TgAbNegativeDTC Patients

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Over the last three decades, many studies have reported that elevated endogenous TSH, or the administration of bovine TSH, increases the serum Tg concentration [104,105]. It is well established that TSH stimulation enhances the sensitivity of using Tg measurements to detect disease [6,8,106,107]. Recently, rhTSH-stimulated Tg testing has become preferred to the practice of withdrawing thyroid hormone to raise endogenous TSH, with its attendant hypothyroid symptoms [108]. There is growing consensus that rhTSH-stimulated Tg testing is superior for detecting recurrent disease compared with diagnostic RAI imaging, even though the serum Tg response to rhTSH administration is only half of the response to the rise in endogenous TSH following thyroid hormone withdrawal [6,20,59,67,68,70,109,110]. There is a linear, approximate 10-fold relationship between the basal (THST) and 72-hour rhTSH-stimulated serum Tg concentrations of both normal control subjects and patients with DTC, as shown in Figure 18.4 [6,72,111,112]. This is in accord with the factors known to influence the degree of TSH-stimulated Tg response, which include: (1) the magnitude and chronicity of the TSH elevation; (2) the mass of remnant thyroid tissue present, and (3) the mass and TSH responsiveness of the tumor [6,72,113]. However, the magnitude of the rhTSH-stimulated response varies considerably among patients (threefold to >20-fold) [6,111,112]. This may relate to differences in body surface area and/or reflect the tumor's intrinsic sensitivity to TSH [6,72,113,114]. Since poorly differentiated tumors display blunted

(less than threefold) increases in serum Tg in response to TSH stimulation, in the future, the magnitude of the rhTSH-stimulated Tg response may prove to be a useful indicator of the tumor's dependence on TSH and thus the efficacy of TSH suppression therapy [72,113]. Because the rhTSH-stimulated Tg response is predictable, rhTSH administration only improves the clinical sensitivity of Tg testing when the basal serum Tg is undetectable during THST. As more sensitive Tg assays become available, the clinical sensitivity of measuring serum Tg during THST will improve (Figure 18.2) and the need for rhTSH stimulation will decline, analogous to the elimination of routine TRH testing after the adoption of more sensitive TSH assays [18,19,115].

When recombinant human TSH was approved for clinical use a 72-hour post rhTSH-stimulated serum Tg value of >2 mg/L was established as the cutoff for a positive response suggestive of disease [6]. Since then, there has been growing recognition that this cutoff level compromises the clinical sensitivity of rhTSH-stimulated Tg testing. Specifically, serum Tg concentrations in the 1-2 mg/L range are close to the lower reference limit for healthy euthyroid subjects with intact thyroid glands, thus making it increasingly difficult to discern between true disease and normal remnant tissue [6,10,20]. It has been recommended that a more conservative rhTSH-stimulated serum Tg cutoff of >1 mg/L should be adopted [69,114].

Figure 18.4 Relationship between the mean basal (THST) serum Tg concentration and the mean 72-hour rhTSH-stimulated serum Tg.Tests were grouped according to the basal Tg concentration. G1 had basal Tg between 0.05 and 0.1 mg/L; G2 between 0.2 and 0.3 mg/L; G3 between 0.1 and 0.2 mg/L; G4 between 0.3 and 0.5 mg/L; G5 between 0.5 and 1.0mg/L; G6 between 1 and 2 mg/L; G7 between 2 and 5mg/L; G8 between 5 and 10mg/L; and G9 was >10 mg/L.

Figure 18.4 Relationship between the mean basal (THST) serum Tg concentration and the mean 72-hour rhTSH-stimulated serum Tg.Tests were grouped according to the basal Tg concentration. G1 had basal Tg between 0.05 and 0.1 mg/L; G2 between 0.2 and 0.3 mg/L; G3 between 0.1 and 0.2 mg/L; G4 between 0.3 and 0.5 mg/L; G5 between 0.5 and 1.0mg/L; G6 between 1 and 2 mg/L; G7 between 2 and 5mg/L; G8 between 5 and 10mg/L; and G9 was >10 mg/L.

Figure 18.5 Meta-analysis of eight studies [68,110,117,141-144] showing the outcome of rhTSH-stimulated serum Tg testing of 784 patients with undetectable serum Tg during thyroid hormone suppression therapy (THST) [20].

With this lower cutoff, 20% of patients with undetectable (<1 mg/L) serum Tg during THST display detectable serum Tg after rhTSH stimulation [6,20,56]. One important drawback of rhTSH-stimulated serum Tg testing is the high number of patients who have rhTSH-stimulated serum Tg in the 1-10 mg/L range and no evidence of disease [20,57,63,116,117]. In fact, the adoption of the <1 mg/L cutoff is associated with ~15% false-positive responses [20,57,70]. Conversely, ~3% of patients with disease have false-negative rhTSH-stimulated Tg responses because the insensitivity of current Tg assays compromises the clinical sensitivity of Tg testing even when rhTSH stimulation is employed [57,70]. In a recent meta-analysis of 784 patients, ~8% of patients with serum Tg <1 mg/L during THST had disease unmasked by rhTSH-stimulated Tg testing (Figure 18.5) [20]. Most (~5%) of the disease was located in lymph nodes and likely could have been detected by ultrasound, suggesting that few patients would have disease revealed by rhTSH-stimulated Tg testing alone [20,57,63,70]. In fact, it is becoming apparent that rhTSH-stimulated Tg testing has a low positive predictive value for disease and that the addition of ultrasound to Tg measured during THST dramatically improves the sensitivity and specificity of monitoring patients for recurrent disease [57,63,70,117]. Since only a minority of patients with negative clinical and/or ultrasound examinations have persistent or recurrent disease detected during follow-up, it is not surprising that only a small percentage of patients have disease unmasked by rhTSH-stimulated Tg testing [57,63]. It follows that the high cost and low yield of rhTSH-stimulated serum Tg testing will increasingly raise questions concerning the cost-benefit ratio of using rhTSH stimulation for diagnostic testing as the sensitivity of Tg methodology improves [18,19,118].

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