Thyroglobulin Autoantibodies Research Articles

Delayed 131-I First Treatment After Surgery has No Impact on the Median Term Outcome of Patients with Intermediate Risk Differentiated Thyroid Cancer

Objective: In intermediate risk (IR) differentiated thyroid cancer (DTC) patients, selective use of radioiodine (131-I) for remnant ablation and/or as adjuvant therapy (RRA) is advocated. The recently suggested postoperative evaluation could delay the use of RRA. The aim of this study was to evaluate if a delayed RRA can worsen the clinical outcome of IR-DTC patients. Methods: Four hundred and fourteen consecutive IR-DTC patients were divided according to the time elapsed from surgery to RRA, <6 months (group A, 186/414 [44.9%]), or ≥6 months (group B, 228/414 [55.1%]). Clinical and biochemical data were collected, and clinical outcome was analyzed at the first evaluation (EV) after RRA (first-EV) and after a median of 6 years of follow-up (last-EV). Results: No difference in the clinical outcome of group A and B was found. Since a different activity of 131-I could have an impact on the outcome, we separately analyzed the groups according to the 131-I activity (low-activity group: 1,110 MBq/30 mCi [n = 320], and high-activity group: 3,700 MBq/100 mCi [n = 94]), further subdivided according to the time elapsed from surgery to RRA. No major differences were found in both the low- and high-activity groups when comparing the features of their subgroups A and B, as far as in their clinical outcome. Conclusion: The time elapsed between surgery and the first 131-I treatment does not influence the clinical outcome of IR-DTC patients. This finding allows a more relaxed attitude in the decision making process whether to perform the RRA in IR-DTC cases in which a selective use of 131-I is recommended. Abbreviations: ATA = American Thyroid Association; DTC = differentiated thyroid cancer; EV = evaluation; HR = high risk; 131-I = radioiodine; IR = intermediate risk; LR = low risk; rhTSH = recombinant human thyroid-stimulating hormone; RRA = radioiodine for remnant ablation; Tg = thyroglobulin; TgAb = thyroglobulin autoantibody; US = ultrasound.

Factors Influencing the Successful Maintenance of Euthyroidism after Lobectomy in Patients with Papillary Thyroid Microcarcinoma: A Single-Center Study

Objective: This study aimed to evaluate factors influencing the successful maintenance of postoperative euthyroidism in patients who did not undergo immediate thyroid hormone replacement after lobectomy for papillary thyroid microcarcinoma (PTMC). Methods: From September 2015 to June 2017, 186 patients underwent lobectomy for PTMC in our hospital. Patients taking medications for hypothyroidism and hyperthyroidism before and after lobectomy were excluded. Multiple parameters, including sex, age, pre-operative free thyroxine (T4), thyroid-stimulating hormone (TSH), thyroglobulin (TG), and thyroid autoantibody levels, body mass index (BMI), postoperative histopathology of the thyroid gland, remnant thyroid gland volume, and session number of levothyroxine discontinuation were retrospectively evaluated. These factors were compared between groups based on the maintenance of postoperative euthyroidism. Results: In 88 of the 175 patients (50.3%), postoperative euthyroidism was successfully maintained without thyroid hormone replacement during the first year after lobectomy. There were significant differences in sex (P = .003), pre-operative TSH levels (P = .002), and histopathology of the thyroid gland (P = .035) between the groups showing maintenance success and failure. The group showing successful maintenance had a higher percentage of male patients, lower levels of pre-operative TSH, and normal parenchymal histology of the thyroid gland. However, there were no significant between-group differences in age, pre-operative free T4, TG, and thyroid autoantibody levels, BMI, remnant thyroid gland volume, and session number of levothyroxine discontinuation. Conclusion: Patient sex, pre-operative TSH levels, and histopathology of the thyroid gland may influence the maintenance of postoperative euthyroidism after lobectomy. Abbreviations: BMI = body mass index; PTMC = papillary thyroid microcarcinoma; RR = reference range; T4 = thyroxine; TFT = thyroid function test; TG = thyroglobulin; TSH = thyroid-stimulating hormone.

