Low Thyroglobulin Research Articles

The Value of Postoperative Baseline Serum Thyroglobulin in Prediction of the Outcome of Radioactive Iodine-131 Thyroid Ablation in differentiated thyroid carcinoma

Background: Thyroglobulin is commonly used to monitor patients with differentiated cancer thyroid. It has also become an excellent biological marker for tumor persistence or recurrence. Aim ofstudy: To study the relation between the level of baseline serum thyroglobulin (TG) and thyroid remnant ablation outcome using radioactive iodine-131 (RAI-131) in patients with differentiated thyroid cancer after surgical treatment.Methods: A prospective study involved 64 patients (age 20-77 years) with differentiated thyroid cancer, referred for post-surgical 131I ablation. All patients performed baseline serum TG, anti-TGAb's under TSH stimulation as well as neck ultrasonography, before receiving RAI-131ablation dose 1110 - 3700 MBq (30 -100 mCi). Follow-up was performed 6-8 months later. Successful ablation was determined by negative whole body 131I scan, negative neck ultrasonography and stimulated serum thyroglobulin level less than 2 ng/mL. Results: Successful ablation was reported in 38 out of 64 cases (59.4 %). Baseline serum thyroglobulin level was significantly predictive of ablation outcome. ROC analysis showed AUC (area under curve) of 0.66 (CI: 0.53 - 0.78; P = 0.03). A cutoff value of 4.4 ng/ml showed sensitivity of 79 % and specificity of 68% in predicting ablation outcome. Patients were divided into high (n = 32) and low (n = 32) baseline TG groups using this cut-off point. Successful ablation significantly higher in low TG group (25/32 vs. 13/32; P=0.002). There was no significant difference between the two groups regarding their clinical and pathological data. Conclusion: Baseline serum thyroglobulin is associated with ablation outcome. Serum TG> 4.4 is linked to significantly higher rates of unsuccessful ablation.

Sustained and Diffuse 131I Avid Bone Metastases With Low Thyroglobulin Levels in a Patient With Papillary Thyroid Carcinoma

A 63-year-old man with papillary thyroid carcinoma (PTC) and bone metastases was treated with 131I residual thyroid ablation (RTA) and 2 repeated post-ablation 131I therapies after total thyroidectomy. 131I whole-body scans (WBS) demonstrated sustained and diffuse 131I avid bone metastases, accompanied by persistent very low thyroglobulin (Tg) levels and negative antithyroglobulin antibody (TgAb) in post-ablation 131I therapies in hypothyroid state after levothyroxine withdrawal. The spread of bone metastases were found on the last therapeutical 131I WBS. The benefit of 131I therapy after levothyroxine withdrawal should be weighed even if the metastases are 131I avid in poorly differentiated thyroid carcinoma.

An unusual presentation of the TENIS syndrome

IntroductionPapillary carcinoma is the commonest subtype of thyroid cancer. Patients are treated with radioactive iodine (RAI), and monitored with RAI scans, serum thyroglobulin levels, and cervical ultrasonography. Elevated serum thyroglobulin despite a negative RAI scan is termed the TENIS syndrome (Truncated Expression of the NIS; NIS represents the sodium-iodide symporter). Alternative imaging is then indicated. Method/ResultA female Caucasian patient with papillary thyroid carcinoma had been followed up at our Thyroid Cancer clinic. A diagnostic scan revealed residual thyroid tissue. RAI ablation of the thyroid remnant was performed with 80mCi of RAI. Two- and five-year follow-up scans were clear. However, thyroglobulin levels remained high, thus a diagnosis of TENIS syndrome was made.An F-18 FDG PET/CT scan was performed which demonstrated inhomogeneous liver uptake (SUV>6). Abdominal CT confirmed multiple liver lesions; ultrasound-guided FNA of these revealed several groups of malignant cells. ConclusionPersistently elevated thyroglobulin levels in the presence of a negative whole-body RAI scan are of great concern. In this patient with unusual liver metastases from papillary thyroid cancer, and relatively low thyroglobulin levels despite significant metastases, F-18 FDG PET/CT has once more proved its efficacy in the evaluation of patients with the TENIS syndrome.

