Thyroid autoimmunity, thyroglobulin autoantibodies, and thyroid cancer prognosis.

The relevance of thyroid autoimmunity to the prognosis of papillary thyroid carcinoma is still unsettled. We decided to investigate the impact of thyroid autoimmunity on the prognosis of papillary thyroid carcinoma and the handling of TgAbs. We evaluated the clinical course of a large group of patients according to the presence (PTC-LT) or absence (PTC) of lymphocytic thyroiditis at histology. We studied 194 consecutive patients with a diagnosis of PTC and treated them with total thyroidectomy plus ¹³¹I ablation between 2007 and 2009. Median follow-up (with 25th-75th percentiles) was 84.0 (56.4-118.0) months. The remission criteria were: basal Tg < 0.2 ng/mL (or stimulated Tg: < 1), TgAbs < 8 IU/mL (otherwise 'decreasing TgAb trend', a decline of ≥20% in sequential TgAb measurements) and unremarkable imaging. PTC-LT and PTC patients had comparable treatment.TgAbs were detectable in 72.5% of PTC-LT and 16.5% of PTC patients. Time to remission was longer in the detectable than in the undetectable TgAb cohort (28.5 vs· 7.5 months (median); HR: 0.54, CI: 0.35-0.83, P = 0.005). When comparing PTC-LT to PTC patients, the difference was maintained in the detectable TgAb (29.3 vs 13.0 months; HR: 0.38, CI: 0.18-0.80; P = 0.01) but not in the undetectable TgAb cohort (7.7 vs 7.3 months; HR: 0.90, CI: 0.55-1.47; P = 0.68). Using the decreasing TgAb trend, the influence of detectable TgAbs on time to remission was abolished. Thyroid autoimmunity does not influence the prognosis of papillary thyroid carcinoma. A decreasing TgAb trend seems an appropriate criterion to establish the remission of papillary thyroid carcinoma.

Management of Thyrotoxicosis Induced by PD1 or PD-L1 Blockade.

CONTEXT: Thyrotoxicosis is a common immune-related adverse event in patients treated with programmed cell death protein-1 (PD1) or programmed cell death protein ligand-1 (PD-L1) blockade. A detailed endocrinological assessment, including thyroid ultrasound and scintigraphy, is lacking, as are data on response to treatment and follow-up. OBJECTIVE: The aim of this study was to better characterize the thyrotoxicosis secondary to immune checkpoint inhibitors, gaining insights into pathogenesis and treatment. METHODS: We conducted a retrospective study of 20 consecutive patients who had normal thyroid function before starting immunotherapy and then experienced thyrotoxicosis on PD1 or PD-L1 blockade. Clinical assessment was combined with thyroid ultrasound, 99mtechnecium scintiscan, and longitudinal thyroid function tests. RESULTS: Five patients had normal or increased scintigraphic uptake (Sci+), no serum antibodies against the thyrotropin receptor, and remained hyperthyroid throughout follow-up. The other 15 patients had no scintigraphic uptake (Sci-) and experienced destructive thyrotoxicosis followed by hypothyroidism (N = 9) or euthyroidism (N = 6). Hypothyroidism was more readily seen in those with normal thyroid volume than in those with goiter (P = .04). Among Sci- individuals, a larger thyroid volume was associated with a longer time to remission (P < .05). Methimazole (MMI) was effective only in Sci+ individuals (P < .05). CONCLUSION: Administration of PD1- or PD-L1-blocking antibodies may induce 2 different forms of thyrotoxicosis that appear similar in clinical severity at onset: a type 1 characterized by persistent hyperthyroidism that requires treatment with MMI, and a type 2, characterized by destructive and transient thyrotoxicosis that evolves to hypothyroidism or euthyroidism. Thyroid scintigraphy and ultrasound help in differentiating and managing these 2 forms of iatrogenic thyrotoxicosis.

Disappearance of Anti-Thyroid Autoantibodies following Thymectomy in Patients with Myasthenia Gravis.