A Novel Anti-Cd40 Monoclonal Antibody, Iscalimab, for Control of Graves’ Hyperthyroidism – A Proof-Of-Concept Trial

Abstract Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves’ disease (GD) by promoting auto-reactive B cell activation. Objective Evaluate efficacy and safety of a human, blocking, non-depleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD Design Open label, phase II proof-of-concept study Setting Multicenter Patients Fifteen with GD Intervention Patients received five doses of iscalimab at 10 mg/kg intravenously over 12 weeks. Main outcome measures Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. Results The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in seven of 15 (47%) patients. Free and total T3 and T4 normalized in seven patients who did not receive any rescue medication with anti-thyroid drugs (ATD), and 2/15 (13.3%) showed normal TSH. Six (40%) patients required ATD. Four of seven responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L versus 4.0 IU/L, 66% reduction, P&lt;0.001) and TSH-R-Ab levels normalized in four (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P&lt;0.001). Twelve (80.0%) patients reported at least one adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. Conclusion Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of Iscalimab should be further tested.

A Novel Anti-Cd40 Monoclonal Antibody, Iscalimab, for Control of Graves’ Hyperthyroidism – A Proof-Of-Concept Trial

Abstract Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves’ disease (GD) by promoting auto-reactive B cell activation. Objective Evaluate efficacy and safety of a human, blocking, non-depleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD Design Open label, phase II proof-of-concept study Setting Multicenter Patients Fifteen with GD Intervention Patients received five doses of iscalimab at 10 mg/kg intravenously over 12 weeks. Main outcome measures Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. Results The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in seven of 15 (47%) patients. Free and total T3 and T4 normalized in seven patients who did not receive any rescue medication with anti-thyroid drugs (ATD), and 2/15 (13.3%) showed normal TSH. Six (40%) patients required ATD. Four of seven responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L versus 4.0 IU/L, 66% reduction, P&lt;0.001) and TSH-R-Ab levels normalized in four (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P&lt;0.001). Twelve (80.0%) patients reported at least one adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. Conclusion Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of Iscalimab should be further tested.

Assessment of serum thyroid hormone autoantibodies in the first trimester of gestation as predictors of postpartum thyroiditis

BackgroundMeasurement of serum thyroperoxidase autoantibodies (TPOAb) during gestation as a classical marker for the risk of postpartum thyroiditis (PPT) predicts PPT in 1/3 to 1/2 of women. Very few studies have measured serum thyroid hormone Ab (THAb) during gestation, and none as a possible marker for PPT. MethodsIn 412 women who were followed up from 7 to 11 weeks of gestation through 12 months after delivery, we measured THAb (T3.IgM, T3.IgG, T4.IgM, T4.IgG), thyroglobulin autoantibodies (TgAb) and TPOAb at study entry (7–11 week of gestation). ResultsSixty-three women (15.3%) developed PPT, which progressed to permanent hypothyroidism (PH) in 34/63 (54%). THAb+ve were 21/412 women (5.1%), the frequency being greater in those who then developed PPT (12/63 [19.0%] vs. 9/349 [2.6%], P = 4.6 × 10−8), and in the PH subgroup (26.5% [9/34] vs. 10.3% [10/29], P = 0.12). THAb positivity occurred in 9/76 women (11.8%) who were TgAb and/or TPOAb+ve compared to 12/336 women who were TgAb and TPOAb negative (3.6%, P = 0.0031). Of these 9 THAb+ve, TgAb and/or TPOAb+ve women, all (100%) developed PPT compared to 3/11 (27.3%, P = 0.0011) THAb+ve, TgAb and/or TPOAb negative women. Of these 9 and 3 PPT women, 8 and 1 progressed to PH (88.9% and 33.3%, respectively, P = 0.12). ConclusionsGestational positivity of THAb enhance enormously the predictivity for PPT of gestational positivity of TPOAb/TgAb. However, their low frequency (5.1%) and their sensitivity (17.5% [21/63]) go against their application in lieu of TPOAb/TgAb.

Measuring thyroglobulin in patients with thyroglobulin autoantibodies: evaluation of the clinical impact of BRAHMS Kryptor® Tg-minirecovery test in a large series of patients with differentiated thyroid carcinoma.