The Effects of TSH level on the Results of F-18 FDG PET/CT in Recurrent Differentiated Thyroid Carcinoma Patients with Elevated Serum Thyroglobulin Level and Negative I-131 WBS.

Purpose : To assess the effects of TSH level on F-18 FDG PET-CT results & its impact on serum thyroglobulin (TG) cut off point and management in recurrent DTC patients with elevated TG level & negative I-131 WBS. Materialand Methods: This prospective work involved 38 histopathologically proved DTC patients underwent total thyroid ablation with elevated serum TG and negative I-131 WBS during follow up. F-18 FDG was done in all patients using standard technique. Results: Patients divided into two groups: (I) Stimulated TSH group (i.e. TSH level > 30 IU/L, 60 ± 20 IU/L): 20 patients. (II) Suppressed TSH group (i.e. TSH level <0.1 IU/L, 0.007 ± 0.003IU/L): 18 patients. Significantly higher overall accuracy, sensitivity & NPV were found in stimulated group (98.5%, 88.6%, 62% respectively) compared to the suppressed group (66%, 62% & 31.5% respectively) that was more obvious in nodal rather than pulmonary deposits (P<0.05). However no significant difference was demonstrated in specificity & PPV between both groups. Significantly lower TG cut off point was demonstrated in stimulated group (15 ng/ml) compared to suppressed group (21 ng/ml) (P<0.05). Moreover significantly higher impact of F-18 FDG PET-CT in TSH stimulated (40%) was demonstrated compared to TSH suppressed (11.2%) group on patient management.Conclusion: High TSH seems to enhance F-18 FDG PET/CT efficiency on nodal rather than pulmonary metastases in recurrent DTC patients with elevated serum TG level and negative I-131 WBS. Moreover it reduces TG cut off point for F-18 FDG PET-CT & escalates its impact on patient management.

Papillary Thyroid Carcinoma Patients Assessed to Be at Low or Intermediary Risk After Primary Treatment Are at Greater Risk of Long Term Recurrence If They Are Thyroglobulin Antibody Positive Or Do Not Have Distinctly Low Thyroglobulin at Initial Assessment

In papillary thyroid carcinoma (PTC), recurrences during long-term follow-up (R-LTFU) occur even in those who appear to have an excellent prognosis after initial thyroid surgery and usually, radioactive iodine (i.e., "primary treatment"). Initial studies that predict R-LTFU are not well defined. Values for serum thyroglobulin (Tg) measurements when serum thyrotropin (TSH) is >30 μU/mL, as a result of either recombinant TSH or L-thyroxine withdrawal, referred to here as stimulated Tg (STg), have been previously evaluated. The aim of the current study was to determine the parameters associated with R-LTFU in patients with PTC categorized as having low-risk disease 9 to 12 months after their primary treatment. This was a retrospective study of 469 patients with PTC with a mean follow-up 5.8±3.9 years. Study patients had to have no uptake in the first postablative diagnostic (131)iodine whole body scan (WBS) performed 9-12 months after primary treatment, a normal cervical ultrasonography (C-US), and STg of <2 ng/mL if their test for antithyroglobulin antibody (anti-Tg) was negative. The first two criteria were required for patients with a positive anti-Tg test, and their nominal serum Tg concentrations were not analyzed. Twelve patients developed recurrences (2.6%) in cervical region. Greater tumor size, higher STg, and positive anti-Tg tests at initial evaluation were associated with greater R-LTFU. The recurrence rates were 1.5% (7/450) and 26% (5/19), respectively, in patients with negative and positive anti-Tg tests at initial evaluation. Recurrence-free survival was lower in the patients with initial lymph node metastases, positive anti-Tg tests, and STg of ≥0.3 ng/mL at the first postablative WBS (p=0.022, 0.001, 0.035, respectively, by log-rank test). Regression analysis in patients who were anti-Tg negative revealed that STg ≥0.3 ng/mL at this first WBS was the only parameter related to recurrence (p=0.031, odds ratio: 10.30, confidence interval: 1.23-83.3). Patients with PTC traditionally categorized as low risk during their first 9 to 12 months after primary treatment have a greater risk of R-LTFU if their postablative STg is ≥0.3 ng/mL, or they have positive anti-Tg, even at this early stage. Periodic C-US is important in these patients and should probably be more frequent in patients with PTC who have positive anti-Tg tests or STg ≥0.3 ng/mL in the first year after diagnosis.