OBJECTIVES: The thymus plays a central role in immune tolerance, which prevents autoimmunity. Myasthenia gravis (MG) is commonly associated with thymoma or thymus hyperplasia, and it can coexist with autoimmune thyroid diseases. However, the role of the thymus in thyroid autoimmunity remains to be clarified, which we investigated here. STUDY DESIGN: The study design entailed the inclusion of consecutive MG patients and the measurement of anti-thyroid autoantibodies at baseline and, limited to autoantibody-positive patients, also at 24 and 48 weeks. One hundred and seven MG patients were studied. The main outcome measure was the behaviour of anti-thyroglobulin autoantibodies (TgAbs) and anti-thyroperoxidase autoantibodies (TPOAbs) over time in relation to thymectomy. RESULTS: Serum TgAbs and/or TPOAbs were detected in ∼20% of patients in the absence of thyroid dysfunction. The prevalence of positive serum TgAbs and/or TPOAbs decreased significantly (p = 0.002) over the follow-up period in patients who underwent thymectomy, but not in patients who were not thymectomized. When the analysis was restricted to TgAbs or TPOAbs, findings were similar. On the same line, there was a general trend towards a reduction in the serum concentrations of anti-thyroid autoantibodies in patients who underwent thymectomy, which was significant for TPOAbs (p = 0.009). CONCLUSIONS: Our findings suggest a role of the thymus in the maintenance of humoral thyroid autoimmunity.

Is Subacute Thyroiditis an Underestimated Manifestation of SARS-CoV-2 Infection? Insights From a Case Series.

CONTEXT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 18 million people worldwide and the pandemic is still spreading. After the first case we reported, we observed 4 additional cases of subacute thyroiditis (SAT) related to SARS-CoV-2 infection. OBJECTIVES: The objective of this work is to describe additional cases of SAT associated with SARS-CoV-2 infection to alert physicians that SAT may be a manifestation of SARS-CoV-2 infection. METHODS: We describe clinical, biochemical, and imaging features of 4 patients with SAT related to SARS-CoV-2 infection. RESULTS: All patients were female (age, 29-46 years). SAT developed 16 to 36 days after the resolution of coronavirus disease 2019 (COVID-19). Neck pain radiated to the jaw and palpitations were the main presenting symptoms and were associated with fever and asthenia. One patient was hospitalized because of atrial fibrillation. Thyroid function tests (available for 3 individuals) were suggestive of destructive thyroiditis, and inflammatory markers were high. At neck ultrasound the thyroid was enlarged, with diffuse and bilateral hypoechoic areas and (in 3 patients) absent vascularization at color Doppler. Symptoms disappeared a few days after commencement of treatment (prednisone in 3 patients and ibuprofen in 1). Six weeks after the onset of SAT, all patients were asymptomatic and inflammatory markers had returned to normal range. Two patients were euthyroid, whereas 2 were diagnosed with subclinical hypothyroidism. CONCLUSIONS: SAT may be an underestimated manifestation of COVID-19. Clinicians should keep in mind the possible occurrence of SAT during and after SARS-CoV-2 infection.

Subacute Thyroiditis After Sars-COV-2 Infection.

CONTEXT: Subacute thyroiditis (SAT) is a thyroid disease of viral or postviral origin. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that began in Wuhan, China, has spread rapidly worldwide and Italy has been severely affected by this outbreak. OBJECTIVES: The objective of this work is to report the first case of SAT related to SARS-CoV-2 infection. METHODS: We describe the clinical, laboratory, and imaging features of an 18-year-old woman who came to our attention for fever, neck pain radiated to the jaw, and palpitations occurring 15 days after a SARS-CoV-2-positive oropharyngeal swab. Coronavirus disease 2019 (COVID-19) had been mild and the patient had completely recovered in a few days. RESULTS: At physical examination the patient presented with a slightly increased heart rate and a painful and enlarged thyroid on palpation. At laboratory exams free thyroxine and free triiodothyronine were high, thyrotropin undetectable, and inflammatory markers and white blood cell count elevated. Bilateral and diffuse hypoechoic areas were detected at neck ultrasound. One month earlier, thyroid function and imaging both were normal. We diagnosed SAT and the patient started prednisone. Neck pain and fever recovered within 2 days and the remaining symptoms within 1 week. Thyroid function and inflammatory markers normalized in 40 days. CONCLUSIONS: We report the first case of SAT after a SARS-CoV-2 infection. We alert clinicians to additional and unreported clinical manifestations associated with COVID-19.

The Detection of Serum IgMs to Thyroglobulin in Subacute Thyroiditis Suggests a Protective Role of IgMs in Thyroid Autoimmunity.

