Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

14.Thyroglobulin

Carole Ann Spencer

Thyroglobulin (Tg), the scaffold protein within which the biologically active thyroid hormones thyroxine (T4) and triiodothyronine (T3) are synthesized, comprises up to 75% of the protein content of the thyroid gland. It contains not only T4 and T3, but also their precursors, diiodotyrosine (DIT) and monoiodotyrosine (MIT). Tg is also an autoantigen involved in thyroid autoimmunity. The tissue-specific origin of Tg has led to its use as a marker for differentiated (papillary and follicular) thyroid carcinoma (hereafter referred to as thyroid carcinoma) (1). Serum Tg concentrations vary in response to changes in thyroid volume, thyroid stimulation, and thyroid damage (2). This chapter will focus on the pathophysiology, methodology, and clinical utility of measurements of serum Tg.

BIOSYNTHESIS, SECRETION, AND METABOLIC CLEARANCE OF THYROGLOBULIN

Tg is a 19S (660 kDa) glycoprotein composed of two identical 12S (330 kDa) subunits produced only by thyroid follicular cells. Tg is encoded by a single-copy gene mapped to chromosome 8q24.2–8q24.3 (see Chapter 5) (3,4). Tg mutations can result in thyroid dyshormonogenesis (see Chapter 48) (5,6,7). There can also be within-individual Tg heterogeneity, as a result of variations in splicing of Tg transcripts (3,6,8). As shown schematically in Figure 14.1(Part 1), Tg gene transcription is regulated by the thyroid-specific transcription factors (TTF-1, TTF-2) and Pax-8 (4,9,10). Hormones such as thyrotropin (TSH), TSH receptor–stimulating antibodies of Graves' disease, interleukin-1, insulin, and insulin-like growth factor-1 act synergistically through cyclic adenosine monophosphate to stimulate Tg gene expression (32,12,13,14,15). There is growing evidence that Tg, particularly poorly iodinated Tg, binds to asialoglycoprotein receptors in the apical membrane of thyroid follicular cells and autoregulates thyroid function by suppressing the expression of the genes for thyroid-specific transcription factors, vascular endothelial growth factor, and the sodium iodide symporter, and by increasing expression of the apical membrane iodide porter, pendrin (9,16,17,18,19,20). Other hormonal factors such as epidermal growth factor, interferon-γ, tumor necrosis factor-α, and retinoic acid inhibit Tg gene expression (22,23,24,25,26,26,27).

FIGURE 14.1. Schematic diagram of the biosynthesis, storage, and breakdown of thyroglobulin. Part 1: A thyroid follicular cell and its constituent organelles (E, endosome; ER, endoplasmic reticulum; G, Golgi apparatus; L, lysosome; M, mitochondrion; N, nucleus; P, peroxisome; R, bound and free ribosome) and proteins [IGF-1, insulin-like growth factor-1; IGF-1-R, receptor for IGF-1; NIS, sodium iodide symporter; Tg, thyroglobulin; TJ, tight function; Tox, thyroid oxidases; TPO, thyroid peroxidase; TSH, thyrotropin; TSH-R, receptor for TSH; 1, thyroid transcription factor-1 (TTF-1); 2, thyroid transcription factor-1 (TTF-2)]. Part 2: Human chromosome 8 expanded to show the thyroglobulin (Tg) (TG) gene and Tg messenger RNA (cell nucleus in background). Part 3: Transcription of Tg messenger RNA and maturation of newly synthesized thyroglobulin, showing chaperone molecules (BIP, GRP94), formation of disulfide bonds (-S-S-), and sites of glycosylation (Asn) (cytoplasm of cell in background). Part 4: Details of glycosylation of thyroglobulin showing sites of carbohydrate attachment (Golgi apparatus in background). Part 5: Mature thyroglogulin in follicular lumen after iodination of tyrosine residues and iodotyrosine coupling to form T4 and T3 (thyroid follicular cell and follicular lumen in background). Part 6: Thyroid follicular cell and follicular lumen showing luminal thyroglobulin and its resorption into the cell and subsequent breakdown in lysomones to form T4, T3, iodine, and amino acids. aa, amino acids; E, endosome; I-, iodine; G, Golgi apparatus; L, lysosomes; M, megalin; PDI, protein disulfide isomerase; TJ, tight junction; 1, thyroid transcription factor-1 (TTF-1); 2, thyroid transcription factor-1 (TTF-2). (Reproduced from van de Graaf SA, Ris-Stalpers C, Pauws E, et al. Up to date with human thyroglobulin. J Endocrinol 2001;170:307, with permission.)