Thyroglobulin Gene Mutations in Congenital Hypothyroidism

Human thyroglobulin (TG) gene is a single copy gene, 270 kb long, that maps on chromosome 8q24.2–8q24.3 and contains an 8.5-kb coding sequence divided into 48 exons. TG is exclusively synthesized in the thyroid gland and represents a highly specialized homodimeric glycoprotein for thyroid hormone biosynthesis. Mutations in the TG gene lead to permanent congenital hypothyroidism. The presence of low TG level and also normal perchlorate discharge test in a goitrous individual suggest a TG gene defect. Until now, 52 mutations have been identified and characterized in the human TG gene with functional impact such as structural changes in the protein that alter the normal protein folding, assembly and biosynthesis of thyroid hormones. 11 of the mutations affect splicing sites, 11 produce premature stop codons, 23 lead to amino acid changes, 6 deletions (5 single and 1 involving a large number of nucleotides) and 1 single nucleotide insertion. TG mutations are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous. The p.R277X, p.C1058R, p.C1977S, p.R1511X, p.A2215D and p.R2223H mutations are the most frequently identified TG mutations. This mini-review focuses on genetic and clinical aspects of TG gene defects.

Clinical, biochemical, and molecular findings in Argentinean patients with goitrous congenital hypothyroidism

We describe the clinical, biochemical, and molecular findings of a cohort of Argentinean patients with congenital hypothyroidism (CH) and goiter studied to characterize iodide organification and thyroglobulin (TG) defects. 20 CH patients (16 unrelated) were grouped according to serum TG levels and a perchlorate discharge test (PDT) in: group 1 (G1): nine patients with high TG and PDT > 10% who were studied for tiroperoxidase (TPO), dual oxidase 2 (DUOX2), and dual oxidase A2 (DUOXA2) defects and group 2 (G2): 11 patients with low TG and PDT < 10% studied for TG defects. Goiter characteristics, outcome, and TT₄ and TT₃ levels without treatment were compared between groups. 6/9 G1 patients harbored mutations in TPO gene and 3/9 in DUOX2 gene. In G2, mutations of TG gene were found in 3/11 homozygous, 5/11 compound heterozygous, and 3/11 heterozygous patients. Goiter was only evidenced by thyroid scan in the neonatal period in both groups; was moderately enlarged in patients diagnosed during infancy. In the late detected patients, goiter was big and nodular in G1 while diffuse and moderate in G2. Early detected patients grew and developed normally while those diagnosed late were severely mentally retarded in G1 and only mildly retarded in G2. Thyroid hormone levels of G1 were significantly lower than those of G2 P < 0.01. Molecular approach to characterize defects in organification and TG defects was optimized by TG measurements and PDT. Clinical and biochemical differences based on molecular findings will allow further investigations on genotype-phenotype relationships.

More hypothyroidism and less hyperthyroidism with sufficient iodine nutrition compared to mild iodine deficiency—A comparative population-based study of older people