CONTEXT: The role of serum immunoglobulin (Ig)Ms in autoimmune thyroid diseases is uncertain. OBJECTIVE: We looked for IgMs to thyroglobulin (Tg) in patients with subacute thyroiditis (SAT), which is characterized by high serum Tg levels, the possible de novo appearance of IgGs to Tg (TgAb-IgGs), and no autoimmune sequelae. MAIN OUTCOME MEASURES: TgAb-IgMs and TgAb-IgGs were detected by binding to Tg using the enzyme-linked immunosorbent assay (ELISA). The upper reference limit of TgAb-IgMs and TgAb-IgGs was established in 40 normal subjects. We looked for TgAb-IgMs in 16 patients with SAT, 11 with Hashimoto's thyroiditis (HT), and 8 with Graves' disease (GD) who were all positive for TgAb-IgGs. IgM binding to bovine serum albumin (BSA), keyhole limpet hemocyanin (KLH), and glucagon in ELISA was measured. Inhibition of TgAb-IgMs binding to coated Tg was evaluated by preincubating serum samples or IgG-depleted samples with soluble Tg. RESULTS: TgAb-IgMs were positive in 10/16 patients with SAT, 2/11 with HT, and 1/8 with GD. TgAb-IgMs were higher in SAT (0.95; 0.42-1.13) (median; 25th-75th percentiles) than in HT (0.47; 0.45-0.51) and GD patients (0.35; 0.33-0.40) (P < .005 for both). IgM binding of SAT sera to BSA, KLH, and glucagon was significantly lower than Tg. Preincubation with soluble Tg reduced the binding of IgMs to coated Tg by 18.2% for serum samples and by 35.0% and 42.1% for 2 IgG-depleted samples. TgAb-IgM levels were inversely, although nonsignificantly, correlated with Tg concentrations. CONCLUSIONS: Tg leak associated with thyroid injury induces the production of specific TgAb-IgMs, which, in turn, increases the clearance of Tg and might prevent the establishment of a persistent thyroid autoimmune response.

Changing Trend of Thyroglobulin Antibodies in Patients With Differentiated Thyroid Cancer Treated With Total Thyroidectomy Without 131I Ablation.

BACKGROUND: Thyroglobulin (Tg) antibodies (TgAb) can interfere with Tg measurement and can be used as "Tg surrogate" in patients with differentiated thyroid cancer (DTC) treated with total thyroidectomy (TTx) and radioiodine remnant ablation (RRA). In contrast, few data, and in patients usually followed for a short-term follow-up, have been reported about the changes of TgAb levels in patients treated with TTx but without RRA. The aims of this study were to evaluate the changes of TgAb levels in DTC patients treated with TTx but not RRA and to identify the factors that influence these changes. METHODS: The change in TgAb levels in 107 DTC (<1 cm) patients submitted to TTx but not RRA was evaluated. Patients were followed for a median of 6.3 years, and all had at least three determinations of TgAb and neck ultrasound (nUS). RESULTS: TgAb levels showed a progressive decrease during follow-up. Initial TgAb levels and degree of lymphocytic infiltration influenced the time but not the rate of TgAb disappearance. No influence on time and rate of the decrease in TgAb was observed when the association with thyroperoxidase antibodies (TPOAb) levels were considered. A TgAb cutoff value of 61.9 IU/mL at first postoperative evaluation was a good indicator for disappearance of the TgAb within six years. No tumor recurrence was observed in the series. In one case, the progressive increase in TgAb anticipated the reappearance of benign thyroid tissue with lymphocytic infiltration. CONCLUSIONS: TgAb levels decline in the majority of DTC patients treated with TTx but not ablated with radioiodine. The levels decrease rapidly after the surgical treatment and continue to decrease over time. The time of disappearance is influenced by the initial TgAb levels and the degree of lymphocytic infiltration. No influence of the actual TPOAb levels has been observed. An increase in TgAb levels should not be overlooked, since it can indicate the presence or reappearance of either normal thyroid tissue or tumor recurrence.

Diagnostic accuracy of a new fluoroenzyme immunoassay for the detection of TSH receptor autoantibodies in Graves' disease.