Background The present study was undertaken to evaluate the clinical impact of a thyroglobulin (Tg) minirecovery test (Tg-mRec) in a large series of differentiated thyroid carcinoma (DTC) patients treated and monitored homogeneously in a tertiary referral center. Methods Included were 1120 serum samples from 798 DTC patients. Tg, Tg autoantibodies (TgAb) and Tg-mrec measurements were performed on the automated Kryptor® platform and results compared to the corresponding clinical status. Results Among included samples 228 (20%) were TgAb-positive (TgAb+) and 892 (80%) TgAb-negative (TgAb-), respectively. Tg cutoff points were settled at 0.31 μg/L and 0.15 μg/L for TgAb- and TgAb+ patients, respectively, by ROC curve analysis. The diagnostic performance of serum Tg was reduced in TgAb+ compared to TgAb- patients, however, 87% of TgAb+ patients with recurrent disease and, particularly, all patients with distant metastases were correctly detected by adopting an optimized Tg cutoff for TgAb+ patients. A disturbed recovery was found in only 1% of TgAb- patients and in these cases no clinically relevant information was added by the Tg-mRec. Among TgAb+ patients with undetectable Tg and undisturbed Tg-mRec, no one had recurrent disease. However, a falsely undetectable Tg was demonstrated in two patients with recurrent disease who next to increased TgAb also had a disturbed Tg-mRec test. Conclusions There is no additional clinical benefit from performing Tg-mRec in most patients. It can however be considered in TgAb+ patients with undetectable Tg levels as it may help differentiate between patients with true negative and false negative Tg levels in the presence of such antibodies.

The case for partitioning of 1st trimester-specific TSH reference intervals

There is growing concern that a universal 1st trimester TSH cut-off of 2.5 mIU/L may cause overdiagnosis and overtreatment of subclinical hypothyroidism in pregnancy.1 New guidelines2 promote the establishment of local population-based trimester-specific reference intervals and a focus on higher upper reference limits in all trimesters. We reviewed 1st trimester TSH Results measured on the Abbott ARCHITECT i4000SR in our population partitioned into two subgroups. Patients with evidence of thyroid peroxidase, thyroglobulin and TSH receptor autoantibodies were excluded. Partitions were decided based on hCG physiology and the literature. Reference intervals were calculated using nonparametric statistics as per CLSI guidelines3 and groups were compared with Analyse-it software applying the Mann-Whitney test. The TSH reference intervals were as follows: weeks 3 to 13, 0.13–3.9 mIU/L; two subgroups: weeks 3 to 6, 0.46–4.4 mIU/L, and weeks 7 to 13, 0.03–3.2 mIU/L. The two subgroups were statistically different (p<0.0001). The most significant decrease in TSH is known to occur in the latter part of the 1st trimester and in view of this we recommend either partitioning the 1st trimester or setting a specific time frame for screening patients for thyroid disease in the 1st trimester of pregnancy.

Clinical Applicability of Low Levels of Thyroglobulin Autoantibodies as Cutoff Point for Thyroglobulin Autoantibody Positivity

Thyroglobulin (Tg) is an established tumor marker in differentiated thyroid carcinoma (DTC). However, Tg assays can be subject to interference by autoantibodies against Tg (TgAbs). No clinical consensus exists on the cutoff value of TgAb positivity and its relationship to Tg assay interference. The aims of this study were to investigate the most applicable cutoff value for TgAb positivity in clinical practice and to evaluate whether tumor characteristics differ between TgAb+ and TgAb- patients during ablation therapy using the manufacturer's cutoff (MCO) and institutional cutoff (ICO). This single-center cohort study included 230 DTC patients diagnosed between January 2006 and December 2014. Serum Tg and TgAbs were measured with the Tg-IRMA (Thermo Fisher Scientific) and ARCHITECT Anti-Tg (Abbott Laboratories) assays. Patients were divided into TgAb- and TgAb+ based on the limit of detection (LoD; ≥0.07 IU/mL), functional sensitivity (FS; ≥0.31 IU/mL), MCO (≥4.11 IU/mL), and ICO (≥10 IU/mL). All patients were TgAb+ based on the LoD; one patient was negative on FS. Fifty-five (23.9%) and 34 (14.8%) patients had TgAbs above the MCO and ICO, respectively. Histology, presence of multifocality, tumor-node-metastasis, and American Thyroid Assocation risk stratification did not differ between TgAb- and TgAb+ patients using MCO and ICO during ablation. This study supports the use of a higher cutoff value than that of the FS for TgAb positivity in clinical settings. The LoD and FS are too sensitive to discriminate TgAb positivity and negativity in DTC patients during ablation therapy. The presence of TgAbs during ablation is not related to tumor characteristics and risk profile. This implies that TgAb positivity should not be considered a separate risk factor.

