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InternalMed_Harrison. Features to be noted include thyroid size, consistency, nodularity, and any tenderness or fixation. An estimate of thyroid size (normally 12–20 g) should be made, and a drawing is often the best way to record findings. However, ultrasound is the method of choice when it is important to determine thyroid size accurately. The size, location, and consistency of any nodules should also be defined. A bruit or thrill over the gland, located over the insertion of the superior and inferior thyroid arteries (superoor inferolaterally), indicates increased vascularity, as occurs in hyperthyroidism. If the lower borders of the thyroid lobes are not clearly felt, a goiter may be retrosternal. Large retrosternal goiters can cause venous distention over the neck and difficulty breathing, especially when the arms are raised (Pemberton’s sign). With any central mass above the thyroid, the tongue should be extended, as thyroglossal cysts then move upward. The thyroid examination is not complete without


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InternalMed_Harrison. the arms are raised (Pemberton’s sign). With any central mass above the thyroid, the tongue should be extended, as thyroglossal cysts then move upward. The thyroid examination is not complete without assessment for lymphadenopathy in the supraclavicular and cervical regions of the neck.


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InternalMed_Harrison. CHAPTER 405 Disorders of the Thyroid Gland 2288 LABORATORY EVALUATION Measurement of Thyroid Hormones The enhanced sensitivity and specificity of TSH assays have greatly improved laboratory assessment of thyroid function. Because TSH levels change dynamically in response to alterations of T4 and T3, a logical approach to thyroid testing is to first determine whether TSH is suppressed, normal, or elevated. With rare exceptions (see below), a normal TSH level excludes a primary abnormality of thyroid function. This strategy depends on the use of immunochemiluminometric assays (ICMAs) for TSH that are sensitive enough to discriminate between the lower limit of the reference range and the suppressed values that occur with thyrotoxicosis. Extremely sensitive (fourth-generation) assays can detect TSH levels ≤0.004 mIU/L, but, for practical purposes, assays sensitive to ≤0.1 mIU/L are sufficient. The widespread availability of the TSH ICMA has rendered the TRH stimulation test obsolete,


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InternalMed_Harrison. detect TSH levels ≤0.004 mIU/L, but, for practical purposes, assays sensitive to ≤0.1 mIU/L are sufficient. The widespread availability of the TSH ICMA has rendered the TRH stimulation test obsolete, because the failure of TSH to rise after an intravenous bolus of 200–400 μg TRH has the same implications as a suppressed basal TSH measured by ICMA. The finding of an abnormal TSH level must be followed by measurements of circulating thyroid hormone levels to confirm the diagnosis of hyperthyroidism (suppressed TSH) or hypothyroidism (elevated TSH). Radioimmunoassays are widely available for serum total T4 and total T3. T4 and T3 are highly protein-bound, and numerous factors (illness, medications, genetic factors) can influence protein binding. It is useful, therefore, to measure the free, or unbound, hormone levels, which correspond to the biologically available hormone pool. Two direct methods are used to measure unbound thyroid hormones: (1) unbound thyroid hormone competition with


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InternalMed_Harrison. or unbound, hormone levels, which correspond to the biologically available hormone pool. Two direct methods are used to measure unbound thyroid hormones: (1) unbound thyroid hormone competition with radiolabeled T4 (or an analogue) for binding to a solid-phase antibody, and (2) physical separation of the unbound hormone fraction by ultracentrifugation or equilibrium dialysis. Although early unbound hormone immunoassays suffered from artifacts, newer assays correlate well with the results of the more technically demanding and expensive physical separation methods. An indirect method that is now less commonly used to estimate unbound thyroid hormone levels is to calculate the free T3 or free T4 index from the total T4 or T3 concentration and the thyroid hormone binding ratio (THBR). The latter is derived from the T3-resin uptake test, which determines the distribution of radiolabeled T3 between an absorbent resin and the unoccupied thyroid hormone binding proteins in the sample. The


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InternalMed_Harrison. latter is derived from the T3-resin uptake test, which determines the distribution of radiolabeled T3 between an absorbent resin and the unoccupied thyroid hormone binding proteins in the sample. The binding of the labeled T3 to the resin is increased when there is reduced unoccupied protein binding sites (e.g., TBG deficiency) or increased total thyroid hormone in the sample; it is decreased under the opposite circumstances. The product of THBR and total T3 or T4 provides the free T3 or T4 index. In effect, the index corrects for anomalous total hormone values caused by abnormalities in hormone-protein binding. Total thyroid hormone levels are elevated when TBG is increased due to estrogens (pregnancy, oral contraceptives, hormone therapy, tamoxifen, selective estrogen receptor modulators, inflammatory liver disease) and decreased when TBG binding is reduced (androgens, nephrotic syndrome). Genetic disorders and acute illness can also cause abnormalities in thyroid hormone binding


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InternalMed_Harrison. inflammatory liver disease) and decreased when TBG binding is reduced (androgens, nephrotic syndrome). Genetic disorders and acute illness can also cause abnormalities in thyroid hormone binding proteins, and various drugs (phenytoin, carbamazepine, salicylates, and nonsteroidal anti-inflammatory drugs [NSAIDs]) can interfere with thyroid hormone binding. Because unbound thyroid hormone levels are normal and the patient is euthyroid in all of these circumstances, assays that measure unbound hormone are preferable to those for total thyroid hormones. For most purposes, the unbound T4 level is sufficient to confirm thyrotoxicosis, but 2–5% of patients have only an elevated T3 level (T3 toxicosis). Thus, unbound T3 levels should be measured in patients with a suppressed TSH but normal unbound T4 levels. There are several clinical conditions in which the use of TSH as a screening test may be misleading, particularly without simultaneous unbound T4 determinations. Any severe nonthyroidal


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InternalMed_Harrison. T4 levels. There are several clinical conditions in which the use of TSH as a screening test may be misleading, particularly without simultaneous unbound T4 determinations. Any severe nonthyroidal illness can cause abnormal TSH levels (see below). Although hypothyroidism is the most common cause of an elevated TSH level, rare causes include a TSH-secreting pituitary tumor (Chap. 403), thyroid hormone resistance, and assay artifact. Conversely, a suppressed TSH level, particularly <0.01 mIU/L, usually indicates thyrotoxicosis. However, subnormal TSH levels between 0.01 and 0.1 mIU/L may be seen during the first trimester of pregnancy (due to hCG secretion), after treatment of hyperthyroidism (because TSH can remain suppressed for several months), and in response to certain medications (e.g., high doses of glucocorticoids or dopamine). Importantly, secondary hypothyroidism, caused by hypothalamic-pituitary disease, is associated with a variable (low to high-normal) TSH level, which is


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InternalMed_Harrison. high doses of glucocorticoids or dopamine). Importantly, secondary hypothyroidism, caused by hypothalamic-pituitary disease, is associated with a variable (low to high-normal) TSH level, which is inappropriate for the low T4 level. Thus, TSH should not be used as an isolated laboratory test to assess thyroid function in patients with suspected or known pituitary disease.


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InternalMed_Harrison. Tests for the end-organ effects of thyroid hormone excess or depletion, such as estimation of basal metabolic rate, tendon reflex relaxation rates, or serum cholesterol, are not useful as clinical determinants of thyroid function. Tests to Determine the Etiology of Thyroid Dysfunction Autoimmune thyroid disease is detected most easily by measuring circulating antibodies against TPO and Tg. Because antibodies to Tg alone are uncommon, it is reasonable to measure only TPO antibodies. About 5–15% of euthyroid women and up to 2% of euthyroid men have thyroid antibodies; such individuals are at increased risk of developing thyroid dysfunction. Almost all patients with autoimmune hypothyroidism, and up to 80% of those with Graves’ disease, have TPO antibodies, usually at high levels.


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InternalMed_Harrison. TSIs are antibodies that stimulate the TSH-R in Graves’ disease. They are most commonly measured by commercially available tracer displacement assays called TRAb (TSH receptor antibody) with the assumption that elevated levels in the setting of clinical hyperthyroidism reflect stimulatory effects on the TSH receptor. A bioassay is less commonly used. The main use of these assays is to predict neonatal thyrotoxicosis caused by high maternal levels of TRAb or TSI (>3× upper limit of normal) in the last trimester of pregnancy.


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InternalMed_Harrison. Serum Tg levels are increased in all types of thyrotoxicosis except thyrotoxicosis factitia caused by self-administration of thyroid hormone. Tg levels are particularly increased in thyroiditis, reflecting thyroid tissue destruction and release of Tg. The main role for Tg measurement, however, is in the follow-up of thyroid cancer patients. After total thyroidectomy and radioablation, Tg levels should be undetectable; in the absence of anti-Tg antibodies, measurable levels indicate incomplete ablation or recurrent cancer. Radioiodine Uptake and Thyroid Scanning The thyroid gland selectively transports radioisotopes of iodine (123I, 125I, 131I) and 99mTc pertechnetate, allowing thyroid imaging and quantitation of radioactive tracer fractional uptake.


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InternalMed_Harrison. Nuclear imaging of Graves’ disease is characterized by an enlarged gland and increased tracer uptake that is distributed homogeneously. Toxic adenomas appear as focal areas of increased uptake, with suppressed tracer uptake in the remainder of the gland. In toxic MNG, the gland is enlarged—often with distorted architecture—and there are multiple areas of relatively increased (functioning nodules) or decreased tracer uptake (suppressed thyroid parenchyma or nonfunctioning nodules). Subacute, viral, and postpartum thyroiditis are associated with very low uptake because of follicular cell damage and TSH suppression. Thyrotoxicosis factitia is also associated with low uptake. In addition, if there is excessive circulating exogenous iodine (e.g., from dietary sources of iodinated contrast dye), the radionuclide uptake is low even in the presence of increased thyroid hormone production.


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InternalMed_Harrison. Thyroid scintigraphy is not used in the routine evaluation of patients with thyroid nodules, but should be performed if the serum TSH level is subnormal to determine if functioning thyroid nodules are present. Functioning or “hot” nodules are almost never malignant, and fine-needle aspiration (FNA) biopsy is not indicated. The vast majority of thyroid nodules do not produce thyroid hormone (“cold” nodules), and these are more likely to be malignant (~5–10%). Whole-body and thyroid scanning is also used in the treatment and surveillance of thyroid cancer. After thyroidectomy for thyroid cancer, the TSH level is raised by either using a thyroid hormone withdrawal protocol or recombinant human TSH injection (see below). Administration of 131I allows whole-body scanning (WBS) to confirm remnant ablation and to detect any functioning metastases. In addition, WBS may be helpful in surveillance of patients at risk for recurrence.