PURPOSE: Thyrotropin receptor (TSHR) autoantibodies (TRAbs) are a hallmark of Graves' disease (GD). The aim of this study was to evaluate the diagnostic accuracy of a new third generation automatic fluorescence enzyme immunoassay for TRAb measurement in GD, in comparison with two current IMAs. METHODS: Sera of 439 subjects (57 patients with untreated GD, 34 with treated GD, 15 with GD and Graves' orbitopathy, 52 with multinodular non-toxic goiter, 86 with Hashimoto's thyroiditis, 20 with toxic adenoma or toxic multinodular goiter, 55 with non-thyroid autoimmune diseases and 120 normal controls) were tested for TRAbs with the ELiA™ anti-TSH-R assay (ThermoFischer Scientific, Uppsala, Sweden), the TRAK™ RIA, Brahms (Thermo Scientific, Hennigsdorf, Germany) and the Immulite™ TSI assay (Siemens Healthcare, Llanberis, UK). RESULTS: Sensitivity and specificity of the ELiA™ anti-TSH-R assay, TRAK™ RIA and Immulite™ TSI assay were 94.7% and 99.6, 100 and 98.2%, 100 and 98.2%, respectively. Spearman's coefficient and Passing-Bablok regression showed a satisfactory correlation between EliA™ and TRAK™ [rho: 0.925; 95% CI: 0.883-0-953. Intercept: - 0.875 (95% CI: - 2.411 to 0.194); slope: 1.086 (95% CI: 0.941 to 1.248)], and between ELiA™ and TSI™ [rho: 0.947; 95% CI: 0.912 0.969. intercept: 1.085 (95% CI: 0.665 to 2.116); slope 1.315 (95% CI:1.116 to 1.700)]. CONCLUSIONS: The diagnostic performance of ELiA™-TSH-R assay is comparable to that of some current TRAb assays. It may be adopted into clinical practice for the differential diagnosis of hyperthyroidism, to screen for transient hyperthyroidism, and to monitor disease activity and treatment effects.

Effect of Thyroglobulin Autoantibodies on the Metabolic Clearance of Serum Thyroglobulin.

BACKGROUND: In order to establish whether thyroglobulin autoantibodies (TgAb) influence the metabolic clearance of thyroglobulin (Tg) in humans, serum Tg and TgAb were correlated shortly after radioiodine (131I) treatment. METHODS: Samples were collected from 30 consecutive patients undergoing 131I activity for Graves' hyperthyroidism at the time of treatment and every 15 days thereafter, up to 90 days. Tg and TgAb were measured by immunometric assays (functional sensitivities: 0.1 ng/mL and 8 IU/mL). RESULTS: Tg was detectable in all patients at day 0. Tg concentrations rose from a mean of 33.2 ng/mL [confidence interval (CI) 17.8-61.0 ng/mL] at day 0 to a mean of 214.6 ng/mL [CI 116.9-393.4 ng/mL] at day 30 and then steadily decreased, reaching the lowest concentration at day 90 (M = 10.9 ng/mL [CI 5.5-20.9 ng/mL]). Compared to their levels at day 0 (M = 23.6 IU/mL [CI 10.5-52.9 IU/mL]), TgAb remained stable through day 15 and then gradually increased up to a mean of 116.6 IU/mL [CI 51.9-262.2 IU/mL] at day 90. Patients were then split into two groups according to their TgAb status at day 0: undetectable (<8 IU/mL; 9 patients) or detectable (≥8 IU/mL; 21 patients) TgAb. Compared to the other cohort, patients with detectable TgAb showed significantly lower Tg concentrations at day 0 (M = 20.3 ng/mL [CI 10.1-40.2 ng/mL] vs. M = 101.8 ng/mL [CI 36.6-279.8 ng/mL]), similar at day 15, lower levels at day 30 (M = 146.5 ng/mL [CI 74.3-287.8 ng/mL] vs. M = 514.8 ng/mL [CI 187.8-1407.9 ng/mL]), at day 45 (M = 87.5 ng/mL [CI 43.1-176.6 ng/mL] vs. M = 337.9 ng/mL [CI 120.1-947.0 ng/mL]), at day 60 (M = 61.6 ng/mL [CI 31.0-121.4 ng/mL] vs. M = 255.8 ng/mL [CI 79.0-823.8 ng/mL]), and at day 75 (M = 24.5 ng/mL [CI 11.9-49.2 ng/mL] vs. M = 249.5 ng/mL [CI 63.5-971.1 ng/mL]), and similar levels at day 90. Patients with detectable TgAb showed a lower (M = 182.5 ng/mL [CI 92.0-361.0 ng/mL] vs. M = 514.8 ng/mL [CI 187.8-1407.9 ng/mL]) and an earlier (day 15 vs. day 30) peak of Tg. The mean Tg concentration was lower in patients with detectable TgAb than in those with undetectable TgAb (area under the curve: 17,340 ± 16,481 ng/mL vs. 36,883 ± 44,625 ng/mL; p = 0.02). CONCLUSIONS: TgAb influence the changes in Tg concentrations observed immediately after 131I treatment, inducing lower levels and an earlier peak of Tg. These observations indicate that TgAb significantly influence the metabolic clearance of Tg, supporting the concept that their interference in the measurement of Tg is mainly due to an in vivo effect.

