Titers Of Antithyroglobulin Antibodies Research Articles

FRI556 Thyroid Autoimmunity Leading To Premature Ovarian Insufficiency (POI) In A Euthyroid Young Woman

Abstract Disclosure: P. rimal: None. M. Moeed: None. C. Musurakis: None. A. Ojha: None. W. Akhtar: None. C.P. Barsano: None. M.F. Siddiqui: None. Introduction: Premature Ovarian Insufficiency is rare in young women and affects only 0.1% before the age of 30. The causes of POI in most cases remain unidentified, with autoimmunity being responsible for 4-30% of the cases. We present the case of a young euthyroid woman who presented for the evaluation of primary amenorrhea and diagnosed with POI associated with thyroid autoimmunity. Clinical Case: A 28-year-old Afghani woman with no known co-morbidities was referred to endocrinology clinic for the work up of primary amenorrhea. She was a goitrous and had normal secondary sexual characteristics and a history of withdrawal bleeding with OCP. There was no known personal or family history of autoimmune disease. Work up revealed hypergonadotropic hypogonadism with high FSH, 55 mIU/ml[Ref range for postmenopausal woman 16.7-113], high LH, 20.28 mIU/ml [Ref range for postmenopausal woman 10.8-58.69] and low estradiol, <2 pg/ml. Anti-Mullerian hormone was low, <0.08ng/ml [RefRange 0.69-13.39] signifying inadequate ovarian reserves and pelvic ultrasound confirmed atrophic ovaries. Etiological work up revealed normal female karyotype, 46XX, and negative FMR gene mutation testing for Fragile X syndrome. Thyroid functions were normal TSH, 3.3 mIU/L (0.27-4.2) and Free T4, 1.29 ng/dl[Ref Range 0.70-2.7]. Autoimmune work up was negative for adrenal 21-OH antibody and anti-ovarian antibodies. However, patient had strongly positive thyroid peroxidase (TPO) antibodies, 613.77 mIU/L[Ref range 0.0-9.0] consistent with thyroid autoimmunity. DXA scan revealed osteopenia. Thus, the diagnosis of POI associated with thyroid autoimmunity was established. HRT with estradiol patch and progesterone was initiated. Calcium, Vitamin D supplements and fertility counseling were provided. Conclusion: Thyroid disease is the most common autoimmune disease associated with POI. Studies have shown higher risk of POI and infertility in patients with Hashimoto’s and Graves’ diseases with co-existing high titers of TPO or anti-thyroglobulin antibodies. Ovaries are subject to autoimmune attack that leads to diminished ovarian reserves. However, until now the association of isolated elevation of TPO antibodies with POI has not been established. A Study by Osuka et al. did not find any significant difference in AMH levels between TPO and non-TPO positive euthyroid women and concluded that unlike hypothyroid women, thyroid autoantibodies were not likely to influence ovarian reserves in euthyroid women. Our case is unique where POI is associated with isolated elevation of TPO antibodies in the absence of clinical thyroid disease. This signifies the possibility that ovarian failure may precede the onset of thyroid disease in patients with thyroid autoimmunity and should be suspected and treated at an early stage, before ovarian reserves are diminished. Presentation: Friday, June 16, 2023

FRI476 Asymptomatic Thyrotropin-secreting Pituitary Microadenoma With Biochemical Secondary Hyperthyroidism: A Diagnostic Conundrum

