Presurgical serum thyroglobulin has no prognostic value in papillary thyroid cancer.

We investigated whether serum thyroglobulin determination before surgery for differentiated thyroid carcinoma may have any prognostic value with regard to tumour extension and disease outcome in a retrospective series of 71 patients with papillary thyroid cancer. Presurgical serum thyroglobulin levels were correlated with the size of the primary tumoral nodule (p = 0.006) and of the whole thyroid (p = 0.02). The same correlation was found in a control group of patients with benign thyroid nodules, confirming that presurgical serum thyroglobulin cannot be used for the differential diagnosis of thyroid carcinoma. Presurgical serum thyroglobulin levels did not differ among patients with tumor limited to thyroid gland or extending to cervical lymph nodes or invading outside the thyroid capsule or metastasising to distant size. In addition presurgical serum thyroglobulin levels were not correlated with the disease outcome after a mean follow-up of 9 years: no difference was found among patients in complete remission or with persistent disease or dead from thyroid cancer. In conclusion, this study failed to show any prognostic value of presurgical serum thyroglobulin determination that consequently should not be measured.     

Prognostic value of serial serum thyroglobulin determinations after total thyroidectomy for differentiated thyroid cancer

Serial weekly serum samples (for 3 weeks) were obtained from 42 patients with differentiated thyroid cancer (DTC, papillary no.=35, follicular no.=6, Hurthle cell no.=1) for serum thyroid hormone, TSH and TG before and after total thyroidectomy. Serum specimens were also obtained one month after radioiodine (131I) therapy followed by suppressive dose of L-thyroxine (L-T4, 2.5 microg/kg). The patients were subdivided into four groups: group I: the DTC was confined to a single solid nodule (no.=1 2); group II: thyroid malignancy invaded local cervical structures but there were no lymph node metastases (no.=8); group III: DTC with lymph node metastases (no.=6); and group IV: DTC with distant metastases (no.=16). In all group I patients serum TG remained undetectable in spite of elevated serum TSH levels at the 3rd week post-surgery (PS). Only one of group II patients had a detectable serum TG value of 5.2 ng/ml (3rd week PS). By contrast, 37.5% of group III patients had detectable serum TG levels, ranging from 3.4 to 16.8 ng/ml (3rd week PS). Lymph node metastases were detected in 5 of these patients by whole body scan (WBS) and removed surgically in 3. As expected, group IV patients had elevated serum TG values ranging 33.0-958.0 ng/ml and distant metastases were confirmed in all of them by WBS. From the calculations through univariate logistic regression comparing TG concentrations at the 3rd week PS from groups I and II vs groups III and IV, we obtained a cut-off value of 2.3 ng/ml with the following efficacy features: sensitivity=74.5%; specificity=95%; positive predictive value=92.3%; negative predictive value=65.5%; and accuracy=73.8%. After 131I and L-T4 suppressive therapy, only 5 out of 36 patients of groups I, II and III had detectable serum TG levels (3.1-7.0 ng/ml) whereas serum TG was detectable in all group IV patients (ranging 2.5-8.6 ng/ml). We concluded that serum TG concentrations above 2.3 ng/ml at the 3rd week PS could be suggestive of lymph node or distant metastases in patients with DTC. Patients with serum TG above this limit could be considered at risk for metastatic disease and higher doses of diagnostic iodine-131 (131I) may be indicated for actinic ablation.     

