X introduce a premature stop codon resulting in a truncated TSH$ subunit, G29R is a nonsense mutation preventing dimer formation, and C105)114X is a frameshift mutation causing disruption of one of the two disulfide bridges stabilizing the seat belt region^7,8,19,20. Plasma TSH levels are variable, the TSH response to TRH is impaired but PRL secretion is normal, and plasma glycoprotein hormone "-subunits are high¹⁹. The target genes of Pit-1 include those of GH, PRL, and TSH . The few patients with identified Pit-1 deficiency had both GH and PRL deficiency; the occurrence of hypothyroidism due to TSH insufficiency is variable ⁹. Cases of central hypothyroidism in childhood are mostly caused by craniopharyngioma (TSH deficiency in 53%) or cranial irradiation for brain tumors like dysgerminoma (TSH deficiency in 6%) or hematological malignancies²⁴. Prophylactic cranial irradiation of the central nervous system in children with acute lymphoblastic leukaemia did not have an adverse effect on thyroid function within a median follow-up time of 8 years²¹.

Central hypothyroidism in adults is most frequently due to pituitary macroadenomas and pituitary surgery or irradiation ²². The occurrence of TSH deficiency occurs usually after loss of GH and gonadotropin secretion. Return to euthyroidism is sometimes observed after selective adenomectomy ¹⁰. Radiotherapy of brain tumors or pituitary adenomas is followed by hypothyroidism in up to 65%; the onset of hypothyroidism may be seen many years after radiotherapy ^11,12. Less common causes of adult central hypothyroidism are head injury ^{13, 25}, ischemic necrosis due to postpartum hemorrhage (Sheehan's syndrome), pituitary apoplexy, infiltrative diseases, and lymphocytic hypophysitis ¹⁴. Lymphocytic hypophysitis seems to be an autoimmune disease; it occurs predominantly in women, especially during and after pregnancy, and the clinical picture is characterized by a pituitary mass and hypopituitarism²⁶.

Dopamine infusion inhibits the release of TSH, which may decrease T4 production rate by 56% ¹⁵. Supraphysiological amounts of endogenous or exogenous glucocorticoids also dampen the release of TSH, but give seldom rise to decreased serum T4 values. The same is true for treatment with long-acting somatostatin analogs. A transient decrease of TSH secretion can be observed after withdrawal of TSH-suppressive doses of L-thyroxine, which may last up to 6 weeks ¹⁶.

A new and novel cause of iatrogenic central hypothyroidism is from the administration of the RXRg-selective ligand, bexarotene (Targretin). This medication is highly effective in cutaneous T cell lymphoma, but as reported by Sherman et al, up to 70% of patients treated with daily doses > 300 mg/m² had symptoms and signs of hypothyroidism. This was associated with reduction of serum TSH to an average of 0.05 mU/l, and reduction of free T4 from 12.9 pmol/l to 5.8 pmol/l¹⁷. In vitro studies have shown that activity of the TSHb subunit gene promoter is suppressed by 9-cis-retinoic acid and bexarotene¹⁷, but other studies have not confirmed this²⁷. The condition can be appropriately treated by administration of thyroid hormone.(17)