The biosynthesis of the mature, iodinated Tg homo dimer is a complex process that is orchestrated by multiple molecular chaperone molecules that transport newly synthesized Tg to the apical membrane (Fig. 14.1, Parts 3,4,5) (28,29,30,31). During this process, Tg is glycosylated and sulfated, and disulfide bonds are formed—steps necessary for appropriate conformational folding and, ultimately, thyroid hormonogenesis (see Chapter 5). Homodimerization to form mature 660 kDa Tg, which is the substrate for thyroid peroxidase/H2O2–mediated iodination, takes place in the follicular lumen. Thereafter, the MIT and DIT residues are coupled to form T4 and T3 within the protein backbone of Tg at specific hormonogenic sites (32,33). Mature hormone-rich Tg is stored as large multimers in the follicular lumen (34); the Tg concentration in the colloid that fills the lumen can be as high as 500 mg/mL (34,35). Liberation and secretion of T4 and T3 requires endocytosis of Tg [which involves asialoglycoprotein and megalin receptors in the apical membrane (Fig. 14.1, Part 6) (18,36,37,38,39)] into the thyroid follicular cells, and the subsequent proteolysis of Tg in lysosomes (40,41,42,43). Tg that is internalized by megalin may be protected from lysosomal proteolysis, and therefore intact Tg may reach the basolateral membrane of the cells (38,39). A small amount of Tg is secreted as such, and perhaps also as Tg-megalin complexes; antimegalin antibodies have been detected in the serum in some patients (38).

TSH regulates trafficking of Tg in thyroid follicular cells in two ways. It stimulates Tg endocytosis at the apical membrane and subsequent Tg proteolysis, and it stimulates receptor-mediated uptake of Tg from the circulation at the basolateral membrane (44,45). Tg is also taken up by nonthyroid cells such as macrophages in the liver and other tissues (46). The mechanisms responsible for Tg uptake by these tissues, which determines the rate of clearance of Tg from the circulation, are poorly understood. The plasma half-life of Tg in patients with benign thyroid disorders and those with thyroid carcinoma is similar (~4 days) (47,48). Tg clearance is influenced by its molecular size and sialic acid content, and thyroid status. The variations in the estimates of Tg half-life may be due to differences in the Tg preparations used in the studies; some were done by measuring the disappearance of exogenously administered Tg that had been purified from thyroid tissue, and others by measuring the disappearance of endogenous Tg after thyroidectomy (48). The high serum Tg concentrations found in some patients with acute and chronic liver diseases may be due to impaired hepatocyte clearance of Tg or increased Tg secretion secondary to a toxic effect of alcohol on the thyroid gland (49).

Physicochemical analysis of Tg extracted from normal and diseased thyroid tissue reveals differences in both Tg glycosylation and iodination (50,51,52,53). These differences may change the molecular conformation of Tg and thereby mask or expose epitopes that alter its immunoactivity (53,54,55,56,57,58,59). In fact, the Tg found in the serum of some patients with thyroid carcinoma differs immunologically from that of normal subjects (51,56,60,61). [These differences have led to the development of several thyroid carcinoma–specific monoclonal Tg antibodies, although none of these antibodies are currently used for diagnostic purposes (61).] The differences can have clinical conse quences; in some patients with thyroid carcinoma, the iodine content of the Tg produced by the tumor is low, with the result that it reacts poorly in assays for serum Tg (55,57,58,60).

MEASUREMENT OF THYROGLOBULIN

Tg is most often measured in serum, but it can also be measured in cyst or pleural fluid and in fluid rinses of needles used for biopsy of neck masses. Its presence in cells or tissue sections can be detected by immunocytochemistry (62,63,64). These latter procedures can be helpful in determining whether a thyroid nodule is a thyroid epithelial carcinoma or a medullary thyroid carcinoma, and whether a neck or other mass is of thyroid or other origin.

Currently, serum Tg is measured by immunometric assay (IMA) or radioimmunoassay (RIA) techniques (2); among them, automated nonisotopic IMA methods are the most widely used. These IMA methods take little time, have a wide working range, and use reagents with a long shelf life (2,65). In contrast, RIA methods are manual, technically demanding, and take longer (2,65). The sensitivity of most current serum Tg assays is 0.5 to 1.0 µg/L (66,67,68). This level of sensitivity is not sufficient to allow reliable distinction between normal subjects and patients with no functioning thyroid tissue.