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InternalMed_Harrison. Thyroid Ultrasound Ultrasonography is valuable for the diagnosis and evaluation of patients with nodular thyroid disease (Table 405-4). Evidence-based guidelines recommend thyroid ultrasonography for all patients suspected of having thyroid nodules by either physical examination or another imaging study. Using 10to 12-MHz linear transducers, resolution and image quality are excellent, allowing the characterization of nodules and cysts >3 mm. Certain sonographic patterns are highly suggestive of malignancy (e.g., hypoechoic solid nodules with infiltrative borders and microcalcifications), whereas other features correlate with benignity (e.g., spongiform nodules defined as those with multiple small internal cystic areas) (Fig. 405-5). In addition to evaluating thyroid nodules, ultrasound is useful for monitoring nodule size and for the aspiration of nodules or cystic lesions. Ultrasound-guided FNA biopsy of thyroid lesions lowers the rate of inadequate sampling and decreases sample


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InternalMed_Harrison. is useful for monitoring nodule size and for the aspiration of nodules or cystic lesions. Ultrasound-guided FNA biopsy of thyroid lesions lowers the rate of inadequate sampling and decreases sample error, thereby reducing the false-negative rate of FNA cytology. Ultrasonography of the central and lateral cervical lymph node compartments is indispensable in the evaluation thyroid cancer patients, preoperatively and during follow-up.


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InternalMed_Harrison. Iodine deficiency remains a common cause of hypothyroidism worldwide. In areas of iodine sufficiency, autoimmune disease (Hashimoto’s Autoimmune hypothyroidism: Hashimoto’s thyroiditis, atrophic thyroiditis Iatrogenic: 131I treatment, subtotal or total thyroidectomy, external irradiation of neck for lymphoma or cancer Drugs: iodine excess (including iodine-containing contrast media and amiodarone), lithium, antithyroid drugs, p-aminosalicylic acid, interferon α and other cytokines, aminoglutethimide, tyrosine kinase inhibitors (e.g., sunitinib) Congenital hypothyroidism: absent or ectopic thyroid gland, dyshormonogenesis, TSH-R mutation Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis, scleroderma, cystinosis, Riedel’s thyroiditis Overexpression of type 3 deiodinase in infantile hemangioma and other tumors Silent thyroiditis, including postpartum thyroiditis Subacute thyroiditis Withdrawal of supraphysiologic thyroxine treatment in individuals with an


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InternalMed_Harrison. Silent thyroiditis, including postpartum thyroiditis Subacute thyroiditis Withdrawal of supraphysiologic thyroxine treatment in individuals with an Hypopituitarism: tumors, pituitary surgery or irradiation, infiltrative disorders, Sheehan’s syndrome, trauma, genetic forms of combined pituitary hormone deficiencies Hypothalamic disease: tumors, trauma, infiltrative disorders, idiopathic Abbreviations: TSH, thyroid-stimulating hormone; TSH-R, TSH receptor. thyroiditis) and iatrogenic causes (treatment of hyperthyroidism) are most common (Table 405-5).


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InternalMed_Harrison. Abbreviations: TSH, thyroid-stimulating hormone; TSH-R, TSH receptor. thyroiditis) and iatrogenic causes (treatment of hyperthyroidism) are most common (Table 405-5). CONGENITAL HYPOTHYROIDISM Prevalence Hypothyroidism occurs in about 1 in 4000 newborns. It may be transient, especially if the mother has TSH-R blocking antibodies or has received antithyroid drugs, but permanent hypothyroidism occurs in the majority. Neonatal hypothyroidism is due to thyroid gland dysgenesis in 80–85%, to inborn errors of thyroid hormone synthesis in 10–15%, and is TSH-R antibody-mediated in 5% of affected newborns. The developmental abnormalities are twice as common in girls. Mutations that cause congenital hypothyroidism are being increasingly identified, but most remain idiopathic (Table 405-1). Disorders of the Thyroid Gland


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InternalMed_Harrison. Disorders of the Thyroid Gland FIGURE 405-5 Sonographic patterns of thyroid nodules. A. High suspicion ultrasound pattern for thyroid malignancy (hypoechoic solid nodule with irregular borders and microcalcifications). B. Very low suspicion ultrasound pattern for thyroid malignancy (spongiform nodule with microcystic areas comprises over >50% of nodule volume). Tiredness, weakness Dry coarse skin; cool peripheral extremities Dry skin Puffy face, hands, and feet Weight gain with poor appetite Carpal tunnel syndrome


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InternalMed_Harrison. Tiredness, weakness Dry coarse skin; cool peripheral extremities Dry skin Puffy face, hands, and feet Weight gain with poor appetite Carpal tunnel syndrome Clinical Manifestations The majority of infants appear normal at birth, and <10% are diagnosed based on clinical features, which include prolonged jaundice, feeding problems, hypotonia, enlarged tongue, delayed bone maturation, and umbilical hernia. Importantly, permanent neurologic damage results if treatment is delayed. Typical features of adult hypothyroidism may also be present (Table 405-6). Other congenital malformations, especially cardiac, are four times more common in congenital hypothyroidism.


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InternalMed_Harrison. Diagnosis and Treatment Because of the severe neurologic consequences of untreated congenital hypothyroidism, neonatal screening programs have been established. These are generally based on measurement of TSH or T4 levels in heel-prick blood specimens. When the diagnosis is confirmed, T4 is instituted at a dose of 10–15 μg/kg per day, and the dose is adjusted by close monitoring of TSH levels. T4 requirements are relatively great during the first year of life, and a high circulating T4 level is usually needed to normalize TSH. Early treatment with T4 results in normal IQ levels, but subtle neurodevelopmental abnormalities may occur in those with the most severe hypothyroidism at diagnosis or when treatment is delayed or suboptimal.


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InternalMed_Harrison. AUTOIMMUNE HYPOTHYROIDISM Classification Autoimmune hypothyroidism may be associated with a goiter (Hashimoto’s, or goitrous thyroiditis) or, at the later stages of the disease, minimal residual thyroid tissue (atrophic thyroiditis). Because the autoimmune process gradually reduces thyroid function, there is a phase of compensation when normal thyroid hormone levels are maintained by a rise in TSH. Although some patients may have minor symptoms, this state is called subclinical hypothyroidism. Later, unbound T4 levels fall and TSH levels rise further; symptoms become more readily apparent at this stage (usually TSH >10 mIU/L), which is referred to as clinical hypothyroidism or overt hypothyroidism.


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InternalMed_Harrison. Prevalence The mean annual incidence rate of autoimmune hypothyroidism is up to 4 per 1000 women and 1 per 1000 men. It is more common in certain populations, such as the Japanese, probably because of genetic factors and chronic exposure to a high-iodine diet. The mean age at diagnosis is 60 years, and the prevalence of overt hypothyroidism increases with age. Subclinical hypothyroidism is found in 6–8% of women (10% over the age of 60) and 3% of men. The annual risk of developing clinical hypothyroidism is about 4% when subclinical hypothyroidism is associated with positive TPO antibodies.


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InternalMed_Harrison. Pathogenesis In Hashimoto’s thyroiditis, there is a marked lymphocytic infiltration of the thyroid with germinal center formation, atrophy of the thyroid follicles accompanied by oxyphil metaplasia, absence of colloid, and mild to moderate fibrosis. In atrophic thyroiditis, the fibrosis is much more extensive, lymphocyte infiltration is less pronounced, and thyroid follicles are almost completely absent. Atrophic thyroiditis likely represents the end stage of Hashimoto’s thyroiditis rather than a distinct disorder.


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InternalMed_Harrison. As with most autoimmune disorders, susceptibility to autoimmune hypothyroidism is determined by a combination of genetic and environmental factors, and the risk of either autoimmune hypothyroidism or Graves’ disease is increased among siblings. HLA-DR polymorphisms are the best documented genetic risk factors for autoimmune hypothyroidism, especially HLA-DR3, -DR4, and -DR5 in Caucasians. A weak association also exists between polymorphisms in CTLA-4, a T cell–regulatory gene, and autoimmune hypothyroidism. Both of these genetic associations are shared by other autoimmune diseases, which may explain the relationship between autoimmune hypothyroidism and other autoimmune diseases, especially type 1 diabetes mellitus, Addison’s disease, pernicious anemia, and vitiligo. HLA-DR and CTLA-4 polymorphisms account for approximately half of the genetic susceptibility to autoimmune hypothyroidism. Other contributory loci remain to be identified. A gene on chromosome 21 may be responsible for


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InternalMed_Harrison. account for approximately half of the genetic susceptibility to autoimmune hypothyroidism. Other contributory loci remain to be identified. A gene on chromosome 21 may be responsible for the association between autoimmune hypothyroidism and Down’s syndrome. The female preponderance of thyroid autoimmunity is most likely due to sex steroid effects on the immune response, but an X chromosome–related genetic factor is also possible and may account for the high frequency of autoimmune hypothyroidism in Turner’s syndrome. Environmental susceptibility factors are poorly defined at present. A high iodine intake and decreased exposure to microorganisms in childhood increase the risk of autoimmune hypothyroidism. These factors may account for the increase in prevalence over the last two to three decades.


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InternalMed_Harrison. The thyroid lymphocytic infiltrate in autoimmune hypothyroidism is composed of activated CD4+ and CD8+ T cells as well as B cells. Thyroid cell destruction is primarily mediated by the CD8+ cytotoxic T cells, which destroy their targets by either perforin-induced cell necrosis or granzyme B–induced apoptosis. In addition, local T cell production of cytokines, such as tumor necrosis factor (TNF), IL-1, and interferon γ (IFN-γ), may render thyroid cells more susceptible to apoptosis mediated by death receptors, such as Fas, which are activated by their respective ligands on T cells. These cytokines also impair thyroid cell function directly and induce the expression of other proinflammatory molecules by the thyroid cells themselves, such as cytokines, HLA class I and class II molecules, adhesion molecules, CD40, and nitric oxide. Administration of high concentrations of cytokines for therapeutic purposes (especially IFN-α) is associated with increased autoimmune thyroid disease,


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InternalMed_Harrison. adhesion molecules, CD40, and nitric oxide. Administration of high concentrations of cytokines for therapeutic purposes (especially IFN-α) is associated with increased autoimmune thyroid disease, possibly through mechanisms similar to those in sporadic disease.


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InternalMed_Harrison. Antibodies to TPO and Tg are clinically useful markers of thyroid autoimmunity, but any pathogenic effect is restricted to a secondary role in amplifying an ongoing autoimmune response. TPO antibodies fix complement, and complement membrane-attack complexes are present in the thyroid in autoimmune hypothyroidism. However, transplacental passage of Tg or TPO antibodies has no effect on the fetal thyroid, which suggests that T cell–mediated injury is required to initiate autoimmune damage to the thyroid.


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InternalMed_Harrison. Up to 20% of patients with autoimmune hypothyroidism have antibodies against the TSH-R, which, in contrast to TSI, do not stimulate the receptor but prevent the binding of TSH. These TSH-R-blocking antibodies, therefore, cause hypothyroidism and, especially in Asian patients, thyroid atrophy. Their transplacental passage may induce transient neonatal hypothyroidism. Rarely, patients have a mixture of TSI and TSH-R-blocking antibodies, and thyroid function can oscillate between hyperthyroidism and hypothyroidism as one or the other antibody becomes dominant. Predicting the course of disease in such individuals is difficult, and they require close monitoring of thyroid function. Bioassays can be used to document that TSH-R-blocking antibodies reduce the cyclic AMP–inducing effect of TSH on cultured TSH-R-expressing cells, but these assays are difficult to perform. Thyrotropin-binding inhibitory immunoglobulin (TBII) assays that measure the binding of antibodies to the receptor by


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InternalMed_Harrison. on cultured TSH-R-expressing cells, but these assays are difficult to perform. Thyrotropin-binding inhibitory immunoglobulin (TBII) assays that measure the binding of antibodies to the receptor by competition with radiolabeled TSH do not distinguish between TSIand TSH-Rblocking antibodies, but a positive result in a patient with spontaneous hypothyroidism is strong evidence for the presence of blocking antibodies. The use of these assays does not generally alter clinical management, although it may be useful to confirm the cause of transient neonatal hypothyroidism.