Relatively high rate of postpartum thyroiditis in the Straits of Messina area. Predictivity of both postpartum thyroiditis and permanent hypothyroidism by performing, in the first trimester of gestation, thyroid ultrasonography and measurement of serum thyroperoxidase and thyroglobulin autoantibodies

The prevalence of postpartum thyroiditis (PPT) averages 5%, with a range from 1% (Thailand) to 22% (Wales, UK, and Liguria, Italy), but 3.6% in another Italian region (Puglia). Evolution of PPT into permanent hypothyroidism (PH) occurs in approximately 50% of cases. Positive thyroperoxidase autoantibodies (TPOAb) in a pregnant woman is a strong predictor of PPT. Because in previous gestational cohorts we found an approximate 12% rate of TPOAb positivity, which compares with 15% in the Liguria cohort and 6% in the Puglia cohort, we hypothesized that the currently unknown prevalence of PPT in Sicily would approximate the said Liguria prevalence. We also explored the predictive value of serum thyroglobulin Ab (TgAb) positivity and ultrasonographic signs suggestive of thyroiditis (UST) at first trimester of gestation for PPT.Of 412 pregnant women who were followed-up for 1 year after delivery, 63 (15.3%) developed PPT, and 54% of them had PH. Gestational rates of TPOAb positivity alone, TgAb positivity alone or UST were 11.4%, 7.8% or 35.0%, with associated PPT rates of 66%, 45% or 36%. TgAb assay allowed detection of 9/63 PPT women (14.3%) who were TPOAb-negative. However, TPOAb remained a better predictor compared to TgAb or UST (odds ratio = 32 vs 10 or 13). Lowering the positivity threshold for either Ab to ≥61 U/ml, Ab-positive were 23.8% of PPT women and 17.7% of pH women. UST was detected in 82.5% of women who developed PPT, precisely 88% of those who evolved into PH and 75.9% of those who did not.Ours is the second study of the new millennium showing a PPT frequency >10%. The dual Ab and lowered threshold strategy correctly predicts more cases of PPT and PH compared to the sole TPOAb strategy. We confirm that half of the PPT women will have PH.

Changes in serum thyroglobulin and antithyroglobulin shortly following high-intensity focused ablation of benign thyroid nodules in patients with positive antithyroglobulin status

Background: We aimed to describe changes in serum thyroglobulin (Tg) and anti-Tg autoantibody shortly following high-intensity focused ultrasound (HIFU) ablation in patients with positive anti-Tg status by comparing them with patients with negative anti-Tg and to correlate them with 6-month nodule shrinkage and treatment success.Methods: From 2015 to 2017, patients who underwent HIFU ablation of a benign thyroid nodule were analysed. Serum Tg and anti-Tg were checked on treatment day (baseline) and 4 days after treatment. Anti-Tg >99 IU/ml were considered positivity. Percentage Tg or anti-Tg change = [Level on Day-4 – baseline level]/[Baseline level] × 100 while nodule shrinkage was measured by volume reduction ratio (VRR) = [Baseline volume – volume at 6 month]/[Baseline volume] × 100. Treatment success was defined as VRR >50%.Results: Among the 276 eligible patients, 85 (30.8%) patients were positive for anti-Tg (Group I) while the others (n = 191, 69.2%) were negative (Group II). Relative to group II, Group I had a less significant Tg rise on Day 4 (4121.78 ± 9321.90% vs. 5711.53 ± 23487.20%, p = .013). There was a fall in anti-Tg on day 4 for group I (−11.56 ± 139.69%). This percentage anti-Tg drop significantly correlated with the 6-month VRR (ρ = −0.602, p = .030) but was not a significant factor of treatment success.Conclusions: Given the fact that the percentage anti-Tg drop correlated significantly with 6-month nodule shrinkage in group I, monitoring early anti-Tg change may help to predict the 6-month nodule shrinkage in patients with positive anti-Tg.

Oral lichen planus - Differential diagnoses, serum autoantibodies, hematinic deficiencies, and management.

Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disease that occurs more frequently in middle-aged and elderly female patients. Previous studies indicate that OLP is a T-cell dysfunction-induced localized autoimmune disease. Clinically, six types of OLP, namely reticular, papular, plaque-like, atrophic/erosive, ulcerative, and bullous types, can be identified. OLP more commonly affects buccal mucosa, tongue, and gingiva. It always has a bilateral and symmetric distribution of the oral lesions. Plaque-like and atrophic/erosive OLP may be misdiagnosed as oral leukoplakia and oral erythroleukoplakia, respectively. Our previous study found serum autoantibodies in 195 (60.9%) of the 320 OLP patients. Specific serum anti-nuclear, anti-smooth muscle, anti-mitochondrial, gastric parietal cell, thyroglobulin, and thyroid microsomal autoantibodies are present in 28.1%, 8.4%, 1.6%, 26.3%, 21.3%, and 24.4% of 320 OLP patients, respectively. Furthermore, we also discovered that 21.9%, 13.6%, 7.1%, 0.3%, and 14.8% of 352 OLP patients have hemoglobin, iron, vitamin B12, and folic acid deficiencies, and abnormally high serum homocysteine level, respectively. Therefore, it is very important to examine the serum autoantibody, hematinic and homocysteine levels in OLP patients before starting the treatments for OLP patients. Because OLP is an immunologically-mediated disease, corticosteroids are the drugs of choice for treatment of OLP.

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

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. 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). 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). 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.

The effect of anti-TNF therapy on thyroid function in patients with inflammatory bowel disease.

The aim of this study was to investigate for first time the thyroid function in patients with inflammatory bowel disease (IBD) and the potential effect of anti-TNF (tumor necrosis factor) therapy. We evaluated 41 patients with IBD (25M/16F, 36.5 ± 11.3 y, 27 with Crohn's disease and 14 with ulcerative colitis), without any known thyroid disorder. Eighteen patients (9M/9F, 33.6 ± 8.8 y) were on anti-TNF therapy, while 23 patients (16M/7F, 38.7 ± 12.5 y) were treated with Azathioprine and Mesalazine (Aza/Mes) for more than 1 year. Twelve patients from the second group were then treated with anti-TNF and studied 6 months later. We assessed thyroid function by measuring thyroid stimulating hormone (TSH), free thyroxine (FT4), triiodothyronine (T3), thyroid peroxidase autoantibodies (TPOAb) and thyroglobulin autoantibodies (TgAb) levels. One patient presented with overt and one with subclinical hyperthyroidism. Thyroid auto-antibodies were positive in 12.2%. Patients from the anti-TNF group had lower levels of FT4 (1.09 ± 0.15 vs. 1.38 ± 0.9 ng/dL, p = 0.042), while TSH and T3 were comparable. The percentage of patients with positive thyroid auto-antibodies was lower in the anti-TNF group (5.6% vs. 17.4%). In the subgroup of patients who changed to anti-TNF, we found statistically significant reduction in FT4 after 6 months (1.26 ± 0.24 vs. 1.08 ± 0.15 ng/dL, p = 0.044), without changes in TSH and T3 levels. There was no change regarding thyroid auto-antibodies. In conclusion, patients with IBD showed a quite high percentage of thyroid autoimmunity. After treatment with anti-TNF, FT4 levels were found to be reduced, while no changes in TSH, T3 levels and thyroid auto-antibodies were noted.

Effects of Toceranib Phosphate on the Hypothalamic-Pituitary-Thyroid Axis in Tumor-Bearing Dogs.

BackgroundThyroid dysfunction is associated with the use of tyrosine kinase inhibitors (TKI) in people.Hypothesis/ObjectivesTo determine whether dysfunction in the hypothalamic‐pituitary‐thyroid axis occurs in dogs receiving the TKI, toceranib phosphate.AnimalsForty‐three client‐owned dogs with cancer.MethodsProspective, observational study. Concentrations of total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), and thyroid‐stimulating hormone (TSH) were evaluated on day 0, 30, and 90. Dogs also were evaluated for the presence of thyroglobulin autoantibodies.ResultsThe proportion of dogs with low TT4, low FT4, low TT3, high TSH, or primary hypothyroidism (increased TSH and decreased TT4, FT4 or both) did not change over 90 days. Hormone concentrations remained within laboratory reference intervals, but FT4 (P = 0.0032) and TSH (P < 0.0001) changed over time. Mean FT4 was 1.22 ng/dL (95% confidence interval [CI], 1.10–1.34) on day 0 and 1.00 ng/dL (95% CI, 0.86–1.16) on day 90. Mean TSH was 0.17 ng/mL (95% CI, 0.13–0.23) on day 0 and 0.34 ng/mL (95% CI, 0.24–0.48) on day 90. Furthermore, TT4/TT3 ratio also changed over time (P = 0.0086). Mean TT4/TT3 ratio was 2.57 (95% CI, 2.26–2.88) on day 0 and 2.02 on day 90 (95% CI, 1.61–2.44). Thyroglobulin autoantibodies were not detected in any dog.Conclusions and Clinical ImportanceToceranib phosphate can disrupt the hypothalamic‐pituitary‐thyroid axis in dogs. Periodic evaluation of TT4, FT4, TT3, and TSH should be carried out in dogs receiving long‐term treatment with this medication.