MEASUREMENTS OF SERUM THYROGLOBULIN IN THE ABSENCE OF THYROGLOBULIN ANTIBODIES

Measurement of serum Tg remains technically challenging, and current Tg assays have several serious limitations. One limitation is the large between-method variation in results, a variation that persists despite the recent availability of an International Reference Preparation (CRM-457) (69,70). Between-method variations are greater than within-person variations (~30% vs. ~15%, respectively), and therefore the same assay should be used during long-term follow-up of patients with thyroid carcinoma (2,68,71,72). Between-method variations are likely to persist because serum Tg is immunologically heterogeneous, especially because many Tg epitopes are conformational (59,61,73,74). Current Tg IMA methods using monoclonal capture antibodies may not recognize well the different forms of Tg that circulate in different patients (75,76). Furthermore, the serum Tg of patients may differ from the Tg extracted from normal thyroid tissue that is used as the standard in different assays, a problem not eliminated by the availability of the reference standard (51,53,56). In addition, any Tg that circulates complexed with its endocytotic receptor, megalin, may not be detected (38,39).

The second limitation of serum Tg assays is suboptimal sensitivity, so that the limit of detection is a little lower than the lower limit of the normal reference range (Fig. 14.2, left panel). The most important consequence of this limitation is that basal (unstimulated) serum Tg measurements cannot be used for the early detection of recurrent thyroid carcinoma (1,2,77). More sensitive assays are being developed (66,67). A 10- to 100-fold increase in sensitivity will likely allow detection of persistent and recurrent thyroid carcinoma without the need for stimulation testing with recombinant human TSH (1,66,67,78).

FIGURE 14.2. Serum thryoglobulin (Tg) concentrations in 88 normal subjects with no detectable serum anti-Tg antibodies (left panel) and 36 normal subjects with high serum anti-Tg antibody concentrations (right panel), as determined by five different methods: (1) RIA, University of Southern California, Los Angeles, CA, USA; (2) Nichols Bead IMA, Nichols Institute Diagnostics, San Juan Capistrano, CA, USA; (3) Nichols Advantage IMA, Nichols Institute Diagnostics, San Juan Capistrano, CA, USA; (4) Access IMA, Beckman-Coulter Co., Fullerton, CA, USA; and (5) Immulite IMA, Diagnostic Products Corporation, Los Angeles, CA, USA. Note the logarithmic scale of the y-axis. The shaded areas indicate the analytical sensitivity of the respective assay. The short bold horizontal lines indicate the median values, with the actual median values shown beside these lines. The symbols in the right panel indicate the results in individual subjects in each of the assays. (Reproduced from Spencer CA. New insights for using serum thyroglobulin (Tg) measurement for managing patients with differentiated thyroid carcinomas. Thyroid International 2003;4:1, with permission.)

MEASUREMENTS OF SERUM THYROGLOBULIN IN THE PRESENCE OF THYROGLOBULIN ANTIBODIES

The most serious limitation of all current methods for serum Tg assay is their susceptibility to interference by anti-Tg antibodies and, to a lesser extent, heterophile antibodies (2,79,80). Estimates of the prevalence of high serum anti-Tg antibody concentrations vary with the sensitivity and specificity of the detection method (79,81,82,83), but most studies suggest that approximately 10% of adults have high concentrations, and the frequency is twofold higher (~20%) in patients with thyroid carcinoma (see Chapter 15) (2,79,84). Given these results, anti-Tg antibodies should be measured in any serum sample in which Tg is to be measured, using immunoassay in preference to agglutination assays because of its greater sensitivity (2,79).

The presence, magnitude, and direction of the effect of anti-Tg antibodies on measurements of serum Tg measurement depend on the method of serum Tg assay (IMA or RIA), the specific reagents used, the assay conditions, and the characteristics of the serum anti-Tg antibodies (Fig. 14.2, right panel) (2,65,79,85,86). There appears to be no serum anti-Tg antibody concentration below which there is no interference (79,87). In IMA assays for serum Tg, the presence of anti-Tg antibodies in serum results is falsely low or undetectable serum Tg values (2,68), presumably because Tg complexed with anti-Tg antibodies in the serum sample cannot bind to the antibodies used in the IMA. In all of the IMA methods used to obtain the results shown in the right panel of Figure 14.2, some patients with serum anti-Tg antibodies had inappropriately low, and in some cases undetectable, serum Tg concentrations. In patients with thyroid carcinoma, a serum Tg value measured by IMA that is artifactually low because of the presence of anti-Tg antibodies can mask clinically important disease (2,79). IMA methods in which the presence of anti-Tg antibodies results in inappropriately low or undetectable serum Tg values are not suitable for monitoring patients with thyroid carcinoma, unless the presence of anti-Tg antibodies has been excluded by sensitive direct assays for anti-Tg antibodies (2).