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InternalMed_Harrison. Clinical Manifestations The main clinical features of hypothyroidism are summarized in Table 405-6. The onset is usually insidious, and the patient may become aware of symptoms only when euthyroidism is restored. Patients with Hashimoto’s thyroiditis may present because of goiter rather than symptoms of hypothyroidism. The goiter may not be large, but it is usually irregular and firm in consistency. It is often possible to palpate a pyramidal lobe, normally a vestigial remnant of the thyroglossal duct. Rarely is uncomplicated Hashimoto’s thyroiditis associated with pain.


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InternalMed_Harrison. Patients with atrophic thyroiditis or the late stage of Hashimoto’s thyroiditis present with symptoms and signs of hypothyroidism. The skin is dry, and there is decreased sweating, thinning of the epidermis, and hyperkeratosis of the stratum corneum. Increased dermal glycosaminoglycan content traps water, giving rise to skin thickening without pitting (myxedema). Typical features include a puffy face with edematous eyelids and nonpitting pretibial edema (Fig. 405-6). There is pallor, often with a yellow tinge to the skin due to carotene accumulation. Nail growth is retarded, and hair is dry, brittle, difficult to manage, and falls out easily. In addition to diffuse alopecia, there is thinning of the outer third of the eyebrows, although this is not a specific sign of hypothyroidism.


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InternalMed_Harrison. Other common features include constipation and weight gain (despite a poor appetite). In contrast to popular perception, the weight gain is usually modest and due mainly to fluid retention in the myxedematous tissues. Libido is decreased in both sexes, and there may be oligomenorrhea or amenorrhea in long-standing disease, but menorrhagia is also common. Fertility is reduced, and the incidence of miscarriage is increased. Prolactin levels are often modestly increased (Chap. 403) and may contribute to alterations in libido and fertility and cause galactorrhea. Myocardial contractility and pulse rate are reduced, leading to a reduced stroke volume and bradycardia. Increased peripheral resistance may be accompanied by hypertension, particularly diastolic. Blood flow is diverted from the skin, producing cool extremities. Pericardial effusions occur in up to 30% of patients but rarely compromise cardiac


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InternalMed_Harrison. FIGURE 405-6 Facial appearance in hypothyroidism. Note puffy eyes and thickened skin. function. Although alterations in myosin heavy chain isoform expres-2291 sion have been documented, cardiomyopathy is unusual. Fluid may also accumulate in other serous cavities and in the middle ear, giving rise to conductive deafness. Pulmonary function is generally normal, but dyspnea may be caused by pleural effusion, impaired respiratory muscle function, diminished ventilatory drive, or sleep apnea.


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InternalMed_Harrison. Carpal tunnel and other entrapment syndromes are common, as is impairment of muscle function with stiffness, cramps, and pain. On examination, there may be slow relaxation of tendon reflexes and pseudomyotonia. Memory and concentration are impaired. Experimentally, positron emission tomography (PET) scans examining glucose metabolism in hypothyroid subjects show lower regional activity in the amygdala, hippocampus, and perigenual anterior cingulated cortex, among other regions, and this activity corrects after thyroxine replacement. Rare neurologic problems include reversible cerebellar ataxia, dementia, psychosis, and myxedema coma. Hashimoto’s encephalopathy has been defined as a steroid-responsive syndrome associated with TPO antibodies, myoclonus, and slow-wave activity on electroencephalography, but the relationship with thyroid autoimmunity or hypothyroidism is not established. The hoarse voice and occasionally clumsy speech of hypothyroidism reflect fluid accumulation in the


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InternalMed_Harrison. but the relationship with thyroid autoimmunity or hypothyroidism is not established. The hoarse voice and occasionally clumsy speech of hypothyroidism reflect fluid accumulation in the vocal cords and tongue.


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InternalMed_Harrison. The features described above are the consequence of thyroid hormone deficiency. However, autoimmune hypothyroidism may be associated with signs or symptoms of other autoimmune diseases, particularly vitiligo, pernicious anemia, Addison’s disease, alopecia areata, and type 1 diabetes mellitus. Less common associations include celiac disease, dermatitis herpetiformis, chronic active hepatitis, rheumatoid arthritis, systemic lupus erythematosus (SLE), myasthenia gravis, and Sjögren’s syndrome. Thyroid-associated ophthalmopathy, which usually occurs in Graves’ disease (see below), occurs in about 5% of patients with autoimmune hypothyroidism.


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InternalMed_Harrison. Autoimmune hypothyroidism is uncommon in children and usually presents with slow growth and delayed facial maturation. The appearance of permanent teeth is also delayed. Myopathy, with muscle swelling, is more common in children than in adults. In most cases, puberty is delayed, but precocious puberty sometimes occurs. There may be intellectual impairment if the onset is before 3 years and the hormone deficiency is severe.


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InternalMed_Harrison. Laboratory Evaluation A summary of the investigations used to determine the existence and cause of hypothyroidism is provided in Fig. 405-7. A normal TSH level excludes primary (but not secondary) hypothyroidism. If the TSH is elevated, an unbound T4 level is needed to confirm the presence of clinical hypothyroidism, but T4 is inferior to TSH when used as a screening test, because it will not detect subclinical hypothyroidism. Circulating unbound T3 levels are normal in about 25% of patients, reflecting adaptive deiodinase responses to hypothyroidism. T3 measurements are, therefore, not indicated.


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InternalMed_Harrison. Once clinical or subclinical hypothyroidism is confirmed, the etiology is usually easily established by demonstrating the presence of TPO antibodies, which are present in >90% of patients with autoimmune hypothyroidism. TBII can be found in 10–20% of patients, but measurement is not needed routinely. If there is any doubt about the cause of a goiter associated with hypothyroidism, FNA biopsy can be used to confirm the presence of autoimmune thyroiditis. Other abnormal laboratory findings in hypothyroidism may include increased creatine phosphokinase, elevated cholesterol and triglycerides, and anemia (usually normocytic or macrocytic). Except when accompanied by iron deficiency, the anemia and other abnormalities gradually resolve with thyroxine replacement.


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InternalMed_Harrison. Differential Diagnosis An asymmetric goiter in Hashimoto’s thyroiditis may be confused with a MNG or thyroid carcinoma, in which thyroid antibodies may also be present. Ultrasound can be used to show the presence of a solitary lesion or an MNG rather than the heterogeneous thyroid enlargement typical of Hashimoto’s thyroiditis. FNA biopsy is useful in the investigation of focal nodules. Other causes of hypothyroidism are discussed below and in Table 405-5 but rarely cause diagnostic confusion. Disorders of the Thyroid Gland however, lower doses suffice until


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InternalMed_Harrison. Disorders of the Thyroid Gland however, lower doses suffice until Measure unbound T4 Mild Primary Pituitary disease suspected? Measure unbound T4 hypothyroidism hypothyroidism tests Measure TSH Elevated Normal Low Normal Normal Low Autoimmune hypothyroidismRule out otherYesNo causes of hypothyroidism T4 treatment Annual follow-up T4 treatment TPOAb+ or TPOAb– , no TPOAb+ TPOAb– symptomatic symptoms No further Rule out drug effects, sick euthyroid syndrome, then evaluate anterior pituitary function No further tests residual thyroid tissue is destroyed. In patients who develop hypothyroidism after the treatment of Graves’ disease, there is often underlying autonomous function, necessitating lower replacement doses (typically 75–125 μg/d).


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InternalMed_Harrison. Adult patients under 60 years old without evidence of heart disease may be started on 50–100 μg levothyroxine (T4) daily. The dose is adjusted on the basis of TSH levels, with the goal of treatment being a normal TSH, ideally in the lower half of the reference range. TSH responses are gradual and should be measured about 2 months after instituting treatment or after any subsequent change in levothyroxine dosage. The clinical effects of levothyroxine replacement are slow to appear. Patients may not experience full relief from symptoms until 3–6 months after normal TSH levels are FIGURE 405-7 Evaluation of hypothyroidism. TPOAb+, thyroid peroxidase antibodies present; restored. Adjustment of levothyroxine TPOAb−, thyroid peroxidase antibodies not present; TSH, thyroid-stimulating hormone. dosage is made in 12.5or 25-μg increments if the TSH is high; decrements of the same magnitude should be made if the TSH is suppressed. Patients with a suppressed TSH of any


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InternalMed_Harrison. dosage is made in 12.5or 25-μg increments if the TSH is high; decrements of the same magnitude should be made if the TSH is suppressed. Patients with a suppressed TSH of any Iatrogenic hypothyroidism is a common cause of hypothyroidism and cause, including T4 overtreatment, have an increased risk of atrial can often be detected by screening before symptoms develop. In the fibrillation and reduced bone density. first 3–4 months after radioiodine treatment, transient hypothyroid- ism may occur due to reversible radiation damage. Low-dose thy- USP) are available, they are not recommended because the ratio of roxine treatment can be withdrawn if recovery occurs. Because TSH


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InternalMed_Harrison. USP) are available, they are not recommended because the ratio of roxine treatment can be withdrawn if recovery occurs. Because TSH T to T is nonphysiologic. The use of levothyroxine combined with levels are suppressed by hyperthyroidism, unbound T4 levels are a 34 liothyronine (triiodothyronine, T ) has been investigated, but benefit better measure of thyroid function than TSH in the months following 3 has not been confirmed in prospective studies. There is no place radioiodine treatment. Mild hypothyroidism after subtotal thyroidec for liothyronine alone as long-term replacement, because the short tomy may also resolve after several months, as the gland remnant is half-life necessitates three or four daily doses and is associated with stimulated by increased TSH levels. fluctuating T levels. Iodine deficiency is responsible for endemic goiter and cretinism 3


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InternalMed_Harrison. fluctuating T levels. Iodine deficiency is responsible for endemic goiter and cretinism 3 Once full replacement is achieved and TSH levels are stable, but is an uncommon cause of adult hypothyroidism unless the iodine follow-up measurement of TSH is recommended at annual intervals intake is very low or there are complicating factors, such as the con- and may be extended to every 2–3 years if a normal TSH is main sumption of thiocyanates in cassava or selenium deficiency. Although tained over several years. It is important to ensure ongoing adher hypothyroidism due to iodine deficiency can be treated with thyroxine, ence, however, as patients do not feel any symptomatic difference public health measures to improve iodine intake should be advocated after missing a few doses of levothyroxine, and this sometimes leads to eliminate this problem. Iodized salt or bread or a single bolus of oral to self-discontinuation. or intramuscular iodized oil have all been used successfully.