Abstract Disclosure: G. Al-Naqeeb: None. R. Ghosh: None. P. Veeraraghavan: None. C. Cochran: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. Background: Thyrotropin (TSH)-secreting pituitary adenomas (TSHAs) are often macroadenomas (>1 cm), and clinically present with secondary hyperthyroidism (SH), but clinically silent microTSHAs (<1 cm) with only biochemical SH pose a diagnostic challenge. Clinical Case: A 49-year-old, healthy male was referred to our center for evaluation of abnormal thyroid function tests (TFTs). Immunoassay (IA) measurements at an outside hospital had identified elevated free T4 (FT4), and an inappropriately normal TSH, and a pituitary magnetic resonance imaging (MRI) had noted an 8mm x 7mm non-invasive adenoma. The patient denied hyperthyroidism symptoms, medication/herbal supplement intake, radiation exposure, headaches, vision changes, and thyroid/pituitary disorders, or abnormal TFTs in relatives. Physical exam revealed no signs and symptoms of hyperthyroidism. No thyromegaly or cervical lymphadenopathy was felt. IA profile at our institute was consistent with an SH pattern [TSH: 3.32 mIU/L (NL: 0.4 - 4.7); FT4: 3 ng/dL (NL: 0.9 - 1.7); total T4: 14.5 mcg/dL (NL: 4.5 - 11.7); triiodothyronine: 266.6 ng/dL (NL: 80 - 200)], with similar values on repeat measurement. Equilibrium dialysis technique also yielded an elevated FT4 value. TSH-receptor, anti-thyroid peroxidase, and anti-thyroglobulin (Tg) antibody (Ab) titers, serum Tg, and thyroid binding globulin levels were normal. Dilution studies ruled out heterophile Ab interference. Familial dysalbuminemic hyperthyroxinemia was unlikely given the elevated FT4 values. Genetic testing revealed a normal THRB gene, thereby ruling out thyroid hormone resistance. THRA gene was not tested due to absence of behavioral or hearing issues. Markers of hyperthyroidism, including angiotensin converting enzyme, carotene, apolipoproteins, and osteocalcin levels were normal, except for an elevated sex hormone binding globulin of 104 nmol/L (NL: 11 - 78). Biochemical evaluation of other pituitary axes was normal. However, an elevated alpha sub-unit fraction (ASF) was noted on two separate measurements. Sonogram revealed a heterogeneous, hypervascular thyroid. Bone densitometry, echocardiogram, and Holter monitor studies were normal. The combination of biochemical SH, elevated ASF, pituitary adenoma, and exclusion of other etiologies causing SH pattern established the diagnosis of TSHA. An active surveillance approach was implemented. A pituitary MRI done 18 months later showed minimal (2mm in one axis) increase in the adenoma size, and the patient continued to demonstrate biochemical SH but remained asymptomatic. Conclusion: MicroTSHAs can present with asymptomatic SH. In this situation, excluding other biochemical SH etiologies is crucial to prevent unnecessary invasive procedures. But once TSHA diagnosis is established, due to the risk of tumor growth leading to symptomatic SH or mass effects, active surveillance is warranted. Presentation: Friday, June 16, 2023

A case of thyroid sclerosing mucoepidermoid carcinoma with eosinophilia indicates interleukin-5 production in a man with a history of Graves’ disease

Thyroid sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is a rare tumor that typically affects women with Hashimoto’s thyroiditis. The present case was a man in his late 50s who was diagnosed with Graves’ disease at the age of 10 and was given antithyroid hormone for five years. The computed tomography scan revealed a nodular lesion in the right lobe, and the lesion was cytologically suspected as papillary carcinoma. No lymph node metastases or distant metastases were found. Before total thyroidectomy, high serum anti-thyroid peroxidase (TPO) and antithyroglobulin (TG) antibody titers, with no eosinophilia were detected. In a few small areas of the tumor center, small tumor cell foci with mild to moderate atypia, displaying mucous glandular cell and squamous cell differentiation, were found. The tumor was completely replaced by prominent sclerosing fibrosis, which was accompanied by tumor cell infiltration. The tumor had invaded the adjacent parenchyma and perithyroidal fatty tissue. In addition to lymphocytes and plasma cells, a large number of eosinophils were observed within the tumor. Immunohistochemically, tumor cells were strongly positive for p63, 34βE12, and TTF-1, but weakly for PAX8. Using fluorescence in situ hybridization (FISH), no MAML2 translocation was detected. Taken together with these findings, the present tumor was diagnosed as primary thyroid sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE). This case is the first to report thyroid SMECE associated with Graves’ disease. IL-5 immunostaining was performed to identify eosinophilia within the present tumor. As a result, the tumor cells were found to be positive for IL-5. The present tumor is also the first to indicate IL-5 production of SMECE.