Diagnostic value of serum thyroglobulin measurements in the follow-up of differentiated thyroid carcinoma, a structured meta-analysis

OBJECTIVE: To investigate to what extent thyroid remnant ablation and withdrawal from thyroxine are required to achieve sufficient accuracy of serum thyroglobulin (Tg) measurements as an indicator of tumour recurrence in the follow-up of patients with differentiated thyroid carcinoma. DESIGN AND METHODS: We conducted a meta-analysis of the literature from 1975 to 2003 on serum Tg measurements in the follow-up of differentiated thyroid carcinoma. In a computer-based search, we initially found 915 articles that were finally narrowed down to 120. These 120 papers were subjected to strict in/and exclusion criteria, leaving 46 articles (totalling 9094 patients). Data from these articles were extracted in a structured fashion and were grouped according to initial therapy, TSH status, Tg assay method and definition of a 'gold standard'. Original 2 x 2 tables were pooled by summary receiver operating characteristic curve analysis (sROCa), best estimates of sensitivity and specificity being obtained by the combination of sROCa and Mantel-Haenszel odds ratios. RESULTS: Despite considerable differences between series in laboratory and clinical methodology, we consistently found higher specificity for Tg measurements after thyroid remnant ablation than after surgery alone. Highest pooled sensitivity 0.961 +/- 0.013 (SE) was found for immunometric assay (IMA) after thyroid remnant ablation and thyroid hormone withdrawal, at a specificity of 0.947 +/- 0.007. Pooled sensitivity decreased significantly if ablated patients were tested while on thyroid hormone (0.778 +/- 0.023, at a specificity of 0.977 +/- 0.005). Significantly decreased pooled specificity was found in patients who did not undergo remnant ablation (sensitivity 0.972 +/- 0.023, at a specificity of 0.759 +/- 0.028). If recombinant human TSH (rhTSH) stimulation was used as a substitute for thyroxine withdrawal, sensitivity remained high (0.925 +/- 0.018) while specificity decreased to 0.880 +/- 0.013. In all analyses, specificity of Tg would decrease when unspecified activity in the thyroid region at scintigraphy was considered benign, whereas sensitivity decreased when such activity was considered malignant. CONCLUSION: This study confirms that the best accuracy of Tg-guided follow-up in patients treated for differentiated thyroid carcinoma is obtained if treatment includes remnant ablation, and Tg testing is performed while off thyroxine.     

Limited value of repeat recombinant human thyrotropin (rhTSH)-stimulated thyroglobulin testing in differentiated thyroid carcinoma patients with previous negative rhTSH-stimulated thyroglobulin and undetectable basal serum thyroglobulin levels

CONTEXT: One year after initial treatment, low-risk differentiated thyroid cancer (DTC) patients undergo recombinant human (rh)TSH-stimulated serum thyroglobulin (Tg) (rhTSH-Tg) and neck ultrasound (US). OBJECTIVE: The need for more rhTSH-Tg in these patients is controversial. We evaluated the utility of a second rhTSH-Tg in DTC patients 2-3 yr after their first evaluation. RESULTS: At the first rhTSH-Tg, basal and stimulated serum Tg was undetectable in 68 of 85 patients. Neck US was unremarkable in all but one, who had evidence of lymph node disease. Seventeen of 85 patients had undetectable serum Tg that became positive after rhTSH, with negative imaging in 10 and evidence of disease in seven. Patients with no evidence of disease were reevaluated 2-3 yr later (second rhTSH-Tg). In patients in which the first stimulated Tg was undetectable, all had undetectable basal serum Tg, which remained undetectable after rhTSH in 66 of 67 patients (98.5%) and became detectable in one (1.5%) (positive neck US). In the 10 patients with detectable stimulated Tg in the first test, basal serum Tg and US were negative at the second test, but rhTSH-Tg became detectable in six. Compared with the first rhTSH-Tg, the second stimulated Tg in these six patients decreased in one, increased in three, and stabilized in two patients. CONCLUSIONS: The second rhTSH-Tg was informative in patients who had first stimulated Tg detectable but not in those who had undetectable Tg at the first test, in which the only patient with recurrence was diagnosed by neck US. Thus, rhTSH-Tg should be repeated only in patients who have had a positive first rhTSH-Tg and negative imaging.     