Objective To assess the occurrence of thyroid disorders and autoimmunity in a geriatric population with long-standing recommended iodine intake of natural origin compared to mild iodine deficiency. Design and setting Cross-sectional, comparative, population-based study in two areas with different iodine intakes due to different tap water iodine contents. Participants Residents of Randers ( n = 212) or Skagen ( n = 218), Denmark, aged 75–80 years. Measures Blood samples were collected for measuring thyrotropin (TSH), triiodothyronine, thyroxine, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TGAb), thyroglobulin (TG); iodine excretion estimated from iodine and creatinine measured in spot urine samples; questionnaire on history of thyroid disease, medication and vitamin use; clinical examination of the neck. Results Median urinary iodine excretion was 50 μg/24 h in Randers and 177 μg/24 h in Skagen ( p < 0.001). A history of thyroid disease was reported by 40 (9.3%) dominated by goitre ( n = 22) in Randers and hypothyroidism and Graves Disease ( n = 15) in Skagen ( p < 0.001). We found visible goitre in 26% of Randers dwellers and none in Skagen ( p < 0.001). Hyperthyroidism with TSH below the reference range was present in 26% of Randers and 6% of Skagen dwellers while 6% and 13%, respectively, were hypothyroid with TSH above the reference range ( p < 0.001). More Randers than Skagen participants harboured a thyroid antibody (42% vs. 32%, p = 0.006). Conclusions Recommended iodine intake associated with more hypothyroidism, less hyperthyroidism and goiters, low TGAb prevalence and lower TG level in serum than did iodine deficiency. TPOAb was similar in the iodine replete and deficient geriatric populations.

Low thyroglobulin concentrations after thyroidectomy increase the prognostic value of undetectable thyroglobulin levels on levo-thyroxine suppressive treatment in low-risk differentiated thyroid cancer

Recombinant human TSH-stimulated thyroglobulin (Tg) levels (rhTSH-Tg) are sufficient for early follow-up of low-risk differentiated thyroid cancer (DTC) patients after thyroidectomy and radioiodine (131I) remnant ablation (RAI). Serum Tg levels at the time of remnant ablation (ablation-Tg) is thought to be related with rhTSH-Tg and may be predictive of recurrent disease. During long-term follow-up, Tg levels on levo-T4 (L-T4) suppressive treatment (suppressive-Tg) is sufficiently sensitive to avoid further evaluations in patients with undetectable rhTSH-Tg. The aim of our study was to verify whether, in a subgroup of low-risk DTC patients, the association of low ablation-Tg levels (<10 microg/l) with undetectable suppressive-Tg concentrations has a sufficient negative predictive value (NPV) for recurrence of disease, leading to avoid rhTSH testing. We enrolled 169 low-risk DTC patients treated by thyroidectomy + RAI and undetectable suppressive-Tg at 12-month followup. In all patients, we retrospectively evaluated ablation-Tg and rhTSH-Tg. For all patients, 2-yr follow-up was available. Based on rhTSH-Tg>2 microg/l, relapsing disease was histologically proven in 2 patients. rhTSH-Tg levels between 0.6-2.0 microg/l, with no evidence of disease, was observed in 10 patients (6%). One hundred and fifty-seven patients showed undetectable rhTSH-Tg. The NPV of undetectable suppressive- Tg was 92.8%. The ablation-Tg level was <10 microg/l in 140 patients. In this group, the NPV of undetectable suppressive- Tg was 100%. Our data indicate that undetectable suppressive-Tg value, combined with ablation- Tg levels <10 microg/l, may avoid a significant number of high-cost rhTSH-Tg test.

A molecular analysis and long-term follow-up of two siblings with severe congenital hypothyroidism carrying the IVS30+1G&gt;T intronic thyroglobulin mutation

To extend the molecular analysis of the IVS30+1G>T intronic thyroglobulin (TG) mutation, and to report the eleven year follow-up of the affected patients. METHOSD: Two siblings with severe congenital hypothyroidism with fetal and neonatal goiter, harboring the IVS30+1G>T mutation were included. Nodular and non-nodular thyroid tissue specimens were collected. Specific thyroid genes expression was evaluated by real-timePCR and by immunohistochemistry. In non-nodular tissue specific thyroid genes mRNA were reduced when compared to normal thyroid sample. In the nodule, TPO and NIS expression was very low. Microscopic examinations showed very large follicular-lumina and swollen vesicles of endoplasmatic-reticulum. Strong cytoplasmatic and low follicular-lumen TG immunostaining were detected. Intracellular NIS, membrane TPO and TSHR immunostaining had higher positivity in non-nodular sample. Both patients had a long-term adequate developmental outcome, besides one patient have been lately-treated. IVS30+1G>T mutation not only lead to very enlarge endoplasmatic-reticulum, but also to alterations of specific thyroid genes expression. The clinical evolution of patients harboring these mutations strengthen the concept of the influence of environment, like iodine nutrition, to determine the final phenotypic appearance.