Significance of Low Levels of Thyroglobulin Autoantibodies Associated with Undetectable Thyroglobulin After Thyroidectomy for Differentiated Thyroid Carcinoma.

BACKGROUND: The management of patients with differentiated thyroid carcinoma (DTC) showing low levels of serum thyroglobulin autoantibodies (TgAb) and undetectable Tg after thyroidectomy is unsettled. This study sought to elucidate the clinical significance of low levels of TgAb and to evaluate their interference with Tg measurement in vitro. METHODS: Tg and TgAb levels were correlated with the post-thyroidectomy staging of 177 consecutive DTC patients undergoing (131)I ablation after total thyroidectomy (clinical study). Tg was measured by an immunometric assay (functional sensitivity: 0.1 ng/mL), and TgAb were evaluated by six assays (functional sensitivities: 1.2-96 IU/mL; positive cutoffs: 4-150 IU/mL). The changes in Tg concentration (Tg recovery) of diluted specimens from DTC patients were also measured after incubation with 67 sera from DTC patients with undetectable Tg and low levels of TgAb (in vitro study). DTC sera containing Tg were diluted serially (from 330 to 0.1 ng/mL) and incubated with TgAb samples; Tg was then measured. RESULTS: In the clinical study: all patients had residual thyroid tissue, and 10 had metastatic disease. Depending on the TgAb assay, median Tg values were 7.0-10.9, 0.0-5.3, and 0.0-0.0 ng/mL in patients with undetectable, borderline (between functional sensitivities and positive cutoffs), and positive TgAb, respectively (p < 0.001). An undetectable Tg value was associated with borderline levels of TgAb in five assays. Only two patients with metastatic disease had undetectable Tg; both were TgAb positive by three or more assays. Conversely, no patient with undetectable Tg and undetectable or borderline TgAb by sensitive assays had metastatic disease. In the in vitro study, TgAb interfered significantly with Tg recovery (p < 0.001), but low levels of TgAb did not abolish Tg recovery. CONCLUSIONS: While low levels of TgAb do not preclude Tg measurement in vitro, they can be associated with an undetectable Tg in DTC patients with residual thyroid tissue after thyroidectomy. However, the finding of low levels of TgAb by sensitive assays associated with an undetectable Tg rules out metastatic disease.

Iodine contributes to thyroid autoimmunity in humans by unmasking a cryptic epitope on thyroglobulin.

CONTEXT: The mechanisms linking thyroid autoimmunity and iodine use in humans are unknown. OBJECTIVE: Our aim was to correlate iodine intake, thyroid autoimmunity, and recognition of thyroglobulin (Tg) epitopes after implementation of iodine prophylaxis. SETTING: The general community living in an Italian village was evaluated. MAIN OUTCOME MEASURES: Thyroglobulin autoantibodies (TgAb), thyroperoxidase autoantibodies (TPOAb), and urinary iodine excretion were assessed in 906 iodized salt users (IS-users) and 389 nonusers (IS-nonusers). Ultrasound (US) was performed to identify thyroid hypoechogenicity, suggestive of Hashimoto thyroiditis (HT). TgAb epitope pattern in 16 IS-users and 17 IS-nonusers was evaluated by an inhibition binding assay to Tg, using human monoclonal TgAb-Fab directed to A, B, C, and D epitopes on Tg. RESULTS: Median urinary iodine excretion was slightly higher in IS-users than in IS-nonusers (112.0 µg/L vs 86.5 µg/L; P < .01). TgAb, and not TPOAb, was more frequent in IS-users (18.9% vs 13.6%, P = .02). HT-US was found in 87 subjects, among whom both positive TgAb (58.4% vs 31.8%, P = .03) and TPOAb (61.5% vs 45.4%. P = .04) were more frequent in IS-users. In this group significantly higher serum levels of TgAb (median 108 U/mL vs 30 U/mL; P = .02), but not of TPOAb, were present. Iodized salt use had no effect on the 1208 non HT-US subjects. TgAb directed to the epitope B of Tg were more frequent in IS-users than in IS-nonusers (27.5% vs 3.0%, P = .047). CONCLUSIONS: Iodine-induced thyroid autoimmunity is related to TgAb and the unmasking of a cryptic epitope on Tg contributes to this relationship in humans.