Definition of the upper reference limit for thyroglobulin antibodies according to the National Academy of Clinical Biochemistry guidelines: comparison of eleven different automated methods

PurposeIn the last two decades, thyroglobulin autoantibodies (TgAb) measurement has progressively switched from marker of thyroid autoimmunity to test associated with thyroglobulin (Tg) to verify the presence or absence of TgAb interference in the follow-up of patients with differentiated thyroid cancer. Of note, TgAb measurement is cumbersome: despite standardization against the International Reference Preparation MRC 65/93, several studies demonstrated high inter-method variability and wide variation in limits of detection and in reference intervals. Taking into account the above considerations, the main aim of the present study was the determination of TgAb upper reference limit (URL), according to the National Academy of Clinical Biochemistry guidelines, through the comparison of eleven commercial automated immunoassay platforms.MethodsThe sera of 120 healthy males, selected from a population survey in the province of Verona, Italy, were tested for TgAb concentration using eleven IMA applied on as many automated analyzers: AIA-2000 (AIA) and AIA-CL2400 (CL2), Tosoh Bioscience; Architect (ARC), Abbott Diagnostics; Advia Centaur XP (CEN) and Immulite 2000 XPi (IMM), Siemens Healthineers; Cobas 6000 (COB), Roche Diagnostics; Kryptor (KRY), Thermo Fisher Scientific BRAHMS, Liaison XL (LIA), Diasorin; Lumipulse G (LUM), Fujirebio; Maglumi 2000 Plus (MAG), Snibe and Phadia 250 (PHA), Phadia AB, Thermo Fisher Scientific. All assays were performed according to manufacturers’ instructions in six different laboratories in Friuli-Venezia Giulia and Veneto regions of Italy [Lab 1 (AIA), Lab 2 (CL2), Lab 3 (ARC, COB and LUM), Lab 4 (CEN, IMM, KRY and MAG), Lab 5 (LIA) and Lab 6 (PHA)]. Since TgAb values were not normally distributed, the experimental URL (e-URL) was established at 97.5 percentile according to the non-parametric method.ResultsTgAb e-URLs showed a significant inter-method variability. Considering the same method, e-URL was much lower than that suggested by manufacturers (m-URL), except for ARC and MAG. Correlation and linear regression were unsatisfactory. Consequently, the agreement between methods was poor, with significant bias in Bland–Altman plot.ConclusionsDespite the efforts for harmonization, TgAb methods cannot be used interchangeably. Therefore, additional effort is required to improve analytical performance taking into consideration approved protocols and guidelines. Moreover, TgAb URL should be used with caution in the management of differentiated thyroid carcinoma patients since the presence and/or the degree of TgAb interference in Tg measurement has not yet been well defined.

Clinical impact of thyroglobulin (Tg) and Tg autoantibody (TgAb) measurements in needle washouts of neck lymph node biopsies in the management of patients with papillary thyroid carcinoma.