One approach designed to overcome interference by anti-Tg antibodies in IMAs has been the use of monoclonal capture antibodies that selectively bind Tg epitopes not involved in thyroid autoimmune disease (88,89). [Epitope mapping of Tg has revealed Tg to have six different antigenic domains (regions 1 to VI), and the reactivity of serum anti-Tg antibodies in normal subjects and patients with thyroid disease with these different domains varies (90).] Unfortunately, anti-Tg antibodies still react in these modified IMAs, probably because of differences in epitope specificity and/or affinity of the anti-Tg antibodies in patients with thyroid carcinoma and those with other thyroid disorders (91,92). One reason for this variation is that the antigenicity of Tg relates to its iodine content (57,58,93); the anti-Tg antibodies produced by patients with nonneoplastic thyroid disorders often have specificity for epitopes close to the iodine (hormone)-rich regions of Tg (94), whereas the anti-Tg antibodies produced by patients with thyroid carcinoma lack this specificity because they are directed against Tg that is iodine-poor (95).

RIA methods for measuring serum Tg are less prone to interference by anti-Tg antibodies than IMA methods, but anti-Tg antibodies can cause falsely high or low serum Tg values in RIAs (79,85). In these assays, the magnitude and direction of the effects of anti-Tg antibodies are determined by the factors that affect the partitioning of Tg between the anti-Tg antibody used in the assay and the endogenous anti-Tg antibodies present in the serum (85). The usual effect of anti-Tg antibodies in serum Tg RIAs is to cause an artifactually high values. Discordance between serum Tg values measured by IMA and RIA, specifically low serum Tg values measured by IMA and high serum Tg values measured by RIA, is an indicator of the presence of serum anti-Tg antibodies (79).

Serum anti-Tg antibodies are usually measured directly by immunoassay, as noted above. They can also be measured indirectly, by determining the recovery of Tg added to the serum sample in vitro (if recovery is high, the serum sample presumably contains no anti-Tg antibodies, and vice versa). There is now consensus, however, that this is not an adequate test for serum anti-Tg antibodies, and that anti-Tg antibodies should be measured directly (2,79,87,96). Not all anti-Tg antibodies are detected by the recovery test, and, in addition, serial measurements of serum anti-Tg antibodies can be used as a surrogate marker for thyroid carcinoma, high values indicating persistent carcinoma and disappearance of the antibodies indicating elimination of all thyroid tissue (79,87,96,97,98).

SERUM THYROGLOBULIN CONCENTRATIONS IN NORMAL ADULTS

All normal subjects should have Tg detected in their serum, since some Tg is always cosecreted with T4 and T3 (2).

A measured serum Tg value is the result of three factors: the mass of thyroid tissue; the presence, if any, of thyroid damage caused by thyroiditis, surgery, hemorrhage, radiation injury, or chemicals or drugs; and the presence, or lack thereof, of TSH, chorionic gonadotropin, or TSH receptor–stimulating antibodies (11,78,99,100,101,102,103,104,105,106,107). Based on the result of twin studies, serum Tg concentrations are to some extent genetically determined, but the above factors are much more important (100,108). There is no diurnal or seasonal variation in serum Tg concentrations (71,100).

Serum Tg concentrations tend to be higher in women than in men (100); it is unclear whether this relates to the effects of estrogen or a higher prevalence of occult thyroid disorders in women (84,109,110). The difference is small, and therefore the same normal reference range is used for women and men (100,108). However, the reference ranges for different assays vary as a consequence of both pathophysiologic and methodologic factors (Fig. 14.2, left panel) (2).

There is a rise in serum Tg concentrations during the first trimester of pregnancy, caused by the high serum chorionic gonadotropin concentrations at that time; during the latter half of gestation, serum Tg concentrations return to pre-pregnancy values if iodine intake is adequate (see Chapter 80) (111,112,113). At delivery, maternal serum Tg concentrations are correlated with thyroid size as assessed by ultrasonography (111,113).

SERUM THYROGLOBULIN CONCENTRATIONS IN FETUSES, INFANTS, AND CHILDREN

Tg is present in the fetal thyroid by 8 weeks of gestation; iodine transport begins several weeks later. The appearance of Tg mRNA coincides with the appearance of the immature 12S Tg protein. Mature 19S Tg is detected later, coincident with iodination, which appears necessary for the aggregation of 12S to form 19S Tg (114). As gestation progresses, Tg iodination and intrathyroidal T4 content increase and approach adult levels at term (see Chapters 74 and 80). Birth weight and gestational age correlate positively with the cord serum concentrations of T4, T3, and free T4, but negatively with cord serum Tg and TSH concentrations (115,116). Cord serum Tg concentrations are higher than maternal serum Tg concentrations and are correlated positively with cord serum TSH concentrations (116,117).