9.3.2 CHRONIC AUTOIMMUNE THYROIDITIS

Chronic autoimmune thyroiditis may eventually cause hypothyroidism, mainly via destruction of thyrocytes (see also Ch. 7). In goitrous autoimmune hypothyroidism (the classical variant originally described by Hashimoto) the histology of the thyroid gland is characterized by massive lymphocytic infiltration with formation of germinal centers and oxyphilic changes of thyrocytes. In atrophic myxedema fibrosis is predominant, next to lymphocytic infiltration. The diffise Hashimoto goiter has a peculiar firm consistency like rubber; the goiter may regress with time but can persist in many cases ¹. In some instances the patient presents with an initial transient hyperthyroid stage, called Hashitoxicosis'. The term Hashimoto's disease is generally used to indicate auto-immune destruction of thyrocytes which may eventually result in hypothyroidism although many cases remain euthyroid (see also Ch. 8). The serological hallmark of Hashimoto's disease is the presence of high titers of thyroid peroxidase (TPO) autoantibodies, formerly known as thyroid microsomal antibodies. The opposite of Hashimoto's disease is Graves' disease characterized by the presence of TSH receptor stimulating antibodies resulting in hyperthyroidism. The two disease entities frequently overlap, and can be viewed as the opposite ends of a continuous spectrum of autoimmune thyroid disease. Indeed, many patients with Graves' disease have TPO antibodies, and some case reports mention classical features of Graves' disease like exophthalmos and pretibial myxedema in the presence of hypothyroidism without any previous thyrotoxicosis ². TSH receptor blocking antibodies do occur in Hashimoto's disease, contributing to thyroid atrophy and hypothyroidism; they are more prevalent in Japanese than in Caucasian patients ^3,4. TSH receptor antibodies in Hashimoto's disease are negatively correlated to serum FT4 and thyroid size ⁵.

The clinical manifestation of Hashimoto's disease with respect to thyroid function and thyroid size depends on the net effect of the various immunologic effector mechanisms involved in chronic autoimmune thyroiditis. Genetic and environmental factors may modulate the expression of the disease. Autoimmune hypothyroidism in Caucasians is weakly associated with HLA-DR3; its prevalence is higher in regions with a high ambient iodine intake than in iodine-deficient areas ^6,7.

9.3.3 REVERSIBLE AUTOIMMUNE HYPOTHYROIDISM

Chronic autoimmune thyroiditis. Conventional wisdom has it that once hypothyroid' means always hypothyroid'. Indeed, the vast majority of patients with hypothyroidism due to chronic autoimmune thyroiditis require life-long thyroxine replacement therapy, but spontaneous recovery does occur in about 5% ¹. Return to the euthyroid state is apparently more frequent in countries like Japan, where - at a high ambient iodine intake - restriction of dietary iodine alone may induce a remission ^2,35.

Conditions that increase the likelihood of spontaneous recovery are the presence of a goiter, a relatively high thyroidal radioiodine uptake, and a preserved increase of T3 after the administration of TRH during thyroxine treatment ^2,3,4. The spontaneous evolution from hypothyroidism back to euthyroidism has been related to the disappearance of TSH receptor blocking antibodies ⁵. Changes in the titers of co-existing TSH receptor blocking and stimulating antibodies explain the sometimes observed alternating course of hypothyroidism and hyperthyroidism in the same subject ⁶.

Silent thyroiditis and postpartum thyroiditis. Silent or painless thyroiditis and postpartum thyroiditis are variant forms of chronic autoimmune thyroiditis. The autoimmune reaction causes a mainly T-cell mediated destructive thyroiditis, which however is self-limiting. The characteristic course of the disease is thus first a thyrotoxic stage due to the release of stored hormone from the disrupted follicles, followed by a hypothyroid stage during the recovery towards a normal thyroid architecture; usually euthyroidism is restored within a few months (see also Ch. 8). In many cases the disease remains unnoticed, as clinical symptoms and signs are mostly limited. In the postpartum period it is also quite natural to attribute emerging complaints - especially if they are nonspecific in nature - to the aftermath of pregnancy and the work load of having a baby. Postpartum thyroiditis is, however, a rather common event, with an incidence of 4-6% as evident from several population-based studies ^7,8. The incidence in type I diabetes mellitus is four times higher, up to 25% ⁹. Postpartum thyroiditis can be predicted to a certain extent from the presence of TPO antibodies in the serum of pregnant women in the first trimester: a titer of =100 kU/l at 2 weeks has a positive predictive value of 0.50 and a negative predictive value of 0.98 in this respect ⁸. The titer of TPO antibodies decreases in the second and third trimester, and increases again in the postpartum period .