A low thyroglobulin level cannot be used to avoid adjuvant 131I therapy after thyroidectomy for thyroid carcinoma

A low thyroglobulin level cannot be used to avoid adjuvant 131I therapy after thyroidectomy for thyroid carcinoma

Factors associated with elevated serum concentrations of anti‐TPO antibodies in subjects with and without diffuse goitre. Results from the Ukrainian–American Cohort Study of Thyroid Cancer and Other Thyroid Diseases Following the Chornobyl Accident

To examine factors associated with the prevalence of elevated anti-thyroid peroxidase antibodies (ATPO) among iodine-deficient adolescents and young adults and test whether associations vary according to the presence of diffuse goitre. Subjects were members of the Ukrainian-American Cohort Study exposed to the Chornobyl accident whose (131)I thyroid dose estimates were below 0.2 Gy. The odds ratios (ORs) for ATPO above 60 U/ml were estimated using logistic regression models for a number of factors in the total population (N = 5133), and separately for thyroid disease-free subjects (N = 3875), those with diffuse goitre (N = 921), and diffuse goitre without autoimmune thyroiditis (AIT; N = 883). Elevated ATPO was found in 9.9% of the total population and ORs were significantly higher in females, older individuals, those examined in earlier calendar years, residents of Kyiv and Chernihiv oblasts, subjects with a family history of thyroid disease, higher thyroid ultrasound volume, suppressed or elevated TSH, blood collection in March to May, very low thyroglobulin (Tg), and shorter serum storage time. When thyroid disease-free subjects and those with diffuse goitre were compared, there were few differences in antibody prevalence, and after excluding individuals with AIT, the only difference was an increased prevalence of elevated ATPO at low urinary iodine in those with goitre alone. Although a number of factors are associated with the prevalence of elevated ATPO in our study group, with the exception of urinary iodine these factors are independent of goitre, and differences between thyroid disease-free subjects and those with diffuse goitre are largely due to AIT.

Congenital hypothyroidism with goitre caused by new mutations in the thyroglobulin gene

Thyroid dyshormonogenesis is associated with mutations in the thyroglobulin (TG) gene and characterized by normal organification of iodide and low serum TG. These mutations give rise to congenital goitrous hypothyroidism, transmitted in an autosomal recessive mode. The aim of this study was to identify new mutations in the TG gene in an attempt to increase the understanding of the molecular basis of this disorder. Three unrelated patients with marked impairment of TG synthesis were studied. The promoter and the complete coding regions of the TG gene, along with the flanking intronic regions, were analysed by direct DNA sequencing. Four different inactivating TG mutations, three novel mutations (c.548G>A, p.C164Y; c.759-760insA, p.L234fsX237; c.6701C>A, p.A2215D) and one previously identified mutation (c.886C>T, p.R277X) were identified. Multiple sequence alignment study revealed that the wild-type cysteine residue at position 164 is strictly conserved in the TG of all the species analysed, whereas the wild-type alanine residue at position 2215 is well conserved in the TG and acetylcholinesterase (AChE) of all the species analysed except in rabbit AChE, in which it is substituted by glutamic acid. We report three patients with congenital hypothyroidism with goitre caused by two compound heterozygous mutations, p.C164Y/p.L234fsX237 and p.R277X/p.A2215D, and one homozygous mutation, p.R277X, in the TG gene. To our knowledge this is the first report of the presence of a nucleotide insertion mutation in the TG gene.