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InternalMed_Harrison. or intramuscular iodized oil have all been used successfully. In patients of normal body weight who are taking ≥200 μg of levo- Paradoxically, chronic iodine excess can also induce goiter and thyroxine per day, an elevated TSH level is often a sign of poor adher hypothyroidism. The intracellular events that account for this effect ence to treatment. This is also the likely explanation for fluctuating are unclear, but individuals with autoimmune thyroiditis are espe- TSH levels, despite a constant levothyroxine dosage. Such patients cially susceptible. Iodine excess is responsible for the hypothyroidism often have normal or high unbound T4 levels, despite an elevated that occurs in up to 13% of patients treated with amiodarone (see


InternalMed_Harrison

InternalMed_Harrison. TSH, because they remember to take medication for a few days below). Other drugs, particularly lithium, may also cause hypothy before testing; this is sufficient to normalize T , but not TSH levels. It roidism. Transient hypothyroidism caused by thyroiditis is discussed 4 is important to consider variable adherence, because this pattern of below. thyroid function tests is otherwise suggestive of disorders associated


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InternalMed_Harrison. Secondary hypothyroidism is usually diagnosed in the context of with inappropriate TSH secretion (Table 405-3). Because T has a long half-life (7 days), patients who miss a dose can be advised to take is very rare (Chap. 402). TSH levels may be low, normal, or even two doses of the skipped tablets at once. Other causes of increased slightly increased in secondary hypothyroidism; the latter is due to levothyroxine requirements must be excluded, particularly malab secretion of immunoactive but bioinactive forms of TSH. The diagno sorption (e.g., celiac disease, small-bowel surgery), estrogen or selec sis is confirmed by detecting a low unbound T level. The goal of treat 4 tive estrogen receptor modulator therapy, ingestion with a meal, ment is to maintain T levels in the upper half of the reference range, 4 and drugs that interfere with T absorption or metabolism such as because TSH levels cannot be used to monitor therapy. 4 cholestyramine, ferrous sulfate, calcium supplements, proton


InternalMed_Harrison

InternalMed_Harrison. range, 4 and drugs that interfere with T absorption or metabolism such as because TSH levels cannot be used to monitor therapy. 4 cholestyramine, ferrous sulfate, calcium supplements, proton pump inhibitors, lovastatin, aluminum hydroxide, rifampicin, amiodarone, carbamazepine, phenytoin, and tyrosine kinase inhibitors.


InternalMed_Harrison

InternalMed_Harrison. If there is no residual thyroid function, the daily replacement dose By definition, subclinical hypothyroidism refers to biochemical of levothyroxine is usually 1.6 μg/kg body weight (typically 100–150 evidence of thyroid hormone deficiency in patients who have few μg), ideally taken at least 30 min before breakfast. In many patients, or no apparent clinical features of hypothyroidism. There are no universally accepted recommendations for the management of subclinical hypothyroidism, but levothyroxine is recommended if the patient is a woman who wishes to conceive or is pregnant, or when TSH levels are above 10 mIU/L. When TSH levels are below 10 mIU/L, treatment should be considered when patients have suggestive symptoms of hypothyroidism, positive TPO antibodies, or any evidence of heart disease. It is important to confirm that any elevation of TSH is sustained over a 3-month period before treatment is given. As long as excessive treatment is avoided, there is no risk in correcting


InternalMed_Harrison

InternalMed_Harrison. disease. It is important to confirm that any elevation of TSH is sustained over a 3-month period before treatment is given. As long as excessive treatment is avoided, there is no risk in correcting a slightly increased TSH. Treatment is administered by starting with a low dose of levothyroxine (25–50 μg/d) with the goal of normalizing TSH. If levothyroxine is not given, thyroid function should be evaluated annually.


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InternalMed_Harrison. Rarely, levothyroxine replacement is associated with pseudotumor cerebri in children. Presentation appears to be idiosyncratic and occurs months after treatment has begun.


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InternalMed_Harrison. Women with a history or high risk of hypothyroidism should ensure that they are euthyroid prior to conception and during early pregnancy because maternal hypothyroidism may adversely affect fetal neural development and cause preterm delivery. The presence of thyroid autoantibodies alone, in a euthyroid patient, is also associated with miscarriage and preterm delivery; it is unclear if levothyroxine therapy improves outcomes. Thyroid function should be evaluated immediately after pregnancy is confirmed and every 4 weeks during the first half of the pregnancy, with less frequent testing after 20 weeks’ gestation (every 6–8 weeks depending on whether levothyroxine dose adjustment is ongoing). The levothyroxine dose may need to be increased by up to 50% during pregnancy, with a goal TSH of less than 2.5 mIU/L during the first trimester and less than 3.0 mIU/L during the second and third trimesters. After delivery, thyroxine doses typically return to prepregnancy levels. Pregnant women


InternalMed_Harrison

InternalMed_Harrison. less than 2.5 mIU/L during the first trimester and less than 3.0 mIU/L during the second and third trimesters. After delivery, thyroxine doses typically return to prepregnancy levels. Pregnant women should be counseled to separate ingestion of prenatal vitamins and iron supplements from levothyroxine by at least 4 h.


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InternalMed_Harrison. Elderly patients may require 20% less thyroxine than younger patients. In the elderly, especially patients with known coronary artery disease, the starting dose of levothyroxine is 12.5–25 μg/d with similar increments every 2–3 months until TSH is normalized. In some patients, it may be impossible to achieve full replacement despite optimal antianginal treatment. Emergency surgery is generally safe in patients with untreated hypothyroidism, although routine surgery in a hypothyroid patient should be deferred until euthyroidism is achieved.


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InternalMed_Harrison. Myxedema coma still has a 20–40% mortality rate, despite intensive treatment, and outcomes are independent of the T4 and TSH levels. Clinical manifestations include reduced level of consciousness, sometimes associated with seizures, as well as the other features of hypothyroidism (Table 405-6). Hypothermia can reach 23°C (74°F). There may be a history of treated hypothyroidism with poor compliance, or the patient may be previously undiagnosed. Myxedema coma almost always occurs in the elderly and is usually precipitated by factors that impair respiration, such as drugs (especially sedatives, anesthetics, and antidepressants), pneumonia, congestive heart failure, myocardial infarction, gastrointestinal bleeding, or cerebrovascular accidents. Sepsis should also be suspected. Exposure to cold may also be a risk factor. Hypoventilation, leading to hypoxia and hypercapnia, plays a major role in pathogenesis; hypoglycemia and dilutional hyponatremia also contribute to the development of


InternalMed_Harrison

InternalMed_Harrison. cold may also be a risk factor. Hypoventilation, leading to hypoxia and hypercapnia, plays a major role in pathogenesis; hypoglycemia and dilutional hyponatremia also contribute to the development of myxedema coma.


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InternalMed_Harrison. Levothyroxine can initially be administered as a single IV bolus of 500 μg, which serves as a loading dose. Although further levothyroxine is not strictly necessary for several days, it is usually continued at a dose of 50–100 μg/d. If suitable IV preparation is not available, the same initial dose of levothyroxine can be given by nasogastric tube (although absorption may be impaired in myxedema). An alternative is to give liothyronine (T3) intravenously or via nasogastric tube, in doses ranging from 10 to 25 μg every 8–12 h. This treatment has been advocated because T4 → T3 conversion is impaired in myxedema coma. However, excess liothyronine has the potential to provoke 2293 arrhythmias. Another option is to combine levothyroxine (200 μg) and liothyronine (25 μg) as a single, initial IV bolus followed by daily treatment with levothyroxine (50–100 μg/d) and liothyronine (10 μg every 8 h).


InternalMed_Harrison

InternalMed_Harrison. Supportive therapy should be provided to correct any associated metabolic disturbances. External warming is indicated only if the temperature is <30°C, as it can result in cardiovascular collapse (Chap. 478e). Space blankets should be used to prevent further heat loss. Parenteral hydrocortisone (50 mg every 6 h) should be administered, because there is impaired adrenal reserve in profound hypothyroidism. Any precipitating factors should be treated, including the early use of broad-spectrum antibiotics, pending the exclusion of infection. Ventilatory support with regular blood gas analysis is usually needed during the first 48 h. Hypertonic saline or IV glucose may be needed if there is severe hyponatremia or hypoglycemia; hypotonic IV fluids should be avoided because they may exacerbate water retention secondary to reduced renal perfusion and inappropriate vasopressin secretion. The metabolism of most medications is impaired, and sedatives should be avoided if possible or used in


InternalMed_Harrison

InternalMed_Harrison. water retention secondary to reduced renal perfusion and inappropriate vasopressin secretion. The metabolism of most medications is impaired, and sedatives should be avoided if possible or used in reduced doses. Medication blood levels should be monitored, when available, to guide dosage.


InternalMed_Harrison

InternalMed_Harrison. Thyrotoxicosis is defined as the state of thyroid hormone excess and is not synonymous with hyperthyroidism, which is the result of excessive thyroid function. However, the major etiologies of thyrotoxicosis are hyperthyroidism caused by Graves’ disease, toxic MNG, and toxic adenomas. Other causes are listed in Table 405-7. GRAVES’ DISEASE Epidemiology Graves’ disease accounts for 60–80% of thyrotoxicosis. The prevalence varies among populations, reflecting genetic factors and iodine intake (high iodine intake is associated with an increased prevalence of Graves’ disease). Graves’ disease occurs in up to 2% of women but is one-tenth as frequent in men. The disorder rarely begins before adolescence and typically occurs between 20 and 50 years of age; it also occurs in the elderly. Activating mutation of the TSH receptor Activating mutation of GSα (McCune-Albright syndrome) Drugs: iodine excess (Jod-Basedow phenomenon)


InternalMed_Harrison

InternalMed_Harrison. Activating mutation of the TSH receptor Activating mutation of GSα (McCune-Albright syndrome) Drugs: iodine excess (Jod-Basedow phenomenon) Subacute thyroiditis Silent thyroiditis Other causes of thyroid destruction: amiodarone, radiation, infarction of adenoma Ingestion of excess thyroid hormone (thyrotoxicosis factitia) or thyroid tissue Thyroid hormone resistance syndrome: occasional patients may have features of thyrotoxicosis Chorionic gonadotropin-secreting tumorsa Gestational thyrotoxicosisa aCirculating TSH levels are low in these forms of secondary hyperthyroidism. Abbreviations: TSH, thyroid-stimulating hormone.