In iodine-deficient areas, the deficient maternal iodine intake is associated with high cord serum TSH and Tg concentrations and increased thyroid volume (111,118), and cord serum Tg concentrations are negatively correlated with maternal urinary iodine excretion (111,116,119). Neonatal serum Tg concentrations are correlated with the serum T3/T4 ratio, but not serum TSH concentrations, suggesting that iodine availability affects the degree of Tg iodination and is an independent determinant of serum Tg concentrations at birth (119). Thyroid size and cord serum Tg concentrations are increased in infants born to mothers who smoke (120,121,122). These changes are thought to be secondary to a goitrogenic effect of thiocyanate, because its concentrations are positively correlated with cord and maternal serum Tg concentrations (123).

In normal full-term infants, serum Tg concentrations increase in the first days after birth, presumably in response to the postnatal surge in TSH secretion (124). This increase is attenuated in sick or preterm infants (125). During the first few months of life, serum Tg concentrations decrease by approximately 50%, and they continue to decline slowly throughout childhood to reach adult levels after puberty (126).

SERUM THYROGLOBULIN CONCENTRATIONS IN THYROID DISEASES

Serum Tg concentrations are high in patients with many thyroid disorders, including patients with any type of thyroid enlargement, autonomy, injury, or stimulation. Serum Tg concentrations are low in patients in whom the thyroid did not develop (thyroid agenesis) and those in whom the gland is destroyed or removed, or its function is suppressed.

Goiter

Patients with simple goiter may have high serum Tg concentrations. The values are usually independent of the patients' serum TSH concentration and markers of autoimmunity, but are correlated inversely with iodine content and intrathyroidal iodine stores (127,128,129,130,131,132). In contrast, patients with a multinodular goiter often have high serum Tg concentrations, and the concentrations are inversely correlated with serum TSH concentrations and positively correlated with goiter size (133). After thyroidectomy, serial measurements of serum Tg can be used to monitor goiter regrowth in these patients (103).

Serum Tg concentrations are high in many patients with iodine deficiency, even those who do not have high serum TSH concentrations (see section on iodine deficiency in Chapter 11). Measurements of serum Tg can be used to monitor the iodine status of populations (100,133,134,135,136,137,138).

Most patients with any type of goiter caused by an increase in TSH secretion, whether clinically euthyroid or hypothyroid, have high serum Tg concentrations. These patients include those with thyroid dyshormonogenesis secondary to molecular defects in thyroid hormone biosynthesis, except for those defecrts that result in defective thyroglobulin synthesis (see Chapter 48). They also include patients with goiter induced by drugs or environmental agents (see Chapter 50). The frequency of goiter is increased in patients with acromegaly. They also tend to have high serum Tg concentrations, and the concentrations are not correlated with serum TSH concentrations. In these patients, the goiter and high serum Tg concentrations are probably caused by insulin-like growth factor-1 (139).

Thyroid Nodular Disease

Patients with benign thyroid nodules, nonfunctioning and autonomously functioning thyroid adenomas, and multi nodular goiter may have normal or high serum Tg concentrations (103,133,134,140). In all these patients, serum Tg concentrations are correlated with the number and size of nodules and their functional activity; the values therefore tend to be higher in those patients with an autonomously functioning thyroid adenoma or a toxic multinodular goiter (see Chapters 25 and 69) (133,140,141,142,143,144,145).

In patients with a solitary nodule, serum Tg concentrations decline when nodule volume shrinks in response to T4 therapy (146,147). In patients at risk for thyroid nodules as a result of head or neck irradiation, a high serum Tg concentration is associated with an increased risk of a nodule during a 10-year follow-up period (142,148). Serum Tg concentrations correlate with the number, not the volume, of nodules present in these patients (142).

Thyrotoxicosis

Serum Tg concentrations are high in patients with thyrotoxicosis caused by excess secretion (hyperthyroidism) or release of T4 and T3, whether caused by Graves' disease, a TSH-secreting pituitary tumor, chorionic gonadotropin, a thyroid adenoma or multinodular goiter, or thyroid inflammation (101,149,150,151,152,153,154,155,156). However, serum Tg measurements in many (40% to 70%) patients with Graves' thyrotoxicosis are confounded by high serum anti-Tg antibody concentrations and their resulting effect in serum Tg assays (see above) (86,87,96,149,157). The only thyrotoxic condition in which serum Tg concentrations are low is that caused by exogenous thyroid hormone, whether iatrogenic or factitious (158,159).