Dépistage des récidives des cancers différenciés de la thyroïde sous TSH recombinante (Thyrogen ®) : évolution de la TSH et de la thyroglobuline

Following total thyroidectomy, serum thyroglobulin measurement and 131I whole body scan (WBS) are the most sensitive markers for disease activity. Thyrogen ® (recombinant human TSH) is used to stimulate thyroglobulin production without requiring thyroid hormone withdrawal. Thyrogen ® 0.9 mg was injected at J1 and J2, followed by 4 mCi 131I at J3. WBS was then done at J5. The aim of our work was: (1) to study evolution of TSH, thyroglobulin and auto-antibodies against thyroglobulin (AAT) serum levels during protocol study, (2) to confirm that thyroglobulin level at J5 is optimum for diagnosis and (3) to verify that 131I do not interfere with 125I radioimmunometric thyroglobulin determination. Fourteen women, one man (24–67 years old) were studied. Serum measurement were done using radioimmunometric and immunoenzymatic methods. No significant difference was found between these two methods. For all subjects studied, serum TSH was above 80 μUI/ml at J3 and decreased to 18.4 μUI/ml on J5. AAT were always undetectable. Twelve subjects (group I) had both, undetectable thyroglobulin level (J3 and J5) and no iodine uptake at WBS, suggesting absence of disease activity. Two subjects (group II) had both elevated thyroglobulin levels (6.6 and 10.4 ng/ml J3 then >10 ng/ml J5) and iodine uptake at WBS, suggesting metastasis. Two subjects (group III) had low thyroglobulin levels (1.8 and 0.53 ng/ml J3 then 3 and 2.5 ng/ml J5) but no iodine uptake at WBS, suggesting no metastasis. In conclusion, Thyrogen ® is a rapid and simple thyroglobulin stimulation test avoiding morbidity associated with hypothyroidy. J3 and J5 TSH levels are similar to those indicated by manufacturer. 131I do not interfere with radioimmunometric determination of serum thyroglobulin. In association with WBS or FDG-PET, thyroglobulin level at J5 seems to be the best one for diagnosis of thyroid persistence or recurrence.

18F]Fluorodeoxyglucose Triple-Head Coincident Imaging as an Adjunct to 131I Scanning for Follow-Up of Papillary Thyroid Carcinoma

To evaluate the feasibility of using [(18)F]fluorodeoxyglucose ((18)FDG) triple-head coincidence imaging as a potential cost-effective alternative to positron emission tomography in the setting of suspected recurrence of papillary thyroid carcinoma. We retrospectively studied 10 patients with suspected recurrence of papillary carcinoma of the thyroid, who underwent (18)FDG coincidence imaging,(131)I scanning, and a reference anatomic scan (computed tomography, magnetic resonance imaging, or both) within 1 year in most cases. The (131)I scan detected the recurrence in five patients (62.5%) and failed to reveal recurrent cancer in three patients (37.5%); in contrast,(18)FDG imaging detected the recurrence in eight patients (100%) and was true negative in two patients in whom the scans were performed more than 1 year after effective therapy for the recurrence. The sensitivity of detection was unrelated to lesion size. The (18)FDG imaging results led to additional radiotherapy in all (131)I-negative patients, two of whom had high thyroglobulin levels and one of whom had a low thyroglobulin concentration but the presence of antithy-roglobulin antibodies. We conclude that (18)FDG triple-head coincidence imaging is useful for routine management of patients with thyroid cancer who have no abnormalities detected on (131)I scans but have high serum thyroglobulin levels. This technique, however, may not be as sensitive as a dedicated positron emission tomographic device, particularly for the assessment of small tumors.

The diagnostic use of the rhTSH/thyroglobulin test in differentiated thyroid cancer patients with persistent disease and low thyroglobulin levels.