The presence of thyroglobulin (Tg) in needle washouts of fine needle aspiration biopsy (Tg-FNAB) in neck lymph nodes (LNs) suspected of metastasis has become a cornerstone in the follow-up of patients with papillary thyroid carcinoma (PTC). However, there are limited data regarding the measurement of anti-Tg antibodies in these washouts (TgAb-FNAB), and it is not clear whether these antibodies interfere with the assessment of Tg-FNAB or whether there are other factors that would more consistently justify the finding of low Tg-FNAB in metastatic LNs. We investigated 232 FNAB samples obtained from suspicious neck LNs of 144 PTC patients. These samples were divided according to the patient's serum TgAb status: sTgAb- (n = 203 samples) and sTgAb+ (n = 29). The TgAb-FNAB levels were measured using two different assays. Tg-FNAB was also measured using two assays when low levels (< 10 ng/mL) were identified in the first assay of the metastatic LNs from the sTgAb+ samples. The TgAb-FNAB results were negative in both assays in all samples. Low levels of Tg-FNAB were identified in 11/16 of the metastatic LNs of the sTgAb+ patients and 16/63 of the sTgAb- patients (p < 0.05) using assay 1. The measurement of the Tg-FNAB levels using assay 2 indicated additional metastases in 5 LNs of the sTgAb+ patients. Factors other than the presence of TgAb-FNAB may contribute to the higher number of metastatic LNs with undetectable Tg-FNAB in the sTgAb+ group. In addition, the measurement of Tg-FNAB using different assays was useful to enhance the diagnosis of metastatic LNs, particularly when cytological and Tg-FNAB results are discordant.

Thyroglobulin autoantibodies before radioiodine ablation predict differentiated thyroid cancer outcome.

Serum thyroglobulin (Tg) is essential to manage differentiated thyroid carcinoma (DTC). However, Tg determination is affected by circulating Tg antibodies (TgAb), and a role of TgAb as surrogate biomarker has been proposed. Here we evaluated the role of TgAb measured before and after radioiodine ablation (RRA) as potential predictors of prognosis. Patients treated since 2006 were screened. Cancers with structural relapse were defined as recurrent. Both Tg and TgAb were measured by immunoassays on the fully automated Kryptor® platform (BRAHMS Gmbh, Henningsdorf, Germany). A series of 215 DTC patients was enrolled, of whom 28.8% had positive preablation TgAb. Overall, 2.8% patients died by DTC and 11% recurred. High-risk class (p=0.004) and cancer relapse (p=0.007) occurred more frequently in positive TgAb, whereas better disease-free survival was observed in negative group (hazard ratio 2.59, p=0.01). Having positive preablation TgAb was significantly associated with risk to develop recurrence (odds ratio 3.57, p=0.004). Among positive TgAb subgroup, higher levels were recorded in recurrent cases (p=0.0001), and the most accurate preablation TgAb threshold was 107.5 IU/mL. When TgAb were measured at first follow-up, recurrence rate was significantly (p<0.0001) higher in persistently TgAb-positive patients (75%) than normalized ones (2.4%). At that time, the highest negative predictive value could be obtained when considering TgAb normalization (<33 IU/mL) or reduction by ≥36.4%. Positive TgAb before RRA indicates higher risk of poor prognosis, but their significant drop 6-12 months later could be considered a favorable factor.

Analytical and clinical performance of thyroglobulin autoantibody assays in thyroid cancer follow-up.

While thyroglobulin autoantibodies (TgAb) can result in false low serum thyroglobulin (Tg) immunoassay (IA) measurements, they might also be indicators of disease persistence/recurrence. Hence, accurate TgAb measurement, in addition to Tg quantification, is crucial for thyroid cancer monitoring. We compared the analytical and clinical performance of four commonly used TgAb IAs. We measured Tg by mass spectrometry (Tg-MS) and by four pairs of Tg and TgAb IAs (Beckman, Roche, Siemens, Thermo) in 576 samples. Limit of quantitation (LOQ) and manufacturers' upper reference interval cut-off (URI) were used for comparisons. Clinical performance was assessed by receiving operator characteristics (ROC) curve analysis. Quantitative and qualitative agreement between TgAb-IAs was moderate with R2 of 0.20-0.70 and κ from 0.41-0.66 using LOQ and 0.47-0.71 using URI. In samples with TgAb interference, detection rates of TgAb were similar using LOQ and URI for Beckman, Siemens, and Thermo, but much lower for the Roche TgAb-IA when the URI was used. In TgAb positive cases, the ROC areas under the curve (AUC) for the TgAb-IAs were 0.59 (Beckman), 0.62 (Siemens), 0.59 (Roche), and 0.59 (Thermo), similar to ROC AUCs achieved with Tg. Combining Tg and TgAb measurements improved the ROC AUCs compared to Tg or TgAb alone. TgAb-IAs show significant qualitative and quantitative differences. For 2 of the 4 TgAb-IAs, using the LOQ improves the detection of interfering TgAbs. All assays showed suboptimal clinical performance when used as surrogate markers of disease, with modest improvements when Tg and TgAb were combined.