Among patients with Graves' thyrotoxicosis, serum Tg concentrations usually decline in response to antithyroid drug treatment, probably as a consequence of a decrease in production of TSH receptor–stimulating antibodies and the resulting decrease in thyroid mass (149,150,151,160). The concentrations tend to remain high in those patients with persistent thyrotoxicosis, even when their serum T4 and T3 concentrations fall to normal in response to the antithyroid drug (149,150). Although serum Tg concentrations seem to be correlated better with the status of Graves' disease than thyroid secretion in these patients, the prognostic value of serum Tg measurements as a marker of the activity of Graves' disease is not high, because serum Tg concentrations are influenced by other factors such as goiter size, an increase in TSH secretion in response to antithyroid drug therapy, and interference by serum anti-Tg antibodies (see Chapter 45) (87,151,152).

Surgical or radioiodine treatment of patients with thyrotoxicosis results in acute (1- to 2-day) and chronic (1- to 3-month) increases in serum Tg concentrations secondary to surgical trauma and radiation-induced thyroid destruction, respectively (101,149,161).

Hypothyroidism

Measurements of serum Tg have little clinical value in the diagnosis or treatment of adults with hypothyroidism.

Patients with the most common cause of hypothyroidism, chronic autoimmune thyroiditis, may have normal or high serum Tg concentrations. However, many of them have high serum anti-Tg antibody concentrations (see Chapter 15), so that serum Tg cannot usually be measured accurately (2,87,162). Indeed, the antigenicity of iodine-rich Tg has been implicated in the initiation of this disorder (see Chapter 47). Serum Tg concentrations are low in most patients who have hypothyroidism after thyroidectomy, radioiodine, or external radiation therapy, or any disorder that destroys thyroid tissue (and that is not mediated by autoimmunity) (163,164). In any of these situations, the serum Tg value will depend on the amount of thyroid tissue remaining and the degree of elevation of TSH secretion. Serum Tg concentrations tend to be low in patients with central hypothyroidism.

Measurements of serum Tg do have value in the evaluation of infants with congenital hypothyroidism, because the results can help to identify the cause of hypothyroidism. Infants with thyroid agenesis have undetectable serum Tg concentrations, and the concentrations are low or undetectable in infants with central hypothyroidism; those with inactivating mutations of the TSH receptor, thyroid transcription factor-1, and the molecular chaperone proteins involved in the maturation of Tg; and mutations in Tg itself (if the protein cannot be exported into the circulation) (5,165,166,167,168). Infants with other causes of hypothyroidism, such as thyroid dysgenesis and other defects in thyroid hormone biosynthesis, have normal or high concentrations (see Chapter 48 and see section on congenital hypothyroidism in Chapter 75).

Thyroiditis

High serum Tg concentrations are a sensitive indicator of thyroid injury caused by both acute and chronic thyroid inflammation. They are, therefore, high in patients with subacute granulomatous thyroiditis (de Quervain's thyroiditis) and in those with silent (painless) thyroiditis (including postpartum thyroiditis) (see Chapters 27 and 28). In all these patients, the concentrations are highest during the thyrotoxic phase of the thyroiditis, but they also may be high during the hypothyroid phase, as a result of TSH stimulation. While recovery is usually complete, some of these patients may have high serum Tg concentrations for a year or two (107,169,170,171). There is a growing list of therapeutic agents (amiodarone, interferon-α, interleukin-2, and lithium) that induce thyroiditis closely mimicking silent thyroiditis (see section on effects of drugs and other substances on thyroid hormone synthesis and metabolism, and section on the effect of excess iodide in Chapter 11) (172,173,174,175,176).

Patients with thyrotoxicosis caused by silent thyroiditis can be distinguished from those with thyrotoxicosis caused by exogenous thyroid hormone by measurements of serum Tg; the values are high in the former and low in the latter (158,177). However, patients with silent thyroiditis may have high serum anti-Tg antibody concentrations during their illness, and women with postpartum thyroiditis usually have high serum anti-Tg antibody concentrations before the onset of thyroiditis. The presence of high serum anti-Tg antibody concentrations may predispose patients to drug-induced thyroiditis.