Serum thyroglobulin (Tg) measurement after TSH stimulation, by either thyroid hormone withdrawal or recombinant human TSH (rhTSH) administration, is the most sensitive method for early detection of patients with persistent or recurrent differentiated thyroid cancer (DTC) after total thyroidectomy and 131I ablation. The use of rhTSH is now increasing because it avoids thyroid hormone suppressive therapy (THST) withdrawal and the consequent symptoms of severe hypothyroidism. Current guidelines suggest measurement of serum Tg 4 days after starting a 2-day course of rhTSH injections, and assumes that Tg reaches maximum serum levels at that time. The present study was carried out to evaluate the accuracy of rhTSH/thyroglobulin test in DTC patients with persistent disease and low thyroglobulin levels. A series of 13 DTC patients was selected because they had proven persistent disease associated with low Tg levels (< 2.0 micro g/l) under l-thyroxine treatment. In all of them, serum Tg was > 5.0 micro g/l at the last THST withdrawal. We measured serum Tg and TSH levels on days 0.5, 1, 1.5, 2, 4, 7, 10 and 15 after the first of a 2-day course of intramuscular rhTSH injections. Serum Tg values were variable in terms of both peak and time-course. Detectable serum Tg levels were recorded on day 4 in all patients. However, among these 13 patients, the peak Tg value was reached earlier than day 4 in three patients and later in two others. In one patient, Tg level at day 2 was higher (3.0 micro g/l) than at day 4 (1.8 micro g/l). In six of the 13 patients studied we compared Tg values after rhTSH to those subsequently obtained after THST withdrawal: in five of them Tg values were two to three times higher after the latter stimulation. Serum Tg value variability after rhTSH was partially accounted for by variability of serum TSH levels, which were inversely related to patient body surface. In DTC patients with persistent disease and low Tg levels, optimization of the diagnostic use of Tg measurement after rhTSH may require rhTSH dose adjustment to the patient body surface area and repeated blood sampling, in order to improve diagnostic accuracy. In these patients not even a TSH-stimulated serum Tg cut-off of 2.0 micro g/l on day 4 provides 100% accuracy, whereas a cut-off of 1.0 micro g/l seems more appropriate. Therefore, in this subset of patients, if any detectable Tg level >or= 1.0 micro g/l is found after rhTSH, re-evaluation after THST should be advised.

Expression of the Sodium Iodide Symporter and Thyroglobulin Genes Are Reduced in Papillary Thyroid Cancer

Altered expression of the gene encoding the sodium iodine symporter (NIS) may be an important factor that leads to the reduced iodine accumulation characteristic of most benign and malignant thyroid nodules. Both up- and down-regulation of NIS gene expression have been reported in thyroid cancer using several different methods. The goal of the present study was to accurately identify alterations in NIS gene expression in benign and malignant thyroid nodules using an accurate real-time quantitative RT-PCR assay system. Total RNA was prepared from 18 benign thyroid nodules, 20 papillary thyroid cancers, and 23 normal thyroid samples from 38 subjects. Quantitative RT-PCR was used to measure NIS and thyroglobulin (TG) mRNA expression in normal thyroid tissue and in each nodular tissue sample. Papillary thyroid cancer samples had significantly lower NIS mRNA expression (72 ± 41 picogram equivalents [pg Eq]), than did benign nodules (829 ± 385 pg Eq), or normal tissues (1907 ± 868 pg Eq, P = 0.04). Most important, in the paired samples, NIS gene expression was decreased in each papillary thyroid cancer compared with normal tissue (69% median decrease; range, 40–96%; P = .013). Eleven of the 12 benign nodules also demonstrated lower NIS gene expression than the normal tissue (49% decrease; range, 2–96%; P = .04). Analysis of the paired samples demonstrated that Tg mRNA expression was significantly lower in each of the thyroid cancer samples than in corresponding normal tissue (759 ± 245 pg Eq vs. 1854 ± 542 pg Eq, P = .03). We have demonstrated a significant decrement in NIS gene expression in all papillary thyroid cancers and in over 90% of benign nodules examined compared with adjacent normal thyroid tissue, using a highly accurate quantitative RT-PCR technique. Similarly, thyroid cancers demonstrated significantly lower TG mRNA expression than corresponding normal thyroid. Reduced NIS expression may be an important factor in the impairment of iodine-concentrating ability of neoplastic thyroid tissues.

Strategies for thyrotropin use to monitor patients with treated thyroid carcinoma.