Women who have experienced postpartum thyroiditis, have a 40% risk to develop again postpartum thyroiditis after a following pregnancy. About 20-30% of women with postpartum thyroiditis will develop permanent hypothyroidism within 5 years; the risk is higher in women with high titers of TPO-antibodies ¹⁰. A subset of women with postpartum thyroiditis experience only a thyrotoxic phase; they are less at risk for later development of hypothyroidism ¹¹. Maternal TPO antibodies are associated with depression in the postpartum period ¹² and with impaired child development ¹³. A low maternal FT4 concentration during early pregnancy is also associated with impaired psychomotor development in infancy ¹⁴.

Cytokine-induced thyroiditis. Cytokines are heavily involved in immune reactions (see Ch. 7), and it is thus not surprising that treatment with pharmacological doses of cytokines may induce autoimmune diseases in susceptible subjects. Treatment with interleukin-2 or interferon-a of patients with malignant tumors or hepatitis B or C is causally related to the occurrence of TPO-antibodies and the development of abnormal thyroid function ^15,16,17. The course of cytokine-induced thyroiditis resembles that of silent and postpartum thyroiditis: a rather sudden onset, a thyrotoxic stage followed by a hypothyroid stage, and usually return to euthyroidism after discontinuation of cytokine treatment. The incidence is about 5-20%; it occurs more often in females with pre-existent thyroid antibodies¹⁸.

9.3.4 POSTOPERATIVE AND POSTRADIATION HYPOTHYROIDISM

Surgery. An important cause of hypothyroidism is surgical removal of the gland. Up to 40 percent of patients who undergo thyroidectomy for Graves' disease develop hypothyroidism (1). Most patients become hypothyroid in the first year after surgery; immediate postoperative hypothyroidism may resolve spontaneously by 6 months. After the first year the cumulative incidence of hypothyroidism rises by 1-2% per year. The frequency of hypothyroidism depends on the zeal of the surgeon and on other factors, such as the function of the thyroid remnant or the presence of active thyroiditis. Its occurrence correlates with the presence of antibodies to thyroid antigens. Thus, progressive destruction of residual tissue by thyroiditis may be the pathogenic mechanism. Hypothyroidism after surgical removal of multinodular goiter is less common (about 15%). Myxedema occurs almost invariably after subtotal thyroidectomy for Hashimoto's thyroiditis and after removal of lingual thyroids.

Radioiodine. A leading cause of hypothyroidism is radioactive iodine (RAI) treatment of Graves' disease. The frequency with which hypothyroidism supervenes RAI therapy is dependent on multiple factors, the principal one being the dose of RAI administered. The incidence of hypothyroidism 10 years after treatment is reported as high as 70 percent ¹. Hypothyroidism frequently develops already in the first year after treatment (with spontaneous return to euthyroidism in some patients), but it may not be manifest until years later in others. Its cumulative occurrence after the first year continues to rise with 0.5-2% annually, and it has been suggested that virtually all patients treated in this way will eventually become hypothyroid. Various treatment schedules have been devised with the hope of diminishing the incidence of RAI-induced hypothyroidism ^2,3, but in general, a lower incidence of hypothyroidism is invariably associated with a higher prevalence of persistent thyrotoxicosis that requires retreatment ^3,4. Inadvertent administration of RAI during gestation may cause neonatal hypothyroidism when given to the mother during the last two trimesters and also occasionally in the first trimester of pregnancy ⁵. Hypothyroidism occurs less often (6-13 %) after 131I treatment of toxic nodular goiter ^6,7.

External irradiation. Hypothyroidism may supervene after therapeutic irradiation of the neck for any of a number of malignant diseases. It is particularly common (25-50%) after irradiation for Hodgkins' and non-Hodgkins' lymphoma, especially when the thyroid has not been shielded during mantle field irradiation and when iodine-containing X-ray contrast agents have been used prior to radiotherapy ⁸. External radiotherapy for head and neck cancer (e.g. laryngeal carcinoma) carries an actuarial risk of 15% for developing overt hypothyroidism three years after treatment¹⁰. Elevated TSH values are even more common, with a 5-year incidence rate of 48% in another study with a median follow-up of 4,4 years¹¹.