The pathogenic role of IFN-α in thyroiditis mouse models

AimPatients with chronic hepatitis C are frequently treated with interferon (IFN)-α. Autoimmune thyroid disease occurs in 20% ~ 40% of IFN-α-treated patients. In this study, the effects of IFN-α administration on triggering and regulating autoimmune thyroiditis in various animal models were evaluated. Main methodsExogenous IFN-α was given to naive CBA mice, and both thyroglobulin (TG) immunization-induced (CBA) and spontaneous autoimmune thyroiditis (NOD·H-2 h4) models. Thyroid function, and anti-thyroglobulin antibody (ATA) and B-cell-activating factor (BAFF) levels were measured. Alterations in transcriptome profiles were analyzed. Key findingsIn the TG-induced thyroiditis model, IFN-α administration reduced plasma free thyroxine levels but did not alter ATA titers, BAFF levels, or the severity of histological changes. Interestingly, even without changes in thyroid functions, four of eight mice in the IFN-α alone group exhibited thyroiditis compared to the control group. Immunologically, mice in the IFN-α group exhibited profound CD3+ cell infiltration in the thyroid and higher plasma BAFF levels compared to the control group. Meanwhile, pathological and serological alterations after IFN-α administration were not observed in the NOD·H-2 h4 model. An RNA sequencing analysis revealed that immunoregulatory signatures were not excited by IFN-α treatment in naive CBA mice. Meanwhile, innate and adaptive immunity, inflammatory cytokine, chemokine, and cell-killing signaling pathways were all stimulated by IFN-α administration after TG immunization of CBA mice. SignificanceWe confirmed the remarkable effects of IFN-α in both initiating thyroid immunity and modulating thyroid function and immunoregulatory signatures in established autoimmune thyroiditis. We suggest that IFN-α should be administered with caution in clinical settings.

Alemtuzumab-induced autoimmune thyroid events in patients with relapsing-remitting multiple sclerosis: A real-life and monocentric experience at a tertiary-level centre.

Alemtuzumab-induced autoimmune thyroid events (AIATEs) are the most common adverse effects observed in relapsing-remitting multiple sclerosis (RRMS) patients. This study aims to explore the clinical and biochemical characteristics of such AIATEs, and to examine the risk factors for their occurrence, particularly for the worst clinical phenotype of fluctuating Graves' disease (GD). We retrospectively analysed a real-life single-centre consecutive series of 57 RRMS patients treated with alemtuzumab whose clinical and biochemical parameters were collected before starting the treatment and then monthly during their follow-up. AIATEs developed in 39% of patients a mean 17 months ± 11 after the first cycle of alemtuzumab. The most common AIATEs were GD (64%), followed by Hashimoto's thyroiditis with hypothyroidism (23%), TSH-receptor-antibody (TRAb)-positive hypothyroidism (9%), and silent thyroiditis (4%). GD showed a fluctuating course in 57% of cases. Baseline positivity for anti-thyroperoxidase antibodies, and higher absolute titers of anti-thyroglobulin and anti-thyroperoxidase antibodies correlated significantly with the risk of developing AIATEs, but TRAb positivity did not. Higher TRAb titers at the time of GD being diagnosed correlated strongly with a greater risk of the fluctuating GD phenotype. On ROC curve analysis, we found that a cut-off of 7.3 IU/L could be used to predict the risk of developing a fluctuating GD, with a positive predictive value of 100%. TRAb levels measured with commercial automatic methods at the time of a patient being diagnosed with alemtuzumab-induced GD emerged as a novel biomarker for predicting a fluctuating disease phenotype, with an influence on subsequent therapeutic decisions and patients' follow-up.

The Impact of Interferon Beta-1b Therapy on Thyroid Function and Autoimmunity Among COVID-19 Survivors.