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Thyroid Gland 2294 Pathogenesis As in autoimmune hypothyroidism, a combination of environmental and genetic factors, including polymorphisms in HLA-DR, the immunoregulatory genes CTLA-4, CD25, PTPN22, FCRL3, and CD226, as well as the TSH-R, contribute to Graves’ disease susceptibility. The concordance for Graves’ disease in monozygotic twins is 20–30%, compared to <5% in dizygotic twins. Indirect evidence suggests that stress is an important environmental factor, presumably operating through neuroendocrine effects on the immune system. Smoking is a minor risk factor for Graves’ disease and a major risk factor for the development of ophthalmopathy. Sudden increases in iodine intake may precipitate Graves’ disease, and there is a threefold increase in the occurrence of Graves’ disease in the postpartum period. Graves’ disease may occur during the immune reconstitution phase after highly active antiretroviral therapy (HAART) or alemtuzumab treatment. The hyperthyroidism


InternalMed_Harrison

InternalMed_Harrison. disease in the postpartum period. Graves’ disease may occur during the immune reconstitution phase after highly active antiretroviral therapy (HAART) or alemtuzumab treatment. The hyperthyroidism of Graves’ disease is caused by TSI that are synthesized in the thyroid gland as well as in bone marrow and lymph nodes. Such antibodies can be detected by bioassays or by using the more widely available TBII assays. The presence of TBII in a patient with thyrotoxicosis implies the existence of TSI, and these assays are useful in monitoring pregnant Graves’ patients in whom high levels of TSI can cross the placenta and cause neonatal thyrotoxicosis. Other thyroid autoimmune responses, similar to those in autoimmune hypothyroidism (see above), occur concurrently in patients with Graves’ disease. In particular, TPO antibodies occur in up to 80% of cases and serve as a readily measurable marker of autoimmunity. Because the coexisting thyroiditis can also affect thyroid function, there is no


InternalMed_Harrison

InternalMed_Harrison. In particular, TPO antibodies occur in up to 80% of cases and serve as a readily measurable marker of autoimmunity. Because the coexisting thyroiditis can also affect thyroid function, there is no direct correlation between the level of TSI and thyroid hormone levels in Graves’ disease. In the long term, spontaneous autoimmune hypothyroidism may develop in up to 15% of patients with Graves’ disease. Cytokines appear to play a major role in thyroid-associated ophthalmopathy. There is infiltration of the extraocular muscles by activated T cells; the release of cytokines such as IFN-γ, TNF, and IL-1 results in fibroblast activation and increased synthesis of glycosaminoglycans that trap water, thereby leading to characteristic muscle swelling. Late in the disease, there is irreversible fibrosis of the muscles. Orbital fibroblasts may be particularly sensitive to cytokines, perhaps explaining the anatomic localization of the immune response. Though the pathogenesis of thyroid-associated


InternalMed_Harrison

InternalMed_Harrison. of the muscles. Orbital fibroblasts may be particularly sensitive to cytokines, perhaps explaining the anatomic localization of the immune response. Though the pathogenesis of thyroid-associated ophthalmopathy remains unclear, there is mounting evidence that the TSH-R may be a shared autoantigen that is expressed in the orbit; this would explain the close association with autoimmune thyroid disease. Increased fat is an additional cause of retrobulbar tissue expansion. The increase in intraorbital pressure can lead to proptosis, diplopia, and optic neuropathy.


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InternalMed_Harrison. Clinical Manifestations Signs and symptoms include features that are common to any cause of thyrotoxicosis (Table 405-8) as well as those specific for Graves’ disease. The clinical presentation depends on the severity of thyrotoxicosis, the duration of disease, individual susceptibility to excess thyroid hormone, and the patient’s age. In the elderly, features of thyrotoxicosis may be subtle or masked, and patients may present mainly with fatigue and weight loss, a condition known as apathetic thyrotoxicosis. Hyperactivity, irritability, dysphoria Tachycardia; atrial fibrillation in the elderly Fatigue and weakness Warm, moist skin Weight loss with increased appetite Muscle weakness, proximal myopathy Oligomenorrhea, loss of libido aExcludes the signs of ophthalmopathy and dermopathy specific for Graves’ disease.


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InternalMed_Harrison. Thyrotoxicosis may cause unexplained weight loss, despite an enhanced appetite, due to the increased metabolic rate. Weight gain occurs in 5% of patients, however, because of increased food intake. Other prominent features include hyperactivity, nervousness, and irritability, ultimately leading to a sense of easy fatigability in some patients. Insomnia and impaired concentration are common; apathetic thyrotoxicosis may be mistaken for depression in the elderly. Fine tremor is a frequent finding, best elicited by having patients stretch out their fingers while feeling the fingertips with the palm. Common neurologic manifestations include hyperreflexia, muscle wasting, and proximal myopathy without fasciculation. Chorea is rare. Thyrotoxicosis is sometimes associated with a form of hypokalemic periodic paralysis; this disorder is particularly common in Asian males with thyrotoxicosis, but it occurs in other ethnic groups as well.


InternalMed_Harrison

InternalMed_Harrison. The most common cardiovascular manifestation is sinus tachycardia, often associated with palpitations, occasionally caused by supra-ventricular tachycardia. The high cardiac output produces a bounding pulse, widened pulse pressure, and an aortic systolic murmur and can lead to worsening of angina or heart failure in the elderly or those with preexisting heart disease. Atrial fibrillation is more common in patients >50 years of age. Treatment of the thyrotoxic state alone converts atrial fibrillation to normal sinus rhythm in about half of patients, suggesting the existence of an underlying cardiac problem in the remainder.


InternalMed_Harrison

InternalMed_Harrison. The skin is usually warm and moist, and the patient may complain of sweating and heat intolerance, particularly during warm weather. Palmar erythema, onycholysis, and, less commonly, pruritus, urticaria, and diffuse hyperpigmentation may be evident. Hair texture may become fine, and a diffuse alopecia occurs in up to 40% of patients, persisting for months after restoration of euthyroidism. Gastrointestinal transit time is decreased, leading to increased stool frequency, often with diarrhea and occasionally mild steatorrhea. Women frequently experience oligomenorrhea or amenorrhea; in men, there may be impaired sexual function and, rarely, gynecomastia. The direct effect of thyroid hormones on bone resorption leads to osteopenia in longstanding thyrotoxicosis; mild hypercalcemia occurs in up to 20% of patients, but hypercalciuria is more common. There is a small increase in fracture rate in patients with a previous history of thyrotoxicosis.


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InternalMed_Harrison. In Graves’ disease, the thyroid is usually diffusely enlarged to two to three times its normal size. The consistency is firm, but not nodular. There may be a thrill or bruit, best detected at the inferolateral margins of the thyroid lobes, due to the increased vascularity of the gland and the hyperdynamic circulation.


InternalMed_Harrison

InternalMed_Harrison. Lid retraction, causing a staring appearance, can occur in any form of thyrotoxicosis and is the result of sympathetic overactivity. However, Graves’ disease is associated with specific eye signs that comprise Graves’ ophthalmopathy (Fig. 405-8A). This condition is also called thyroid-associated ophthalmopathy, because it occurs in the absence of hyperthyroidism in 10% of patients. Most of these individuals have autoimmune hypothyroidism or thyroid antibodies. The onset of Graves’ ophthalmopathy occurs within the year before or after the diagnosis of thyrotoxicosis in 75% of patients but can sometimes precede or follow thyrotoxicosis by several years, accounting for some cases of euthyroid ophthalmopathy.


InternalMed_Harrison

InternalMed_Harrison. Some patients with Graves’ disease have little clinical evidence of ophthalmopathy. However, the enlarged extraocular muscles typical of the disease, and other subtle features, can be detected in almost all patients when investigated by ultrasound or computed tomography (CT) imaging of the orbits. Unilateral signs are found in up to 10% of patients. The earliest manifestations of ophthalmopathy are usually a sensation of grittiness, eye discomfort, and excess tearing. About one-third of patients have proptosis, best detected by visualization of the sclera between the lower border of the iris and the lower eyelid, with the eyes in the primary position. Proptosis can be measured using an exophthalmometer. In severe cases, proptosis may cause corneal exposure and damage, especially if the lids fail to close during sleep. Periorbital edema, scleral injection, and chemosis are also frequent. In 5–10% of patients, the muscle swelling is so severe that diplopia results, typically, but not


InternalMed_Harrison

InternalMed_Harrison. lids fail to close during sleep. Periorbital edema, scleral injection, and chemosis are also frequent. In 5–10% of patients, the muscle swelling is so severe that diplopia results, typically, but not exclusively, when the patient looks up and laterally. The most serious manifestation is compression of the optic nerve at


InternalMed_Harrison

InternalMed_Harrison. Primary thyrotoxicosis Features of Graves’ diseasea? T3 toxicosis Subclinical hyperthyroidism TSH low, unbound T4 high Measure TSH, unbound T4 Normal Measure unbound T3 TSH normal or increased, high unbound T4 TSH-secreting pituitary adenoma or thyroid hormone resistance syndrome Follow up in 6-12 weeks High TSH low, unbound T4 normal TSH and unbound T4 normal No further tests Graves’ disease Multinodular goiter or toxic adenomab? Yes No Toxic nodular hyperthyroidism Low radionuclide uptake? Yes No Destructive thyroiditis, iodine excess or excess thyroid hormone Rule out other causes including stimulation by chorionic gonadotropin


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Thyroid Gland that assess disease activity are preferable for monitoring purposes. When Graves’ eye disease is active and severe, referral to an ophthalmologist is indicated and objective measurements are needed, such as lid-fissure width; corneal staining with fluorescein; and evaluation of extraocular muscle function (e.g., Hess chart), intra-ocular pressure and visual fields, acuity, and color vision. Thyroid dermopathy occurs in <5% of patients with Graves’ disease (Fig. 405-8B), almost always in the presence of moderate or severe ophthalmopathy. Although most frequent over the anterior and lateral aspects of the lower leg FIGURE 405-9 Evaluation of thyrotoxicosis. aDiffuse goiter, positive TPO antibodies or TRAb, (hence the term pretibial myxedema), ophthalmopathy, dermopathy. bCan be confirmed by radionuclide scan. TSH, thyroid-stimulating skin changes can occur at other sites, hormone.


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InternalMed_Harrison. FIGURE 405-8 Features of Graves’ disease. A. Ophthalmopathy in Graves’ disease; lid retraction, periorbital edema, conjunctival injection, and proptosis are marked. B. Thyroid dermopathy over the lateral aspects of the shins. C. Thyroid acropachy. the apex of the orbit, leading to papilledema; peripheral field defects; and, if left untreated, permanent loss of vision. The “NO SPECS” scoring system to evaluate ophthalmopathy is an acronym derived from the following changes: 0 = No signs or symptoms 1 = Only signs (lid retraction or lag), no symptoms 2 = Soft tissue involvement (periorbital


InternalMed_Harrison

InternalMed_Harrison. Although useful as a mnemonic, the NO SPECS scheme is inadequate to describe the eye disease fully, and patients do not necessarily progress from one class to another; alternative scoring systems particularly after trauma. The typical lesion is a noninflamed, indu-2295 rated plaque with a deep pink or purple color and an “orange skin” appearance. Nodular involvement can occur, and the condition can rarely extend over the whole lower leg and foot, mimicking elephantiasis. Thyroid acropachy refers to a form of clubbing found in <1% of patients with Graves’ disease (Fig. 405-8C). It is so strongly associated with thyroid dermopathy that an alternative cause of clubbing should be sought in a Graves’ patient without coincident skin and orbital involvement.