Total body irradiation with subsequent bone marrow transplantation for acute leukemia or aplastic anemia may cause (subclinical) hypothyroidism in about 25%, usually occurring after one year and transient in half of the patients ⁹. Probably because of radiation damage, subclinical or overt hypothyroidism is common among surviving bone marrow transplant recipients. There is a greater risk among younger patients, and need for life-long surveillance.(J Clin Endocrinol Metab. 2004 Dec;89(12):5981-6. Long-term follow-up of thyroid function in patients who received bone marrow transplantation during childhood and adolescence.Ishiguro H, Yasuda Y, Tomita Y, Shinagawa T, Shimizu T, Morimoto T, Hattori K,Matsumoto M, Inoue H, Yabe H, Yabe M, Shinohara O, Kato S.)

9.3.5 INFILTRATIVE AND INFECTIOUS DISEASES

The production of hypothyroidism by infiltrative disease is mentioned for completeness, despite the rarity of these conditions. Among these rare causes of primary hypothyroidism are sarcoidosis, cystinosis ¹ (up to 86% in adults), progressive systemic sclerosis and amyloidosis ². Hypothyroidism is a frequent sequela of invasive fibrous thyroiditis of Riedel, occurring in 30-40% of the patients.

Hypothyroidism due to infectious disease is equally rare. Infection of the thyroid gland is somewhat more frequent in immunocompromised patients and in subjects with pre-existent thyroid abnormalities. Hypothyroidism in the recovery phase of subacute thyroiditis of De Quervain - a condition most likely related to a previous viral infection- is in contrast a very common event (see Ch. 19).

9.3.6 CONGENITAL HYPOTHYROIDISM

Congenital hypothyroidism can be permanent or transient in nature. Transient cases might be caused by transplacental passage of TSH receptor blocking antibodies, or iodine excess. Permanent cases are caused by either loss of functional tissue (mostly thyroid dysgenesis), by functional defects in thyroid hormone biosynthesis ( loss of function' mutations in genes encoding for the TSH-R, NIS, Tg, THOX or TPO), or by thyroid hormone resistance (TR mutations). For full discussion: see Ch. 15 and 16.

9.3.7 IODINE DEFICIENCY AND IODINE EXCESS

Hypothyroidism caused by iodine deficiency is discussed in Ch. 20. It is remarkable that hypothyroidism can also be caused by iodine excess, a condition described in the literature as iodide-induced myxedema'. It can be explained by autoregulatory mechanisms operative in the thyroid gland. Inorganic iodide in excess of daily doses of 500-1000 µg inhibits organification of iodide; this phenomenon is known as the Wolff-Chaikoff effect. Usually an escape from the Wolff-Chaikoff effect occurs after several weeks. An unidentified iodinated product of the organification process (presumably an iodinated lipid) seems to be involved, which inhibits thyroidal iodide transport: consequently, the intrathyroidal iodine concentration falls below the level required for inhibition of organification ¹. Failure to escape from the Wolff-Chaikoff effect may produce hypothyroidism and this occurs preferentially in subjects with pre-existent subtle organification defects. Indeed patients with chronic autoimmune thyroiditis, previous subacute or postpartum thyroiditis, or previous radioiodine or surgical therapy are prone to iodide-induced hypothyroidism ^2,3.

Sources of iodine excess are an iodine-rich diet (e.g. seaweed ) and iodine-containing drugs like potassium iodide, some vitamin preparations, kelp tablets, topical antiseptics, radiographic contrast agents, and amiodarone. Amiodarone contains 39% of iodine by weight; large quantities of iodine are released during the biotransformation of the drug, giving rise to a 45-60 times higher iodine exposure than the optimal daily iodine intake of 150-300 µg recommended by the WHO.

Amiodarone-induced hypothyroidism occurs predominantly in the first 18 months of treatment, especially in females with pre-existent thyroid antibodies ⁴. Its incidence is higher in regions with a high ambient iodine intake than in areas with a lower iodine intake (22% and 5% respectively) ⁵.