BackgroundSome studies have indicated that interferon (IFN) may be valuable in COVID-19. We aimed to evaluate the impact of short-term IFN on incident thyroid dysfunction and autoimmunity among COVID-19 survivors.MethodsWe included consecutive adults without known thyroid disorder admitted to Queen Mary Hospital for COVID-19 from July 2020 to January 2021 who had thyroid function tests (TFTs) and anti-thyroid antibodies measured both on admission and at three months.Results226 patients were included (median age 55.0 years; 49.6% men): 135 were IFN-treated. There tended to be more abnormal TFTs upon reassessment in IFN-treated patients (8.1% vs 2.2%, p=0.080). 179 patients (65.4% IFN-treated) had a complete reassessment of anti-thyroid antibodies. There were significant increases in titres of both anti-thyroid peroxidase antibodies (anti-TPO: baseline 29.21 units [IQR: 14.97 – 67.14] vs reassessment 34.30 units [IQR: 18.82 – 94.65], p<0.001) and anti-thyroglobulin antibodies (anti-Tg: baseline 8.23 units [IQR: 5.40 – 18.44] vs reassessment 9.14 units [IQR: 6.83 – 17.17], p=0.001) in the IFN-treated group but not IFN-naïve group. IFN treatment (standardised beta 0.245, p=0.001) was independently associated with changes in anti-TPO titre. Of the 143 patients negative for anti-TPO at baseline, 8 became anti-TPO positive upon reassessment (seven IFN-treated; one IFN-naïve). Incident anti-TPO positivity was more likely to be associated with abnormal TFTs upon reassessment (phi 0.188, p=0.025).ConclusionIFN for COVID-19 was associated with modest increases in anti-thyroid antibody titres, and a trend of more incident anti-TPO positivity and abnormal TFTs during convalescence. Our findings suggest that clinicians monitor the thyroid function and anti-thyroid antibodies among IFN-treated COVID-19 survivors, and call for further follow-up studies regarding the clinical significance of these changes.

Peri-tumor administration of controlled release anti-CTLA-4 synergizes with systemic anti-PD-1 to induce systemic antitumor immunity while sparing autoimmune toxicity.

Combination immunotherapy targeting the PD-1 and CTLA-4 checkpoint inhibitor pathways provides substantial clinical benefit in patients with advanced-stage cancer but at the risk of dose-limiting inflammatory and autoimmune toxicity. The delicate balance that exists between unleashing tumor killing and promoting systemic autoimmune toxicity represents a major clinical challenge. We hypothesized that targeting anti-CTLA-4 so that it perfuses tumor-draining lymph nodes would provide a significant therapeutic advantage and developed an injectable hydrogel with controlled antibody release characteristics for this purpose. Injection of hydrogel-encapsulated anti-CTLA-4 at a peri-tumor location (MC-38 tumor model) produced dose-dependent antitumor responses and survival that exceeded those by anti-CTLA-4 alone (p < 0.05). Responses to 100µg of targeted anti-CTLA-4 also equaled or exceeded those observed with a series of systemic injections delivering 600µg (p < 0.05). While preserving antitumor activity, this approach resulted in serum anti-CTLA-4 exposure (area under the curve) that averaged only 1/16th of that measured with systemic therapy. Consistent with the marked differences in systemic exposure, systemic anti-CTLA-4 stimulated the onset of autoimmune thyroiditis in iodide-exposed NOD.H-2h4 mice, as measured by anti-thyroglobulin antibody titer, while hydrogel-encapsulated anti-CTLA-4 had a minimal effect (p ≤ 0.01). At the same time, this targeted low-dose anti-CTLA-4 approach synergized well with systemic anti-PD-1 to control tumor growth and resulted in a high frequency of complete responders that were immune to tumor re-challenge at a distant site. We conclude that targeted and controlled delivery of low-dose anti-CTLA-4 has the potential to improve the benefit-risk ratio associated with combination checkpoint inhibitor therapy.

Growth arrest-specific protein 6 (Gas6) attenuates inflammatory injury and apoptosis in iodine-induced NOD.H-2h4 mice