InternalMed_Harrison

InternalMed_Harrison. Laboratory Evaluation Investigations used to determine the existence and cause of thyrotoxicosis are summarized in Fig. 405-9. In Graves’ disease, the TSH level is suppressed, and total and unbound thyroid hormone levels are increased. In 2–5% of patients (and more in areas of borderline iodine intake), only T3 is increased (T3 toxicosis). The converse state of T4 toxicosis, with elevated total and unbound T4 and normal T3 levels, is occasionally seen when hyperthyroidism is induced by excess iodine, providing surplus substrate for thyroid hormone synthesis. Measurement of TPO antibodies or TRAb may be useful if the diagnosis is unclear clinically but is not needed routinely. Associated abnormalities that may cause diagnostic confusion in thyrotoxicosis include elevation of bilirubin, liver enzymes, and ferritin. Microcytic anemia and thrombocytopenia may occur.


InternalMed_Harrison

InternalMed_Harrison. Differential Diagnosis Diagnosis of Graves’ disease is straightforward in a patient with biochemically confirmed thyrotoxicosis, diffuse goiter on palpation, ophthalmopathy, and often a personal or family history of autoimmune disorders. For patients with thyrotoxicosis who lack these features, the diagnosis is generally established by a radionuclide (99mTc, 123I, or 131I) scan and uptake of the thyroid, which will distinguish the diffuse, high uptake of Graves’ disease from destructive thyroiditis, ectopic thyroid tissue, and factitious thyrotoxicosis. Scintigraphy is the preferred diagnostic test; however, TRAb measurement can be used to assess autoimmune activity. In secondary hyperthyroidism due to a 2296 TSH-secreting pituitary tumor, there is also a diffuse goiter. The presence of a nonsuppressed TSH level and the finding of a pituitary tumor on CT or magnetic resonance scan (MRI) scan suggest this diagnosis. Clinical features of thyrotoxicosis can mimic certain aspects of other


InternalMed_Harrison

InternalMed_Harrison. nonsuppressed TSH level and the finding of a pituitary tumor on CT or magnetic resonance scan (MRI) scan suggest this diagnosis. Clinical features of thyrotoxicosis can mimic certain aspects of other disorders, including panic attacks, mania, pheochromocytoma, and weight loss associated with malignancy. The diagnosis of thyrotoxicosis can be easily excluded if the TSH and unbound T4 and T3 levels are normal. A normal TSH also excludes Graves’ disease as a cause of diffuse goiter.


InternalMed_Harrison

InternalMed_Harrison. Clinical Course Clinical features generally worsen without treatment; mortality was 10–30% before the introduction of satisfactory therapy. Some patients with mild Graves’ disease experience spontaneous relapses and remissions. Rarely, there may be fluctuation between hypoand hyperthyroidism due to changes in the functional activity of TSH-R antibodies. About 15% of patients who enter remission after treatment develop hypothyroidism 10–15 years later as a result of the destructive autoimmune process.


InternalMed_Harrison

InternalMed_Harrison. The clinical course of ophthalmopathy does not follow that of the thyroid disease. Ophthalmopathy typically worsens over the initial 3–6 months, followed by a plateau phase over the next 12–18 months, with spontaneous improvement, particularly in the soft tissue changes. However, the course is more fulminant in up to 5% of patients, requiring intervention in the acute phase if there is optic nerve compression or corneal ulceration. Diplopia may appear late in the disease due to fibrosis of the extraocular muscles. Radioiodine treatment for hyperthyroidism worsens the eye disease in a small proportion of patients (especially smokers). Antithyroid drugs or surgery have no adverse effects on the clinical course of ophthalmopathy. Thyroid dermopathy, when it occurs, usually appears 1–2 years after the development of Graves’ hyperthyroidism; it may improve spontaneously.


InternalMed_Harrison

InternalMed_Harrison. The hyperthyroidism of Graves’ disease is treated by reducing thyroid hormone synthesis, using antithyroid drugs, or reducing the amount of thyroid tissue with radioiodine (131I) treatment or by thyroidectomy. Antithyroid drugs are the predominant therapy in many centers in Europe and Japan, whereas radioiodine is more often the first line of treatment in North America. These differences reflect the fact that no single approach is optimal and that patients may require multiple treatments to achieve remission.


InternalMed_Harrison

InternalMed_Harrison. The main antithyroid drugs are the thionamides, such as propylthiouracil, carbimazole (not available in the United States), and the active metabolite of the latter, methimazole. All inhibit the function of TPO, reducing oxidation and organification of iodide. These drugs also reduce thyroid antibody levels by mechanisms that remain unclear, and they appear to enhance rates of remission. Propylthiouracil inhibits deiodination of T4 → T3. However, this effect is of minor benefit, except in the most severe thyrotoxicosis, and is offset by the much shorter half-life of this drug (90 min) compared to methimazole (6 h). Due to the hepatotoxicity of propylthiouracil, the U.S. Food and Drug Administration (FDA) has limited indications for its use to the first trimester of pregnancy, the treatment of thyroid storm, and patients with minor adverse reactions to methimazole. If propylthiouracil is used, monitoring of liver function tests is recommended.


InternalMed_Harrison

InternalMed_Harrison. There are many variations of antithyroid drug regimens. The initial dose of carbimazole or methimazole is usually 10–20 mg every 8 or 12 h, but once-daily dosing is possible after euthyroidism is restored. Propylthiouracil is given at a dose of 100–200 mg every 6–8 h, and divided doses are usually given throughout the course. Lower doses of each drug may suffice in areas of low iodine intake. The starting dose of antithyroid drugs can be gradually reduced (titration regimen) as thyrotoxicosis improves. Alternatively, high doses may be given combined with levothyroxine supplementation (block-replace regimen) to avoid drug-induced hypothyroidism. The titration regimen is preferred to minimize the dose of antithyroid drug and provide an index of treatment response.


InternalMed_Harrison

InternalMed_Harrison. Thyroid function tests and clinical manifestations are reviewed 4–6 weeks after starting treatment, and the dose is titrated based on unbound T4 levels. Most patients do not achieve euthyroidism until 6–8 weeks after treatment is initiated. TSH levels often remain suppressed for several months and therefore do not provide a sensitive index of treatment response. The usual daily maintenance doses of antithyroid drugs in the titration regimen are 2.5–10 mg of carbimazole or methimazole and 50–100 mg of propylthiouracil. In the block-replace regimen, the initial dose of antithyroid drug is held constant, and the dose of levothyroxine is adjusted to maintain normal unbound T4 levels. When TSH suppression is alleviated, TSH levels can also be used to monitor therapy.


InternalMed_Harrison

InternalMed_Harrison. Maximum remission rates (up to 30–60% in some populations) are achieved by 12–18 months for the titration regimen and by 6 months for the block-replace regimen. For unclear reasons, remission rates appear to vary in different geographic regions. Younger patients, males, smokers, and patients with severe hyperthyroidism and large goiters are most likely to relapse when treatment stops, but outcomes are difficult to predict. All patients should be followed closely for relapse during the first year after treatment and at least annually thereafter.


InternalMed_Harrison

InternalMed_Harrison. The common minor side effects of antithyroid drugs are rash, urticaria, fever, and arthralgia (1–5% of patients). These may resolve spontaneously or after substituting an alternative antithyroid drug. Rare but major side effects include hepatitis (propylthiouracil; avoid use in children) and cholestasis (methimazole and carbimazole); an SLE-like syndrome; and, most important, agranulocytosis (<1%). It is essential that antithyroid drugs are stopped and not restarted if a patient develops major side effects. Written instructions should be provided regarding the symptoms of possible agranulocytosis (e.g., sore throat, fever, mouth ulcers) and the need to stop treatment pending an urgent complete blood count to confirm that agranulocytosis is not present. Management of agranulocytosis is described in Chap. 130. It is not useful to monitor blood counts prospectively, because the onset of agranulocytosis is idiosyncratic and abrupt.


InternalMed_Harrison

InternalMed_Harrison. Propranolol (20–40 mg every 6 h) or longer-acting selective β1 receptor blockers such as atenolol may be helpful to control adrenergic symptoms, especially in the early stages before antithyroid drugs take effect. Beta blockers are also useful in patients with thyrotoxic periodic paralysis, pending correction of thyrotoxicosis. In consultation with a cardiologist, anticoagulation with warfarin should be considered in all patients with atrial fibrillation who often spontaneously revert to sinus rhythm with control of hyperthyroidism. Decreased warfarin doses are required when patients are thyrotoxic. If digoxin is used, increased doses are often needed in the thyrotoxic state.


InternalMed_Harrison

InternalMed_Harrison. Radioiodine causes progressive destruction of thyroid cells and can be used as initial treatment or for relapses after a trial of antithyroid drugs. There is a small risk of thyrotoxic crisis (see below) after radioiodine, which can be minimized by pretreatment with antithyroid drugs for at least a month before treatment. Antecedent treatment with antithyroid drugs should be considered for all elderly patients or for those with cardiac problems to deplete thyroid hormone stores before administration of radioiodine. Carbimazole or methimazole must be stopped 3–5 days before radioiodine administration to achieve optimum iodine uptake. Propylthiouracil appears to have a prolonged radioprotective effect and should be stopped for a longer period before radioiodine is given, or a larger dose of radioiodine will be necessary.


InternalMed_Harrison

InternalMed_Harrison. Efforts to calculate an optimal dose of radioiodine that achieves euthyroidism without a high incidence of relapse or progression to hypothyroidism have not been successful. Some patients inevitably relapse after a single dose because the biologic effects of radiation vary between individuals, and hypothyroidism cannot be uniformly avoided even using accurate dosimetry. A practical strategy is to give a fixed dose based on clinical features, such as the severity of thyrotoxicosis, the size of the goiter (increases the dose needed), and the level of radioiodine uptake (decreases the dose needed). 131I dosage generally ranges between 370 MBq (10 mCi) and 555 MBq (15 mCi). Most authorities favor an approach aimed at thyroid ablation (as opposed to euthyroidism), given that levothyroxine replacement is straightforward and most patients ultimately progress to hypothyroidism over 5–10 years, frequently with some delay in the diagnosis of hypothyroidism.


InternalMed_Harrison

InternalMed_Harrison. Certain radiation safety precautions are necessary in the first few days after radioiodine treatment, but the exact guidelines vary depending on local protocols. In general, patients need to avoid close, prolonged contact with children and pregnant women for 5–7 days because of possible transmission of residual isotope and exposure to radiation emanating from the gland. Rarely, there may be mild pain due to radiation thyroiditis 1–2 weeks after treatment. Hyperthyroidism can persist for 2–3 months before radioiodine takes full effect. For this reason, β-adrenergic blockers or antithyroid drugs can be used to control symptoms during this interval. Persistent hyperthyroidism can be treated with a second dose of radioiodine, usually 6 months after the first dose. The risk of hypothyroidism after radioiodine depends on the dosage but is at least 10–20% in the first year and 5% per year thereafter. Patients should be informed of this possibility before treatment and require close follow-up


InternalMed_Harrison

InternalMed_Harrison. radioiodine depends on the dosage but is at least 10–20% in the first year and 5% per year thereafter. Patients should be informed of this possibility before treatment and require close follow-up during the first year followed by annual thyroid function testing.