Thyroglobulin autoantibodies in patients with papillary thyroid carcinoma: comparison of different assays and evaluation of causes of discrepancies.

CONTEXT: Thyroglobulin autoantibodies (TgAb) have been proposed as a surrogate marker of thyroglobulin in the follow-up of differentiated thyroid carcinoma. Commercially available TgAb assays are often discordant. We investigated the causes of discrepancy. DESIGN: TgAb were measured by three noncompetitive immunometric assays and three competitive RIA in 72 patients with papillary thyroid carcinoma and associated lymphocytic thyroiditis (PTC-T), 105 with papillary thyroid carcinoma and no lymphocytic thyroiditis (PTC), 160 with Hashimoto's thyroiditis, and in 150 normal subjects. The results of the six assays were correlated. TgAb epitope pattern, evaluated by inhibition of serum TgAb binding to thyroglobulin by TgAb-Fab regions A, B, C, and D, were compared in sera which were positive in all six assays (concordant sera) and positive in only one to five assays (discordant sera) were compared. TgAb International Reference Preparation (IRP) was measured in 2007 and 2009. RESULTS: The correlations of the six assays ranged from -0.01 to 0.93 and were higher in PTC-T and Hashimoto's thyroiditis than in PTC and normal subjects. Two uncorrelated components, one including the three immunometric assays, the other the three RIA, explained 40 and 37% of the total variance of the results of the six assays. The levels of inhibition were higher in concordant sera than in discordant sera by TgAb-Fab region B (27.0%, 21.2-34.0 vs. 6.0%, and 2.7-12.7%) and region C (30.5%, 21.3-37.7 vs. 4.0%, and 1.0-6.5%); thus, the epitope pattern was more homogeneous in concordant sera than in discordant sera. TgAb IRP ranged from 157 to 1088 (expected 1000) IU/ml in 2009; results in 2007 were similar in all but two assays. CONCLUSIONS: TgAb assays are highly discordant. Discrepancy is lower when comparing assays with similar methodology. Results of TgAb from PTC-T are more concordant than those from PTC because their epitope pattern is more restricted. The internal standardization of TgAb is generally, but not completely, satisfactory.

Lymphocytic thyroiditis on histology correlates with serum thyroglobulin autoantibodies in patients with papillary thyroid carcinoma: impact on detection of serum thyroglobulin.

CONTEXT: Serum thyroglobulin (Tg), the marker of residual tumor in papillary thyroid carcinoma, can be underestimated in patients with Tg autoantibodies (TgAb). TgAb are due to a coexistent lymphocytic thyroiditis (LT) or the papillary thyroid carcinoma per se. TgAb assays are highly discordant. DESIGN: We evaluated 141 patients with a clinical diagnosis of nodular thyroid disease, 32 of Hashimoto's thyroiditis, and four of Graves' disease, who underwent total thyroidectomy for an associated papillary thyroid carcinoma. Patients were classified as papillary thyroid carcinoma-lymphocytic thyroiditis (PTC-T) and papillary thyroid carcinoma (PTC) according to the presence or absence of LT on histology. Tg was measured before thyroid remnant ablation, when it is expectedly detectable, by an immunometric assay (IMA) and TgAb by three noncompetitive IMA and three competitive radioimmunoassays (RIA). The number of lymphocytes was compared with TgAb concentration. RESULTS: Seventy-two of 177 patients (40.7%) were classified as PTC-T and 105 (59.3%) as PTC. Although the tumor stage was similar in the two groups, Tg was undetectable in more PTC-T (37 of 72) than PTC (12 of 105) (P < 0.01), and Tg values were lower in the former (0; 0-4.7 ng/ml) (median; 25th to 75th percentiles) than in the latter group (9.7; 2.7-24.2) (P < 0.01). Accordingly, the percent of positive TgAb by the six assays resulted in higher PTC-T (29.2-50.0%) than PTC (1.9-6.7%) (P < 0.01). Among 49 patients with undetectable Tg, TgAb were more frequently positive by IMA (57.1-63.3%) than RIA (30.6-42.9%). The number of lymphocytes correlated with TgAb concentration in all six assays (0.34 < Rho < 0.46) (all P < 0.01). CONCLUSIONS: In papillary thyroid carcinoma, LT on histology must be carefully searched for because it is frequently associated with TgAb and therefore mistakenly low or undetectable Tg. TgAb can be missed by some assays. In absence of LT, TgAb are rare.