PurposeGrowth arrest-specific protein 6 (Gas6) is a vitamin K-dependent protein that plays an important role in the pathogenesis of autoimmune diseases. The purpose of this study was to explore the expression of Gas6 and its effects on autoimmune thyroiditis (AIT). MethodA total of 24 male NOD.H-2h4 mice were randomly assigned to three groups: (1) a control group supplied with regular water; (2) a sodium iodide (NaI) group supplied with 0.005% sodium iodide water; and (3) a group treated with recombinant mouse Gas6 (rmGas6) after iodine supplementation (NaI + Gas6 group). The severity of lymphocytic infiltration in the thyroid was measured through histopathology. Serum levels of tumor necrosis factor α (TNF-α), interleukin (IL) 6 and IL-1β, as well as anti-thyroglobulin antibody (TgAb) titers were measured using an enzyme-linked immunosorbent assay. In addition, the expression of Gas6, Caspase 3, TAM receptors (Axl and MerTK), nuclear factor κB (NF-κB) and I-kappa-B α (IκB-α) were measured by Western blotting. Finally, the proportions of T cells were determined in the splenocytes of NOD.H-2h4 mice by flow cytometry. ResultsThe mRNA and protein expression of Gas6 was significantly lower in the NaI group compared to the control group. Serum levels of TgAb, TNF-α, IL-6 and IL-1β were also significantly higher in the NaI group but were dramatically reduced after rmGas6 injection. The prevalence of thyroiditis and the infiltration of lymphocytes were significantly lower in the NaI + Gas6 group compared to the NaI group. The protein expression of cleaved-Caspase 3, phosphorylation of MerTK, and NF-κB and IκB-α in the thyroid gland were significantly reduced after rmGas6 administration. The proportion of Th1, Th2 and Th17 cells in splenocytes were also significantly reduced after rmGas6 treatment, whereas there was a dramatic increase in the proportion of Treg cells. ConclusionGas6 exerts an anti-inflammatory effect in a mouse model of AIT and may therefore be a potential therapeutic target.

Semi-quantitative assessment of diffuse hepatic uptake seen in I-131 scans \u2013 an indicator of functioning thyroid tissue and disease burden in differentiated thyroid cancer

BackgroundTo semi-quantitatively analyze liver uptake of I-131 in diagnostic and post-therapy scans by calculating hepatic to thigh ratios (HTR) and evaluate its clinical significance in management of differentiated thyroid cancer.MethodTwo hundred forty-nine patients were included in the study. Hepatic to thigh ratio (HTR) of counts were calculated for 249 diagnostic and 104 post-therapy scans. Patients were divided into six study groups based on their disease status:1-Serum thyroglobulin (serum Tg) negative (serum Tg ≤ 4 ng/dl) and scan negative; 2-Thyroid remnant only; 3-Thyroid remnant and lymph node metastasis; 4- Tg positive (serum Tg > 4 ng/dl) and scan negative; 5-Bone or/and lung metastasis, and 6-Only lymph node metastasis. Comparison of HTR between these groups was done using one-way ANOVA test. Correlation of HTR with serum Tg, serum thyroid stimulating hormone (TSH), anti-thyroglobulin antibody (ATg) titer and therapeutic dose of I-131 was also assessed.ResultsComparison of HTR between different study groups (1 to 6) showed significant difference in HTR (p = .001). Study group 5 (bone or/and lung metastasis) showed significantly higher mean HTR compared to other groups (p = 0.001). There was only a weak correlation between serum Tg and HTR (r = 0.395). Dose of I-131 administered also had a weak correlation with HTR (r = 0.207).ConclusionHTR has good correlation with functional status of tumor cells, while it has weak correlation to therapeutic dose of I-131 administered and serum Tg. Increased HTR predicts significant disease burden in the form of distant bone and lung metastasis and may potentially be used as a second prognostic factor apart from serum Tg.

Decreased effector regulatory T cells and increased activated CD4+ T cells in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a clinical syndrome defined by the loss of ovarian activity before 40years old. An autoimmune mechanism is suggested to be involved in the development of POI. Therefore, we examined the relationship between peripheral blood regulatory T (Treg) cells and autoantibodies in POI. Thirty POI patients and 23 control women were enrolled in the study. Using flow cytometry, we measured the abundance of CD4+ T, CD4+ CD69+ T, CD8+ T, CD8+ CD69+ T, naive Treg, effector Treg, and FOXP3+ effector T cells in peripheral blood. Antinuclear and anti-thyroglobulin antibody (Tg-Ab) titers were measured in POI patients. The number of CD4+ T or CD4+ CD69+ T cells was significantly higher in POI patients (P=0.045, and P=0.030), and there were significantly fewer effector Treg cells in POI patients (P=0.016) than in the controls. There were significant negative correlations between effector Treg cells and Tg-Abs (r=-0.584, P=0.0282), and between effector Treg cells and CD4+ CD69+ T cells (r=-0.415, P=0.0226) in POI patients. This is the first report of decreased numbers of effector Treg cells and increased CD4+ CD69+ activated T cells in peripheral blood in POI, suggesting that POI is an autoimmune disease.