InternalMed_Harrison

InternalMed_Harrison. Pregnancy and breast-feeding are absolute contraindications to radioiodine treatment, but patients can conceive safely 6 months after treatment. The presence of severe ophthalmopathy requires caution, and some authorities advocate the use of prednisone, 40 mg/d, at the time of radioiodine treatment, tapered over 6–12 weeks to prevent exacerbation of ophthalmopathy. The overall risk of cancer after radioiodine treatment in adults is not increased. Although many physicians avoid radioiodine in children and adolescents because of the theoretical risks of malignancy, emerging evidence suggests that radioiodine can be used safely in older children.


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InternalMed_Harrison. Subtotal or near-total thyroidectomy is an option for patients who relapse after antithyroid drugs and prefer this treatment to radioiodine. Some experts recommend surgery in young individuals, particularly when the goiter is very large. Careful control of thyrotoxicosis with antithyroid drugs, followed by potassium iodide (3 drops SSKI orally tid), is needed prior to surgery to avoid thyrotoxic crisis and to reduce the vascularity of the gland. The major complications of surgery—bleeding, laryngeal edema, hypoparathyroidism, and damage to the recurrent laryngeal nerves—are unusual when the procedure is performed by highly experienced surgeons. Recurrence rates in the best series are <2%, but the rate of hypothyroidism is only slightly less than that following radioiodine treatment.


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InternalMed_Harrison. The titration regimen of antithyroid drugs should be used to manage Graves’ disease in pregnancy because transplacental passage of these drugs may produce fetal hypothyroidism and goiter if the maternal dose is excessive. If available, propylthiouracil should be used in early gestation because of the association of rare cases of fetal aplasia cutis and other defects, such as choanal atresia with carbimazole and methimazole. As noted above, because of its rare association with hepatotoxicity, propylthiouracil should be limited to the first trimester and then maternal therapy should be converted to methimazole (or carbimazole) at a ratio of 15–20 mg of propylthiouracil to 1 mg of methimazole The lowest effective antithyroid drug dose should be used throughout gestation to maintain the maternal serum free T4 level at the upper limit of the nonpregnant normal reference range. It is often possible to stop treatment in the last trimester because TSIs tend to decline in pregnancy.


InternalMed_Harrison

InternalMed_Harrison. the maternal serum free T4 level at the upper limit of the nonpregnant normal reference range. It is often possible to stop treatment in the last trimester because TSIs tend to decline in pregnancy. Nonetheless, the transplacental transfer of these antibodies rarely causes fetal or neonatal thyrotoxicosis. Poor intrauterine growth, a fetal heart rate of >160 beats/min, and high levels of maternal TSI in the last trimester may herald this complication. Antithyroid drugs given to the mother can be used to treat the fetus and may be needed for 1–3 months after delivery, until the maternal antibodies disappear from the baby’s circulation. The postpartum period is a time of major risk for relapse of Graves’ disease. Breast-feeding is safe with low doses of antithyroid drugs. Graves’ disease in children is usually managed with methimazole or carbimazole (avoid propylthiouracil), often given as a prolonged 2297 course of the titration regimen. Surgery or radioiodine may be indicated for


InternalMed_Harrison

InternalMed_Harrison. in children is usually managed with methimazole or carbimazole (avoid propylthiouracil), often given as a prolonged 2297 course of the titration regimen. Surgery or radioiodine may be indicated for severe disease.


InternalMed_Harrison

InternalMed_Harrison. Thyrotoxic crisis, or thyroid storm, is rare and presents as a life-threatening exacerbation of hyperthyroidism, accompanied by fever, delirium, seizures, coma, vomiting, diarrhea, and jaundice. The mortality rate due to cardiac failure, arrhythmia, or hyperthermia is as high as 30%, even with treatment. Thyrotoxic crisis is usually precipitated by acute illness (e.g., stroke, infection, trauma, diabetic ketoacidosis), surgery (especially on the thyroid), or radioiodine treatment of a patient with partially treated or untreated hyperthyroidism. Management requires intensive monitoring and supportive care, identification and treatment of the precipitating cause, and measures that reduce thyroid hormone synthesis. Large doses of propylthiouracil (500–1000 mg loading dose and 250 mg every 4 h) should be given orally or by nasogastric tube or per rectum; the drug’s inhibitory action on T4 → T3 conversion makes it the antithyroid drug of choice. If not available, methimazole can be used in


InternalMed_Harrison

InternalMed_Harrison. should be given orally or by nasogastric tube or per rectum; the drug’s inhibitory action on T4 → T3 conversion makes it the antithyroid drug of choice. If not available, methimazole can be used in doses up to 30 mg every 12 h. One hour after the first dose of propylthiouracil, stable iodide is given to block thyroid hormone synthesis via the Wolff-Chaikoff effect (the delay allows the antithyroid drug to prevent the excess iodine from being incorporated into new hormone). A saturated solution of potassium iodide (5 drops SSKI every 6 h) or, where available, ipodate or iopanoic acid (500 mg per 12 h) may be given orally. Sodium iodide, 0.25 g IV every 6 h, is an alternative but is not generally available. Propranolol should also be given to reduce tachycardia and other adrenergic manifestations (60–80 mg PO every 4 h; or 2 mg IV every 4 h). Although other β-adrenergic blockers can be used, high doses of propranolol decrease T4 → T3 conversion, and the doses can be easily adjusted.


InternalMed_Harrison

InternalMed_Harrison. (60–80 mg PO every 4 h; or 2 mg IV every 4 h). Although other β-adrenergic blockers can be used, high doses of propranolol decrease T4 → T3 conversion, and the doses can be easily adjusted. Caution is needed to avoid acute negative inotropic effects, but controlling the heart rate is important, as some patients develop a form of high-output heart failure. Short-acting IV esmolol can be used to decrease heart rate while monitoring for signs of heart failure. Additional therapeutic measures include glucocorticoids (e.g., hydrocortisone 300 mg IV bolus, then 100 mg every 8 h), antibiotics if infection is present, cooling, oxygen, and IV fluids.


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InternalMed_Harrison. Ophthalmopathy requires no active treatment when it is mild or moderate, because there is usually spontaneous improvement. General measures include meticulous control of thyroid hormone levels, cessation of smoking, and an explanation of the natural history of ophthalmopathy. Discomfort can be relieved with artificial tears (e.g., 1% methylcellulose), eye ointment, and the use of dark glasses with side frames. Periorbital edema may respond to a more upright sleeping position or a diuretic. Corneal exposure during sleep can be avoided by using patches or taping the eyelids shut. Minor degrees of diplopia improve with prisms fitted to spectacles. Severe ophthalmopathy, with optic nerve involvement or chemosis resulting in corneal damage, is an emergency requiring joint management with an ophthalmologist. Pulse therapy with IV methylprednisolone (e.g., 500 mg of methylprednisolone once weekly for 6 weeks, then 250 mg once weekly for 6 weeks) is preferable to oral glucocorticoids, which


InternalMed_Harrison

InternalMed_Harrison. Pulse therapy with IV methylprednisolone (e.g., 500 mg of methylprednisolone once weekly for 6 weeks, then 250 mg once weekly for 6 weeks) is preferable to oral glucocorticoids, which are used for moderately active disease. When glucocorticoids are ineffective, orbital decompression can be achieved by removing bone from any wall of the orbit, thereby allowing displacement of fat and swollen extraocular muscles. The transantral route is used most often because it requires no external incision. Proptosis recedes an average of 5 mm, but there may be residual or even worsened diplopia. Once the eye disease has stabilized, surgery may be indicated for relief of diplopia and correction of the appearance. External beam radiotherapy of the orbits has been used for many years, but the efficacy of this therapy remains unclear, and it is best reserved for those with moderately active disease who have failed or are not candidates for glucocorticoid therapy. Other immunosuppressive agents such as


InternalMed_Harrison

InternalMed_Harrison. this therapy remains unclear, and it is best reserved for those with moderately active disease who have failed or are not candidates for glucocorticoid therapy. Other immunosuppressive agents such as rituximab have shown some benefit, but their role is yet to be established.


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InternalMed_Harrison. Thyroid dermopathy does not usually require treatment, but it can cause cosmetic problems or interfere with the fit of shoes. Surgical Disorders of the Thyroid Gland 2298 removal is not indicated. If necessary, treatment consists of topical, high-potency glucocorticoid ointment under an occlusive dressing. Octreotide may be beneficial in some cases.


InternalMed_Harrison

InternalMed_Harrison. Destructive thyroiditis (subacute or silent thyroiditis) typically presents with a short thyrotoxic phase due to the release of preformed thyroid hormones and catabolism of Tg (see “Subacute Thyroiditis,” below). True hyperthyroidism is absent, as demonstrated by a low radionuclide uptake. Circulating Tg levels are usually increased. Other causes of thyrotoxicosis with low or absent thyroid radionuclide uptake include thyrotoxicosis factitia, iodine excess, and, rarely, ectopic thyroid tissue, particularly teratomas of the ovary (struma ovarii) and functional metastatic follicular carcinoma. Whole-body radionuclide studies can demonstrate ectopic thyroid tissue, and thyrotoxicosis factitia can be distinguished from destructive thyroiditis by the clinical features and low levels of Tg. Amiodarone treatment is associated with thyrotoxicosis in up to 10% of patients, particularly in areas of low iodine intake (see below).


InternalMed_Harrison

InternalMed_Harrison. TSH-secreting pituitary adenoma is a rare cause of thyrotoxicosis. It is characterized by the presence of an inappropriately normal or increased TSH level in a patient with hyperthyroidism, diffuse goiter, and elevated T4 and T3 levels (Chap. 403). Elevated levels of the α-subunit of TSH, released by the TSH-secreting adenoma, support this diagnosis, which can be confirmed by demonstrating the pituitary tumor on MRI or CT scan. A combination of transsphenoidal surgery, sella irradiation, and octreotide may be required to normalize TSH, because many of these tumors are large and locally invasive at the time of diagnosis. Radioiodine or antithyroid drugs can be used to control thyrotoxicosis. Thyrotoxicosis caused by toxic MNG and hyperfunctioning solitary nodules is discussed below. A clinically useful classification of thyroiditis is based on the onset and duration of disease (Table 405-9).