Characterization of thyroglobulin epitopes in Sardinian adults and juveniles with Hashimoto's thyroiditis: evidence against a major effect of age and genetic background on B-cell epitopes.

BACKGROUND: Using recombinant human monoclonal thyroglobulin antibodies expressed as Fab molecules (TgAb-Fab), we have recently confirmed the restriction of Tg epitopes in Hashimoto's thyroiditis (HT). OBJECTIVE: To investigate Tg epitopes of serum TgAb in HT adults and HT juveniles from a geographically isolated area (Sardinia). DESIGN AND PATIENTS: Serum TgAb of 39 Sardinian HT adults, 53 Sardinian HT juveniles and 45 non-Sardinian HT adults were evaluated. The binding of serum TgAb to Tg in ELISA was inhibited by four recombinant human TgAb-Fab, identifying Tg epitopic regions A-D. The percentage of Tg binding inhibition was calculated comparing the binding of serum TgAb in presence of each TgAb-Fab with that in its absence. RESULTS: In the whole cohort of 137 patients, A region TgAb-Fab induced the highest levels of inhibition (55.3 +/- 17.8%) (mean +/- SD). Lower levels of inhibition were induced by TgAb-Fab of regions B (27.8 +/- 25.8%), C (26.8 +/- 24.6%) and D (17.5 +/- 18.4%). In Sardinian HT adults inhibition by TgAb-Fab of regions A, B and C were comparable to Sardinian HT juveniles; the marginal D region TgAb-Fab induced a slightly higher inhibition (22.1 vs. 13.8%; P = 0.034) in the former than in the latter group. In Sardinian and non-Sardinian HT adults inhibitions by the four TgAb-Fab were similar. CONCLUSIONS: In HT, the Tg epitope pattern of serum TgAb was similar in juveniles and adults from a geographically restricted area and in two adult populations from different geographical areas. Thus, in HT, neither age nor genetic background appear to influence B-cell epitopes.

Characterization of thyroglobulin epitopes in patients with autoimmune and non-autoimmune thyroid diseases using recombinant human monoclonal thyroglobulin autoantibodies.

CONTEXT: Thyroglobulin (Tg) epitopes of serum Tg autoantibodies (TgAb) have been characterized using inhibition of Tg binding by human monoclonal TgAb in autoimmune thyroid diseases (AITD) [Hashimoto's thyroiditis (HT) and Graves' disease (GD)] but not in non-AITD [nontoxic multinodular goiter (NTMG) and papillary thyroid carcinoma (PTC)]. OBJECTIVE: Our objective was to compare Tg epitopes of serum TgAb from patients with AITD, non-AITD, and PTC associated with histological thyroiditis (PTC-T) using inhibition of Tg binding by four recombinant human TgAb-Fab (epitopic regions A-D). DESIGN: Inhibition of Tg binding of 24 HT, 25 GD, 19 NTMG, 15 PTC, and 25 PTC-T TgAb-positive sera by each TgAb-Fab was evaluated in ELISA. Inhibition by the pool of the four TgAb-Fab was evaluated using labeled Tg. RESULTS: Levels of inhibition were different for TgAb-Fab regions A (P = 0.001), B (0.007), and D (0.011). Inhibition by region A TgAb-Fab was significantly higher in HT, GD, and PTC-T than in NTMG and PTC patients. Inhibition levels by region B TgAb-Fab were significantly higher in HT compared with NTMG and PTC patients and in GD compared with NTMG patients. Inhibition by D region TgAb-Fab was significantly lower in NTMG than in the other groups. Inhibition by the pool ranged from 44% (NTMG) to 72% (GD). CONCLUSIONS: The pattern of Tg recognition is similar when HT patients are compared to GD and NTMG to PTC patients and differs when AITD are compared with non-AITD patients. In PTC-T patients, it is similar to that of AITD patients.