Iodination of salt-Mild iodide fortification of salt in Denmark increased average urinary iodide from the 45-61ug/l range up to 86-93ug/l. This cautious iodization of salt was accompanied by a moderate increase in the baseline incidence rate of overt hypothyroidism (38/100,000/yr) by 20-30%. This occurred primarily in young and middle-aged subjects with previous moderate ID. (Pedersen IB, Laurberg P, Knudsen N, Jørgensen T, Perrild H, Ovesen L, Rasmussen LB.  An increased incidence of overt hypothyroidism after iodine fortification of salt in Denmark: a prospective population study  J Clin Endocrinol Metab. 2007 Aug;92(8):3122-7. Epub 2007 May 15)

9.3.8 DRUG-INDUCED HYPOTHYROIDISM

A variety of therapeutic drugs can lead to moderate or even severe hypothyroidism (see also Ch. 9.8.3). The common antithyroid drugs (carbimazole, methimazole, and propylthiouracil) if given in sufficient quantity will cause hypothyroidism. This is also theoretically possible with agents that can block the uptake of iodide by the thyroid, such as perchlorate or thiocyanate, although these are rarely given. In susceptible individuals, primarily those with a history of autoimmune thyroid disease such as Hashimoto's or Graves' disease or in patients who have had either radiation or surgical trauma to the thyroid gland, large doses of iodide can cause goitrous hypothyroidism ^1,2 (see also Ch. 9.3.7). While this is now less common, since iodides are no longer given for chronic pulmonary disease and lipid-soluble contrast agents are no longer used in diagnostic procedures, the problem may arise with patients taking iodine supplements or natural foods with high iodine content. Lithium has similar effects to those of iodide; it inhibits thyroid hormone release as well as hormone synthesis ³. While lithium-induced hypothyroidism is more common in patients with underlying autoimmune disease, it has been reported in individuals with apparently normal thyroid glands. Long-term treatment with lithium results in goiter in about 50%, in subclinical hypothyroidism in about 20%, and in overt hypothyroidism also in 20% ⁴. There are a large number of organic compounds that may impair thyroid function. These include phenol derivatives such as resorcinol, benzoic acid compounds such as para-aminosalicylic acid, the oral sulfonylurea compounds, phenylbutazone, aminoglutethimide, and a number of other agents ⁵. Industrial pollution with polychlorinated biphenyls can also cause goitrous hypothyroidism ⁶.

9.3.9 MASSIVE INFANTILE HEMANGIOMA

Severe hypothyroidism has been described in a few infants with massive hemangiomas, due to high levels of activity of type 3 iodothyronine deiodinase in the hemangioma tissue¹. Type 3 deiodinase inactivates T4 by conversion into reverse T3 (explaining the paradoxically high serum rT3 concentrations in these hypothyroid patients), and T3 by conversion into 3,3?-diiodothyronine. The high level of expression of type 3 deiodinase is likely induced by gowth factors. The infants have no evidence of thyroid gland disease, and their hypothyroidism is apparently caused by an increased rate of thyroid hormone degradation in extra-thyroidal tissues outstripping the rate of thyroid hormone production: a nice example of ?consumptive? hypothyroidism. This type of ?peripheral? hypothyroidism has also been observed in a young adult³. Surgical removal of the hemangioma restores euthyroidism.

9.4 PATHOLOGY OF HYPOTHYROIDISM

The characteristic pathologic finding in hypothyroidism is a peculiar mucinous nonpitting edema (myxedema), which is most obvious in the dermis but can be present in many organs. The myxedema is due to accumulation of hyaluronic acid and other glycosaminoglycans in interstitial tissue; these hydrophilic molecules attract much water ¹. The deposits of glycosaminoglycans have been related to loss of the inhibitory effects of thyroid hormone on the synthesis of hyaluronate, fibronectin and collagen by fibroblasts ^2,3.

The skin is distinctly abnormal. There is hyperkeratotic plugging of sweat glands and hair follicles. The dermis is edematous, and the collagen fibers are separated, swollen, and frayed. Extracellular material that appears eosinophilic or basophilic in hematoxylin and eosin stains, or that appears pink (metachromatic) with toluidine blue, or takes the periodic acid-Schiff (PAS) stain for mucopolysaccharides is much increased in the dermis. A sparse mononuclear cell infiltrate may be found about the blood vessels.