Detection of residual and recurrent thyroid carcinoma requires long-term monitoring of patients with serum thyroglobulin measurement and radioiodine scanning during temporary thyrotropin (TSH) stimulation. Recombinant thyrotropin (rTSH) permits these studies to be performed without the morbidity associated with withdrawal of thyroid hormone therapy. A protocol for rTSH use is proposed, beginning with measurement of serum thyroglobulin during TSH suppression. Patients at significant risk of recurrence with a low initial thyroglobulin level then have rTSH stimulation testing. Patients with positive rTSH-stimulated thyroglobulin concentrations and/or radioiodine scans can then be directed for appropriate therapy. The previously studied 2-dose rTSH protocol with imaging at 48 hours after 131I dosing requires Monday-through-Friday testing in most settings, but new regimens may be established. rTSH-stimulated testing may be less accurate in patients with thyroglobulin autoantibodies and those with residual normal thyroid tissue, and is generally unnecessary when there is other evidence of residual disease. Physicians should consider patients' pretest probability of disease in deciding whether and how often to perform rTSH-stimulated testing after primary treatment for thyroid carcinoma.

Immunoradiometric assay of thyroglobulin in patients with differentiated thyroid carcinomas: need for thyroglobulin recovery tests.

As interference from thyroglobulin autoantibodies appears to have been overcome in new commercial thyroglobulin assays by the use of monoclonal antibodies, the need for thyroglobulin recovery tests became uncertain. Sera (n=45) from patients with differentiated thyroid carcinomas were selected on the basis of a thyroglobulin recovery value below 70% in the Dynotest Tg immunoradiometric assay (Brahms) routinely used in our laboratory. Serum thyroglobulin levels were then measured using three other commercial immunoradiometric assays: thyroglobulin ERIA (Pasteur), HTGK (Sorin) and ELSA HTG (Cis Bio International). Thyroglobulin autoantibodies were measured using the Thyrak assay (Brahms). Although many patients were thyroglobulin antibodies-negative (< 200 U/ml, n=26), most immunoradiometric assays failed to detect thyroglobulin in patients with evidence of recurrence. Low thyroglobulin values associated with low thyroglobulin recovery in thyroglobulin antibody-negative patients appear to be more biologically relevant than a single low thyroglobulin value, which can lead to lack of medical intervention. We conclude that the thyroglobulin recovery test is a prerequisite for the correct interpretation of serum thyroglobulin levels determined with immunoradiometric assays in the follow-up of thyroglobulin autoantibody-negative patients treated for differentiated thyroid carcinomas.

Hypothyroid patients showing shortened responsiveness to oral iodized oil have paradoxically low serum thyroglobulin and low thyroid reserve. Thyroglobulin/thyrotropin ratio as a measure of thyroid damage

In Central Africa, all of northern Zaire is very severely deficient in iodine. A peculiar feature of this endemia is that iodine deficiency and the ensuing thyroid gland stimulation not only leads to goitre formation but also to progressive thyroid involution and to myxoedematous cretinism. An iodine supplementation trial based on oral administration of small doses of iodine was made in 81 schoolchildren. All of them received a small dose of iodine (0.1 ml containing 48 mg) per os and the thyroid status was followed during 4 months. Blood and urine samples were collected at the start of the study, then 2 weeks, 2 months and 4 months after iodine administration. Before iodine supplementation the mean urinary iodine level was 0.18 +/- 0.02 micromol/l, and 10% of the subjects had a urinary iodine level below 0.08 micromol/l. Fifty-two percent of the subjects had a serum thyrotropin (TSH) level above 10 mU/l. All the subjects responded to the administration of iodine. and all of them recovered a euthyroid status. Most of them were still euthyroid at the end of the study. However. within 4 or even 2 months, some subjects (15 % of the total) reverted to hypothyroidism. At the entry of the study these subjects were all hypothyroid and had elevated TSH and paradoxically low serum thyroglobulin (TG) values. In myxoedematous cretins living in the same area, even lower serum TG levels were found. Together with the absence of goitre, a paradoxically low serum TG Suggests a low thyroid reserve, and in the present case a reduced amount of functional thyroid tissue. We show that the serum TG/TSH ratio may be used as a predictive index of thyroid reserve and of positive response to iodine administration. These data further suggest that thyroid damage is not confined to myxoedematous cretins. but is widely distributed in the phenotypically normal population. Widely distributed thyroid damage may render iodine prophylaxis based on oral administration unpredictable.