Thyroid profile and autoantibodies in Type 1 diabetes subjects: A perspective from Eastern India.

Context:There has been a rise in the incidence of type 1 diabetes mellitus (T1DM) in India. The prevalence of thyroid autoantibodies and thyroid dysfunction is common in T1DM.Aims:The aim of this study is to determine the incidence of thyroid dysfunction and thyroid autoantibodies in T1DM subjects, without any history of thyroid disease, and the prevalence of glutamic acid decarboxylase (GAD) antibody, Islet antigen-2 antibody (IA2), thyroid peroxidase (TPO), and thyroglobulin autoantibodies (Tg-AB) in T1DM subjects.Settings and Design:This was a cross-sectional clinical-based study.Subjects and Methods:Fifty subjects (29 males, 31 females) with T1DM and without any history of thyroid dysfunction were included in the study. All subjects were tested for GAD antibody, IA2 antibody, TPO antibody, thyroglobulin antibody, free thyroxine, and thyroid-stimulating hormone.Statistical Analysis Used:A Chi-square/pooled Chi-square test was used to assess the trends in the prevalence of hypothyroidism. A two-tailed P < 0.05 was considered statistically significant.Results:The mean age of the subjects was 23.50 years. 9.8% of subjects were below the age of 12 years, 27.45% of subjects were of age 12–18 years, 37.25% of subjects were of age 19–30 years, and 25.49% of subjects were above 30 years. 78% were positive autoantibody for GAD, 30% for IA-2, 24% for TPO, and 16% were positive for Tg-AB. A total of 6.0% of T1DM subjects had evidence of clinical hypothyroidism, but the prevalence of subclinical hyperthyroidism (SCH) varied from 32% to 68.0% for we considered different definitions of SCH as advocated by different guidelines. All subjects with overt hypothyroidism had positive GAD and thyroid autoantibodies. One (2%) subject had clinical hyperthyroidism with strongly positive GAD, TPO, and Tg-AB.Conclusions:We found a high prevalence of GAD, IA2, TPO, and Tg-AB in our T1DM subjects. A substantial proportion of our subjects had undiagnosed thyroid dysfunction with a preponderance of subclinical hypothyroidism. All T1DM subjects with overt hypothyroidism or hyperthyroidism had positive GAD and thyroid autoantibodies. The high prevalence of undiagnosed thyroid dysfunction highlights the importance of regular thyroid screening in T1DM subjects.

Selenium Supplementation Significantly Reduces Thyroid Autoantibody Levels in Patients with Chronic Autoimmune Thyroiditis: A Systematic Review and Meta-Analysis.

Selenium supplementation may decrease circulating thyroid autoantibodies in patients with chronic autoimmune thyroiditis (AIT), but the available trials are heterogenous. This study expands and critically reappraises the knowledge on this topic. A literature search identified 3366 records. Controlled trials in adults (≥18 years of age) with AIT, comparing selenium with or without levothyroxine (LT4), versus placebo and/or LT4, were eligible. Assessed outcomes were serum thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) autoantibody levels, and immunomodulatory effects. After screening and full-text assessment, 16 controlled trials were included in the systematic review. Random-effects meta-analyses in weighted mean difference (WMD) were performed for 3, 6, and 12 months of supplementation in two different populations: one receiving LT4 therapy and one newly diagnosed and LT4-untreated. Heterogeneity was estimated using I2, and quality of evidence was assessed per outcome, using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. In LT4-treated populations, the selenium group had significantly lower TPOAb levels after three months (seven studies: WMD = -271 [confidence interval (CI) -366 to -175]; p < 0.0001; I2 = 45.4%), which was consistent at six months (three studies) and 12 months (one study). TgAb decreased at 12 months, but not at three or six months. In LT4-untreated populations, the selenium group showed a decrease in TPOAb levels after three months (three studies: WMD = -512 [CI -626 to -398]; p < 0.0001, I2 = 0.0%), but not after 6 or 12 months. TgAb decreased at 3 months, but not at 6 or 12 months. Quality of evidence was generally assessed as low. Study participants receiving selenium had a significantly higher risk than controls of reporting adverse effects (p = 0.036). Selenium supplementation reduced serum TPOAb levels after 3, 6, and 12 months in an LT4-treated AIT population, and after three months in an untreated AIT population. Whether these effects correlate with clinically relevant measures remains to be demonstrated.