Skeletal muscle cells are swollen and appear grossly to be pale and edematous. Frequently microscopic examination reveals no significant abnormality. Alternatively, the normal striations are lost, and degenerative foci are seen in the cells. The fibers are separated in these degenerative foci by accumulations of a basophilic, PAS-positive homogenous infiltrate. This infiltrate may appear as a semilunar deposit under the sarcolemma.

The heart may be dilated and hypertrophied. Interstitial edema and an increase in fibrous tissue are present. The individual muscle cells may show the same changes seen in skeletal muscle. The serous cavities may all contain abnormal amounts of fluid with a normal or high protein content. The liver may appear normal or may show evidence of edema. Central congestive fibrosis in the absence of congestive heart failure has been described. The mitochondria tend to be spherical and their limiting membranes smooth, whereas those of the liver in thyrotoxicosis vary in shape and have wrinkled outer membranes ⁴. The skeleton may be unusually dense on radiographic examination. In children, bone maturation is usually retarded, and typical epiphyseal dysgenesis of hypothyroidism is present ⁵. The brain may show atrophy of cells, gliosis, and foci of degeneration. Deposition of mucinous material and round bodies containing glycogen (neural myxedematous bodies) has been found in the cerebellum of patients with long-standing myxedema and ataxia ⁶. In uncorrected congenital hypothyroidism , the brain retains infantile characteristics. There is neuronal hypoplasia, retarded myelination, and decreased vascularity (see Ch. 15). The blood vessels often show prominent atherosclerosis. Whether this condition is more severe than might be anticipated on the basis of the patient's age and sex remains an unsettled question. In the intestinal tract there is an accumulation of mast cells and interstitial mucoid material, especially near the basement membrane. The smooth muscle cells may show lesions similar to those seen in skeletal muscle. The mucosa of the stomach, small bowel, and large bowel may be atrophic. The rest of the gastrointestinal tract, especially the colon, may be very dilated (myxedema megacolon). The uterus typically has a proliferative or atrophic endometrium in premenopausal women.

The kidney is grossly normal. Light and electron microscopic studies of renal biopsy samples have demonstrated thickening of the glomerular and tubular basement membranes, proliferation of the endothelial and mesangial cells, intracellular inclusions, and extracellular deposition of amorphous material with characteristics of acid mucopolysaccharides ^8,9.

In the pituitary in primary myxedema there is an increase in a class of cells that can be identified by the iron-periodic, acid Schiff, or aldehyde fuchsin staining techniques ¹⁰. These are referred to variously as gamma cells, sparsely granulated basophils, or amphophils. Presumably they are derived from basophilic cells or chromophobes and are active in secreting TSH. Acidophilic cells are decreased. Patients who are congenitally hypothyroid and those who are hypothyroid during childhood may develop pituitary fossa enlargement. Occasionally prolonged hypothyroidism leads to sella enlargement in the adolescent and adult, and pituitary tumors have been described ¹¹. In these glands acidophils are virtually absent. In pituitary hypothyroidism the pituitary may be replaced by fibrous and cystic structures, granulomas, or neoplasia. Occasionally hypothyroidism due to deficient TSH secretion occurs in patients having the empty sella syndrome or because of isolated TSH or TRH deficiency. The adrenals may be normal or their cortex may be atrophied. The combination of adrenal cortical atrophy and hypothyroidism is known as Schmidt's syndrome and is thought to be of autoimmune etiology. Bloodworth found clinical evidence for hypothyroidism in 9 of 35 patients with Addison's disease; in 8 there was fibrosis of thethyroid, with atrophy in 4. The adrenal medulla appeared normal ¹². The ovaries and parathyroids have shown no definite abnormalities. The testes may show Leydig cells with involutionary nucleus and cytoplasm, hyalinization, or involution of the tubular cells, and proliferation of intertubular connective tissue in hypothyroidism with onset before puberty. Onset after maturity, in one case, led to similar changes that were restricted to the tubules.

The pancreatic islets are usually normal, although hyperplasia was present in one of our autopsied cases.