European interlaboratory comparison of serum thyroglobulin measurement

A European interlaboratory comparison of serum thyroglobulin measurements was performed after an initiative from the European Organization of Research and Therapy of Cancer. Fifty-two laboratories were addressed and 45 of these (83%) participated in the study by measuring serum thyroglobulin and its autoantibody in 5 thyroglobulin containing sera. Thyroglobulin antibodies were added to two of the sera. Two commercial kits were used by a large number of the laboratories (11 and 8, respectively). Each kit showed a reasonably low interlaboratory coefficient of variation at concentrations above 25 micrograms/l, but with discrepancy between the methods. The remaining miscellaneous methods (24) showed a variation above 65% in all samples. In all laboratories the addition of thyroglobulin antibodies resulted in false thyroglobulin measurements with either elevated or depressed levels. It is concluded that a reference calibrator for serum thyroglobulin is strongly needed as the first essential step towards interlaboratory standardization of serum thyroglobulin, thereby opening a possibility for multicentre studies of its value in the post-therapy follow-up of patients with differentiated thyroid carcinoma.     

影响血清甲状腺球蛋白水平因素的流行病学研究

目的 研究不同因素对≥14周岁人群血清甲状腺球蛋白(TG)水平的影响。方法 选择碘缺乏、碘充足和碘过量的3个农村社区,测定3地区甲状腺球蛋白抗体(TGAb)阴性的3335例居民的血清TG、促甲状腺激素(TSH)水平和甲状腺体积(B超法)。结果 在尿碘中位数(MUI)80—650μg/L人群中,血清TG浓度呈现一个V型变化,即碘缺乏和碘过量状态都可以导致血清TG的升高;血清TSH浓度与血清TC浓度也呈现V型的关系,即血清TSH低于0．3mU／L时,血清TG显著升高;血清TSH高于4．8mU／L时,血清TG也显著升高;甲状腺的体积与血清TG的水平呈现明显正相关的关系;女性的血清TG浓度显著高于男性;年龄对血清TG的影响仅发生在碘缺乏地区,50岁以上人群的血清TG水平显著增高。结论 性别、碘摄入量、血清TSH浓度和甲状腺体积因素影响血清TG浓度。     

Identification of thyroid hormone residues on serum thyroglobulin: a clue to the source of circulating thyroglobulin in thyroid diseases

Thyroglobulin (Tg) present in the serum of normal individuals and patients with thyroid disorders could be partly newly synthesized non-iodinated Tg and partly Tg containing iodine and hormone residues originating from the lumen of thyroid follicles. With the aim of examining the contribution of the latter source of Tg to the elevation of serum Tg concentration in thyroid pathophysiological situations, we devised a procedure to identify thyroxine (T4) and tri-iodothyronine (T3) residues on Tg from unfractionated serum. A two-step method, basedon (i)adsorption of Tg on an immobilized anti-human Tg (hTg) monoclonal antibody (mAb) and (ii)recognition of hormone residues on adsorbed Tg by binding of radioiodinated anti-T4 mAb and anti-T3 mAb, was used to analyze serum Tg from patients with either Graves' disease (GD), subacute thyroiditis (ST) or metastatic differentiated thyroid cancer (DTC). Purified hTg preparations with different iodine and hormone contents were used as reference. Adsorption of purified Tg and serum Tg on immobilized anti-hTg mAb ranged between 85 and 90% over a wide concentration range. Labeled anti-T4 and anti-T3 mAbs bound to adsorbed purified Tg in amounts related to its iodine content. Tg adsorbed from six out of six sera from ST exhibited anti-T4 and anti-T3 mAb binding activities. In contrast, significant mAb binding was only observed in one out of eight sera from untreated GD patients and in 1 out of 13 sera from patients with DTC. The patient with DTC, whose serum Tg contained T4 and T3, represented a case of hyperthyroidism caused by a metastatic follicular carcinoma. In conclusion, we have identified, for the first time, T4 and T3 residues on circulating Tg. The presence of Tg with hormone residues in serum is occasional in GD and DTC but is a common and probably distinctive feature of ST.     