InternalMed_Harrison

InternalMed_Harrison. Acute thyroiditis is rare and due to suppurative infection of the thyroid. In children and young adults, the most common cause is the presence of a piriform sinus, a remnant of the fourth branchial pouch that connects the oropharynx with the thyroid. Such sinuses are predominantly left-sided. A long-standing goiter and degeneration in a thyroid malignancy are risk factors in the elderly. The patient presents with thyroid pain, often referred to the throat or ears, and a small, tender goiter that may be asym-metric. Fever, dysphagia, and erythema over the thyroid are common, as are systemic symptoms of a febrile illness and lymphadenopathy. TAblE 405-9 CAuSES of THyRoiDiTiS Acute Bacterial infection: especially Staphylococcus, Streptococcus, and Enterobacter Fungal infection: Aspergillus, Candida, Coccidioides, Histoplasma, and Pneumocystis Radiation thyroiditis after 131I treatment 50 ESR TSH (mU/L)UT4 (pmol/L)5 0.5 0.01 40 30 10 0 20ESR (mm/h) 100 0 50 UT4 TSH


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InternalMed_Harrison. Viral (or granulomatous) thyroiditis Silent thyroiditis (including postpartum thyroiditis) Mycobacterial infection Drug induced (interferon, amiodarone) Autoimmunity: focal thyroiditis, Hashimoto’s thyroiditis, atrophic thyroiditis Riedel’s thyroiditis Parasitic thyroiditis: echinococcosis, strongyloidiasis, cysticercosis Traumatic: after palpation


InternalMed_Harrison

InternalMed_Harrison. The differential diagnosis of thyroid pain includes subacute or, rarely, chronic thyroiditis; hemorrhage into a cyst; malignancy including lymphoma; and, rarely, amiodarone-induced thyroiditis or amyloidosis. However, the abrupt presentation and clinical features of acute thyroiditis rarely cause confusion. The erythrocyte sedimentation rate (ESR) and white cell count are usually increased, but thyroid function is normal. FNA biopsy shows infiltration by polymorphonuclear leukocytes; culture of the sample can identify the organism. Caution is needed in immunocompromised patients as fungal, mycobacterial, or Pneumocystis thyroiditis can occur in this setting. Antibiotic treatment is guided initially by Gram stain and, subsequently, by cultures of the FNA biopsy. Surgery may be needed to drain an abscess, which can be localized by CT scan or ultrasound. Tracheal obstruction, septicemia, retropharyngeal abscess, mediastinitis, and jugular venous thrombosis may complicate acute


InternalMed_Harrison

InternalMed_Harrison. to drain an abscess, which can be localized by CT scan or ultrasound. Tracheal obstruction, septicemia, retropharyngeal abscess, mediastinitis, and jugular venous thrombosis may complicate acute thyroiditis but are uncommon with prompt use of antibiotics.


InternalMed_Harrison

InternalMed_Harrison. This is also termed de Quervain’s thyroiditis, granulomatous thyroiditis, or viral thyroiditis. Many viruses have been implicated, including mumps, coxsackie, influenza, adenoviruses, and echoviruses, but attempts to identify the virus in an individual patient are often unsuccessful and do not influence management. The diagnosis of subacute thyroiditis is often overlooked because the symptoms can mimic pharyngitis. The peak incidence occurs at 30–50 years, and women are affected three times more frequently than men.


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InternalMed_Harrison. Pathophysiology The thyroid shows a characteristic patchy inflammatory infiltrate with disruption of the thyroid follicles and multinucleated giant cells within some follicles. The follicular changes progress to granulomas accompanied by fibrosis. Finally, the thyroid returns to normal, usually several months after onset. During the initial phase of follicular destruction, there is release of Tg and thyroid hormones, leading to increased circulating T4 and T3 and suppression of TSH (Fig. 405-10). During this destructive phase, radioactive iodine uptake is low or undetectable. After several weeks, the thyroid is depleted of stored thyroid hormone and a phase of hypothyroidism typically occurs, with low unbound T4 (and sometimes T3) and moderately increased TSH levels. Radioactive iodine uptake returns to normal or is even increased as a result of the rise in TSH. Finally, thyroid hormone and TSH levels return to normal as the disease subsides.


InternalMed_Harrison

InternalMed_Harrison. Clinical Manifestations The patient usually presents with a painful and enlarged thyroid, sometimes accompanied by fever. There may be FIGURE 405-10 Clinical course of subacute thyroiditis. The release of thyroid hormones is initially associated with a thyrotoxic phase and suppressed thyroid-stimulating hormone (TSH). A hypothyroid phase then ensues, with low T4 and TSH levels that are initially low but gradually increase. During the recovery phase, increased TSH levels combined with resolution of thyroid follicular injury lead to normalization of thyroid function, often several months after the beginning of the illness. ESR, erythrocyte sedimentation rate; UT4, free or unbound T4.


InternalMed_Harrison

InternalMed_Harrison. features of thyrotoxicosis or hypothyroidism, depending on the phase of the illness. Malaise and symptoms of an upper respiratory tract infection may precede the thyroid-related features by several weeks. In other patients, the onset is acute, severe, and without obvious antecedent. The patient typically complains of a sore throat, and examination reveals a small goiter that is exquisitely tender. Pain is often referred to the jaw or ear. Complete resolution is the usual outcome, but late-onset permanent hypothyroidism occurs in 15% of cases, particularly in those with coincidental thyroid autoimmunity. A prolonged course over many months, with one or more relapses, occurs in a small percentage of patients.


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InternalMed_Harrison. Laboratory Evaluation As depicted in Fig. 405-10, thyroid function tests characteristically evolve through three distinct phases over about 6 months: (1) thyrotoxic phase, (2) hypothyroid phase, and (3) recovery phase. In the thyrotoxic phase, T4 and T3 levels are increased, reflecting their discharge from the damaged thyroid cells, and TSH is suppressed. The T4/T3 ratio is greater than in Graves’ disease or thyroid autonomy, in which T3 is often disproportionately increased. The diagnosis is confirmed by a high ESR and low uptake of radioiodine (<5%) or 99mTc pertechnetate (as compared to salivary gland pertechnetate concentration). The white blood cell count may be increased, and thyroid antibodies are negative. If the diagnosis is in doubt, FNA biopsy may be useful, particularly to distinguish unilateral involvement from bleeding into a cyst or neoplasm.


InternalMed_Harrison

InternalMed_Harrison. Relatively large doses of aspirin (e.g., 600 mg every 4–6 h) or NSAIDs are sufficient to control symptoms in many cases. If this treatment is inadequate, or if the patient has marked local or systemic symptoms, glucocorticoids should be given. The usual starting dose is 40–60 mg of prednisone, depending on severity. The dose is gradually tapered over 6–8 weeks, in response to improvement in symptoms and the ESR. If a relapse occurs during glucocorticoid withdrawal, treatment should be started again and withdrawn more gradually. In these patients, it is useful to wait until the radioactive iodine uptake normalizes before stopping treatment. Thyroid function should be monitored every 2–4 weeks using TSH and unbound T4 levels. Symptoms of thyrotoxicosis improve spontaneously but may be ameliorated by β-adrenergic blockers; antithyroid drugs play no role in treatment of the thyrotoxic phase. Levothyroxine replacement may be needed if the hypothyroid phase is prolonged, but doses should be


InternalMed_Harrison

InternalMed_Harrison. by β-adrenergic blockers; antithyroid drugs play no role in treatment of the thyrotoxic phase. Levothyroxine replacement may be needed if the hypothyroid phase is prolonged, but doses should be low enough (50–100 μg daily) to allow TSH-mediated recovery.


InternalMed_Harrison

InternalMed_Harrison. Painless thyroiditis, or “silent” thyroiditis, occurs in patients with underlying autoimmune thyroid disease and has a clinical course similar to that of subacute thyroiditis. The condition occurs in up to 5% of women 3–6 months after pregnancy and is then termed postpartum thyroiditis. Typically, patients have a brief phase of thyrotoxicosis lasting 2–4 weeks, followed by hypothyroidism for 4–12 weeks, and then resolution; often, however, only one phase is apparent. The condition is associated with the presence of TPO antibodies antepartum, and it is three times more common in women with type 1 diabetes mellitus. As in subacute thyroiditis, the uptake of 99mTc pertechnetate or radioactive iodine is initially suppressed. In addition to the painless goiter, silent thyroiditis can be distinguished from subacute thyroiditis by a normal ESR and the presence of TPO antibodies. Glucocorticoid treatment is not indicated for silent thyroiditis. Severe thyrotoxic symptoms can be managed with a


InternalMed_Harrison

InternalMed_Harrison. from subacute thyroiditis by a normal ESR and the presence of TPO antibodies. Glucocorticoid treatment is not indicated for silent thyroiditis. Severe thyrotoxic symptoms can be managed with a brief course of propranolol, 20–40 mg three or four times daily. Thyroxine replacement may be needed for the hypothyroid phase but should be withdrawn after 6–9 months, as recovery is the rule. Annual follow-up thereafter is recommended, because a proportion of these individuals develop permanent hypothyroidism. The condition may recur in subsequent pregnancies.


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InternalMed_Harrison. Patients receiving cytokines such as IFN-α or IL-2 may develop painless thyroiditis. IFN-α, which is used to treat chronic hepatitis B or C and hematologic and skin malignancies, causes thyroid dysfunction in up to 5% of treated patients. It has been associated with painless thyroiditis, hypothyroidism, and Graves’ disease, and is most common in women with TPO antibodies prior to treatment. For discussion of amiodarone, see “Amiodarone Effects on Thyroid Function,” below.


InternalMed_Harrison

InternalMed_Harrison. Focal thyroiditis is present in 20–40% of euthyroid autopsy cases and is associated with serologic evidence of autoimmunity, particularly the presence of TPO antibodies. The most common clinically apparent cause of chronic thyroiditis is Hashimoto’s thyroiditis, an autoimmune disorder that often presents as a firm or hard goiter of variable size (see above). Riedel’s thyroiditis is a rare disorder that typically occurs in middle-aged women. It presents with an insidious, painless goiter with local symptoms due to compression of the esophagus, trachea, neck veins, or recurrent laryngeal nerves. Dense fibrosis disrupts normal gland architecture and can extend outside the thyroid capsule. Despite these extensive histologic changes, thyroid dysfunction is uncommon. The goiter is hard, nontender, often asymmetric, and fixed, leading to suspicion of a malignancy. Diagnosis requires open biopsy as FNA biopsy is usually inadequate. Treatment is directed to surgical relief of compressive


InternalMed_Harrison

InternalMed_Harrison. often asymmetric, and fixed, leading to suspicion of a malignancy. Diagnosis requires open biopsy as FNA biopsy is usually inadequate. Treatment is directed to surgical relief of compressive symptoms. Tamoxifen may also be beneficial. There is an association between Riedel’s thyroiditis and IgG4-related systemic disease causing idiopathic fibrosis at other sites (retroperitoneum, mediastinum, biliary tree, lung, and orbit).


InternalMed_Harrison

InternalMed_Harrison. Any acute, severe illness can cause abnormalities of circulating TSH or thyroid hormone levels in the absence of underlying thyroid disease, making these measurements potentially misleading. The major cause of these hormonal changes is the release of cytokines such as IL-6. Unless a thyroid disorder is strongly suspected, the routine testing of thyroid function should be avoided in acutely ill patients.


InternalMed_Harrison

InternalMed_Harrison. The most common hormone pattern in sick euthyroid syndrome (SES) is a decrease in total and unbound T3 levels (low T3 syndrome) with normal levels of T4 and TSH. The magnitude of the fall in T3 correlates with the severity of the illness. T4 conversion to T3 via peripheral 5′ (outer ring) deiodination is impaired, leading to increased reverse T3 (rT3). Since rT3 is metabolized by 5′ deiodination, its clearance is also reduced. Thus, decreased clearance rather than increased production is the major basis for increased rT3. Also, T4 is alternately metabolized to the hormonally inactive T3 sulfate. It is generally assumed that this low T3 state is adaptive, because it can be induced in normal individuals by fasting. Teleologically, the fall in T3 may limit catabolism in starved or ill patients.