Thyroid Carcinoma

Most differentiated thyroid carcinomas produce Tg, although their content of Tg messenger RNA (mRNA) transcripts tends to be lower that that of normal thyroid tissue (178,179,180). The content of Tg mRNA and Tg protein in thyroid carcinomas varies and correlates poorly with serum Tg concentrations (181,182,183,184). Rarely, medullary carcinomas express both calcitonin and Tg (185,186). Anaplastic thyroid carcinomas produce little Tg, and among differentiated carcinomas its production is correlated with the degree of differentiation of the tumor (179,187). As these carcinomas dedifferentiate, expression of sodium iodide symporters and TSH receptors disappears before expression of Tg, so that the patients have detectable serum Tg concentrations, but their tumors do not concentrate radioiodine (188,189,190,191,192,193,194).

Many patients with thyroid carcinoma, especially those with follicular carcinoma, have high serum Tg concen trations at the time of diagnosis (195,196). However, measurements of serum Tg do not aid in the diagnosis of thyroid carcinoma, because many patients with benign nodules also have high serum Tg concentrations (195). In patients with thyroid carcinoma, preoperative serum Tg concentrations are correlated with the degree of differentiation and extent of tumor (193,195,196,197,198); patients with metastases, especially bony metastases, have the highest (often > 1000 µg/L) serum Tg concentrations (199,200). A high serum Tg concentration at this time suggests not only that the tumor produces Tg, but also that postoperative measurements of serum Tg will be useful for monitoring changes in tumor burden (99,201). The difference between pre- and postoperative serum Tg values provides an indicator of the completeness of surgery, and patients with more extensive disease tend to have higher postoperative serum Tg concentrations (99,202,203).

After thyroidectomy and radioiodine therapy, patients are monitored indefinitely for recurrent disease using serial serum Tg measurements, in conjunction with a variety of imaging techniques (see section on radioiodine therapy and other treatments and outcomes in Chapter 70) (203,204,205). In this regard, measurements of serum Tg have proven very useful, and indeed their main value is in the follow-up of patients with thyroid carcinoma. The specificity of postoperative serum Tg monitoring for detection of recurrent carcinoma is highest in patients with no residual normal thyroid tissue (201,206). However, this monitoring is also valuable in patients who were treated with surgery and radioiodine but in whom the thyroid remnant was not destroyed (207,208).

In patients with thyroid carcinoma, postoperative serum Tg concentrations should be interpreted relative to the reference values of the assay used, the extent of surgery, whether radioiodine was given, and the patient's serum TSH concentration (Fig. 14.3)(2,202). In particular, serum Tg values cannot be interpreted without knowing the patients' serum TSH concentration and whether they were given TSH. In patients who have detectable serum Tg concentrations while receiving T4 therapy, serum Tg concentrations increase from 3- to 100-fold in response to TSH administration (1,68,78,209,210,211,212,213,214,215,216).

FIGURE 14.3. Expected serum thyroglobulin (Tg) concentrations as a function of thyroid mass and changes in serum TSH concentrations in normal subjects [mean (±SD) serum Tg concentration, 13.5 µg/L; range, 3 to 40 µg/L], normal subjects taking T4 to inhibit TSH secretion (maximal serum Tg value, 20 µg/L), and patients with differentiated thyroid carcinoma (DTC) after thyroid lobectomy (maximal serum Tg value, < 10 µg/L), after near-total thyroidectomy (Nr. Total Tx.) (maximal serum Tg value, < 2 µg/L), and after thyroidectomy and radioiodine therapy (Athyreotic) (maximal serum Tg value, 1 µg/L). Normal thyroid mass, 10 to 15 g, i.e., 1 g normal thyroid tissue, produces ~1 µg Tg/L of serum when the serum TSH concentration is ~1.3 mU/L, and it produces ~0.5 µg Tg/L of serum when the TSH concentration is < 0.1 mU/L. (From Baloch Z, Carayon P, Conte-Devoix B, et al. Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13:3, modified with permission.)

Approximately 80% of patients with thyroid carcinoma have an undetectable postoperative serum Tg concentration (< 1 µg/L, using current Tg methodology) while being treated with T4 (7). In approximately 20% of these patients, serum Tg will be detectable after T4 is stopped or they are given TSH (1). These patients must be evaluated further, by ultrasonography of the neck and radioiodine and other imaging procedures, for possible recurrent carcinoma (1,217). Not all of them have recurrent carcinoma. In some, the rise in serum Tg concentration results from stimulation of normal thyroid tissue that was not destroyed by previous surgical and radioiodine therapy (206,218,219). In others, ultrasonography and diagnostic radioiodine imaging studies reveal no evidence of recurrent carcinoma (1,220,221,222,223).

Some of these patients have disease revealed by scanning after high-dose radioiodine therapy (221,222,223,224,225). False-negative radioiodine scans are characteristic of more poorly differentiated carcinomas that concentrate little if any iodine because of a loss of sodium iodide symporters and TSH receptors (188,189,190,191,192,193,194). These poorly differentiated carcinomas may be detected by positron emission tomography after administration of 18-F-fluorodeoxygluose (226,227).