A radioimmunoassay for murine thyroglobulin in serum: age-related increase of serum thyroglobulin levels in AKR/J mice

Possible regulation of the synthesis of murine thyroglobulin (mTg) and a possible role for the major histocompatibility complex in this process were evaluated in 18 inbred strains of mice. A double antibody RIA was first developed to measure mTg in serum. The isolated mTG was labeled with 131I since 125I rapidly degraded the mTg molecule. The sensitivity of this mTg assay allowed detection of 15-20 ng/ml. Specificity was demonstrated by the minimal cross-reactivity with rat Tg (0.008%) and the total lack of cross-reactivity with human Tg. There was no correlation between H-2 haplotype and serum mTg levels. In five strains of mice with the H-2k haplotype, mTg levels varied from 30 +/- 2 to 48 +/- 11 ng/ml (mean +/- SD); however, only aged AKR/J mice (H-2k) exceeded this range (196 +/- 27 ng/ml). Strains with other haplotypes (a, b, d, g, q, v) demonstrated a similar range of mTg levels, but none had this age-related increase in mTg levels. The high levels of mTg were not caused by a decrease in the half-life of this protein and probably not caused by virus-induced alterations in the thyroid economy. Thyroids from the AKR/J mice, however, had larger follicles and flatter epithelia compared to thyroids from other strains. These studies suggest that AKR/J mice may represent a useful animal model for the study of goitrogenesis.     

Decreased serum thyroglobulin levels in the late stage of pregnancy

Serum thyroglobulin levels were serially measured in 25 normal pregnant women to evaluate thyroidal activity during normal pregnancy. Measurements included serum T3, T4, free T4, TBG, and TSH. Tg and FT4 levels were found to be decreased in the third trimester when compared with those of the first trimester and with those of normal non-pregnant individuals (P less than 0.01). TSH levels were higher than normal in pregnant women at all stages of pregnancy, with a significant rise at the third trimester. These findings suggest the presence of a subclinical hypothyroid state in the late stage of normal pregnancy.     

血清抗甲状腺球蛋白抗体对分化型甲状腺癌术后复发/转移的诊断价值

目的 评价甲状腺组织完全去除后当血清甲状腺球蛋白(TG)阴性时,抗甲状腺球蛋白抗体(TGAb)对分化型甲状腺癌(DTC)的诊断价值,确定TGAb的诊断临界点.方法 选择169例术后病理诊断为DTC,残留甲状腺组织已完全去除,TG阴性、TGAb阳性的患者,将其分为:复发/转移组(A组)59例和无复发/转移组(B组)110例.以电化学发光法测定血清TG、TGAb水平,根据其TGAb值进行受试者工作特征(ROC)曲线及不同阈值的阳性分层似然比分析.结果 A组的TGAb值(1 368±1 343)IU/ml明显高于B组(154±539)IU/ml(P＜0.01).ROC曲线下面积为0.945(P＜0.01),说明TGAb对这类患者具有较高的诊断价值.诊断临界点为204 IU/ml,其敏感度、特异度分别为91.50%、89.10%,与金标准相比较,诊断效率差异无统计学意义(P=0.143),吻合度较强(k=0.785,P＜0.01).当验前概率固定且排除其它混杂因素作用,TGAb＞1 000 IU/ml发生复发/转移的可能性为204 IU/ml≤TGAb≤1 000 IU/ml的1.12倍、100 IU/ml≤TGAb＜204 IU/ml的4.03倍、10 IU/ml≤TGAb＜100 IU/ml的24.79倍.结论 TGAb可作为监测术后残留甲状腺组织已完全去除且TG阴性TGAb阳性DTC患者发生复发/转移的指标,其诊断临界点为204 IU/ml.TGAb值越高,发生复发/转移的可能性越大.