Notwithstanding these inconsistencies between the results of serum Tg measurements and other tests for detecting recurrent thyroid carcinoma, the overall value of serum Tg measurements, particularly serum Tg measurements after endogenous or exogenous TSH stimulation, as a marker of thyroid carcinoma is high. Among over 1000 patients who had serum Tg concentrations < 1 µg/L while taking T4, approximately 80% had no increase in serum Tg in response to TSH stimulation, and may be considered free of disease (Fig. 14.4). Among the approximately 20% who had a rise in serum Tg in response to TSH stimulation, less than half had evidence of recurrent carcinoma (8.7% of those with unstimulated serum TSH concentrations < 1 µg/L) (1,211,212,213,214,215,216,217). In the future, more sensitive serum Tg assays are likely to make it unnecessary to stop T4 therapy or administer TSH before measuring serum Tg during follow-up of patients with thyroid carcinoma.

FIGURE 14.4. Diagram summarizing the results of measurements of serum thyroglobulin (Tg) and anti-Tg antibodies (TgAb) in 1285 patients (from eight studies) with thyroid carcinoma considered at low risk of recurrence after thyroidectomy and radioiodine therapy. All patients were receiving T4 therapy (L-T4 Rx.) in doses sufficient to suppress TSH secretion to below normal (THST). The patients who had undetectable serum Tg concentrations (< 1.0 µg/L) received recombinant human TSH (rhTSH) and then underwent radioiodine scanning (RAI Scan) and measurement of serum Tg. Further study was based on the results of these tests. (From Mazzaferri EL, Robbins RJ, Spencer CA, et al. A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 2003;88:1433; Haugen BR, Pacini F, Reiners, C, et al. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999;84:3877; David A, Blotta A, Bondanelli M, et al. Serum thyroglobulin concentrations and (131)I whole-body scan results in patients with differentiated thyroid carcinoma after administration of recombinant human thyroid-stimulating hormone. J Nucl Med 2001;42:1470; Giovanni V, Arianna LG, Antonio C, et al. The use of recombinant human TSH in the follow-up of differentiated thyroid cancer: experience from a large patient cohort in a single centre. Clin Endocrinol (Oxf) 2002;56:247; Haugen BR, Ridgway EC, McLaughlin BA, et al. Clinical comparison of whole-body radioiodine scan and serum thyroglobulin after stimulation with recombinant human thyrotropin. Thyroid 2002; 12:37; Mazzaferri EL, Kloos RT. Is diagnostic iodine-131 scanning with recombinant human TSH useful in the follow-up of differentiated thyroid cancer after thyroid ablation? J Clin Endocrinol Metab 2002:87:1490; Pacini F, Molinaris E, Lippi F, et al. Prediction of disease status by recombinant human TSH-stimulated serum Tg in the postsurgical follow-up of differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001;86:5686; Robbins RJ, Chon JT, Fleisher M, et al. Is the serum thyroglobulin response to recombinant human thyrotropin sufficient, by itself, to monitor for residual thyroid carcinoma? J Clin Endocrinol Metab 2002; 87:3242; and Wartofsky L. Management of low-risk well-differentiated thyroid cancer based only on thyroglobulin measurement after recombinant human thyrotropin. Thyroid 2002;12: 583, with permission.)

MEASUREMENT OF THYROGLOBULIN MRNA IN PERIPHERAL BLOOD

Tg mRNA transcripts can be detected in peripheral blood by molecular biologic techniques, suggesting that measurements of Tg mRNA could be used as a tumor marker in patients with thyroid carcinoma in whom serum Tg cannot be measured because of the presence of anti-Tg antibodies (182,228). Tg mRNA has been measured by quantitative reverse transcriptase-polymerase chain reaction in both peripheral blood and cervical lymph node metastases using different Tg primers (229,230,231). The blood levels of Tg mRNA are TSH-dependent, but do not correlate with thyroid pathology (231,232). Tg mRNA is always detected in peripheral blood of normal subjects and in patients with an intact thyroid gland; patients with metastatic thyroid carcinoma may or may not have detectable levels (181,182,229,231,233). The false-negative Tg mRNA results could be due production of fewer Tg transcripts or production of splice-variant forms of Tg mRNA (4,180). Conversely, false-positive Tg mRNA results have been found in patients with no thyroid tissue, including patients with congenital athyreosis, raising the question of tissue specificity of the origin of Tg mRNA (181,233,234).

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