Effects of exogenous melatonin on clinical and pathological features of a human thyroglobulin-induced experimental autoimmune thyroiditis mouse model

Melatonin (MLT) plays a significant role in both innate and adaptive immunity, and dysregulation of the MLT signature can modify autoimmune disease phenotypes. In this study, the influence of exogenous MLT administration on regulating autoimmune thyroiditis animal models was evaluated. An experimental autoimmune thyroiditis model was established in MLT-synthesizing (CBA) and MLT-deficient (C57BL/6) mice by immunization with human thyroidglobulin (TG), which features thyrotoxicosis, thyrocyte damage, and CD3+ T cell infiltration. In TG-immunized CBA mice, exogenous MLT administration in drinking water (6 μg/ml) enhanced thyroiditis and increased TG-specific splenocyte proliferation but not the anti-thyroglobulin antibody (ATA) titer, while MLT alone caused no significant alteration in thyroid function or histopathology. Meanwhile, MLT administration did not modify thyroid function, the ATA titer, or the thyroid histopathology, but results showed an increase in the splenocyte proliferative capacity in TG-immunized C57BL/6 mice. Collectively, our data showed that early exogenous MLT modified the progression of autoimmune thyroiditis through T cell-driven immunity, and excess MLT worsened the clinical and pathological features.

Correlation between anti-thyroid peroxidase antibody levels and diffuse thyroid uptake of 18F-fluorodeoxyglucose in Hashimoto\u2019s thyroiditis: a retrospective study

BackgroundOn 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET), diffuse uptake in the thyroid gland is often observed in patients with Hashimoto’s thyroiditis. In this study, we evaluated the factors associated with diffuse uptake by comparing Hashimoto’s thyroiditis patients with or without diffuse uptake in the thyroid.MethodsA retrospective study was conducted of 18 patients with Hashimoto’s thyroiditis who underwent blood tests, thyroid ultrasonography, and FDG-PET during the period from 2014 to 2015. The patients were divided into two groups: one with diffuse thyroid uptake (group 1, n = 13) and one without diffuse thyroid uptake (group 2, n = 5). Clinical and laboratory parameters, including maximum standardized uptake in the thyroid (SUVmax), which was defined as the higher value obtained in either the right or left thyroid lobe, were compared in the two groups.ResultsThe frequency of abnormal findings, such as a rough or heterogeneous pattern, was significantly higher in group 1 (p < 0.01), as were anti-thyroid peroxidase (TPO) antibody titers, anti-thyroglobulin (Tg) antibody titers, and SUVmax (p < 0.01). The frequency of hypothyroidism did not differ significantly in the two groups. Anti-TPO and anti-Tg titers were positively correlated with SUVmax (r = 0.856, p < 0.01 and r = 0.821, p < 0.01, respectively); in univariate analysis, anti-TPO titer was predictive of SUVmax (p < 0.01).ConclusionsThe results of the current study suggest that Hashimoto’s thyroiditis patients with high titers of anti-thyroid antibodies are likely to exhibit intense diffuse FDG uptake in the thyroid, and that thyroid function may be clearly impaired, even in the presence of mild FDG uptake in the thyroid.

Thyroid autoimmune antibodies in patients with papillary thyroid carcinoma: a double-edged sword?

The relationship between thyroid autoimmunity and thyroid cancer remains controversial. The objective of this study is to comprehensively analyze the association between thyroid autoimmune antibodies and disease statuses of papillary thyroid carcinoma (PTC). Patients were divided into different groups according to their final diagnoses after radioiodine therapy as well as their serum anti-thyroglobulin antibody (TgAb) and anti-thyroidperoxidase antibody (TPOAb) titers. Clinicopathologic characteristics were then compared between groups. In all, 1126 PTC patients met the inclusion criteria. When compared with thyroid autoimmune antibody negative group, patients in positive group were young female predominant. After age and gender adjusted, patients in thyroid autoimmune antibody positive group had much more cervical metastatic node count and this effect was limited to the central compartment but not to the lateral compartment. Antibody positivity rate was much lower in patients with distant metastasis and multivariable logistic regression analysis showed positive status of antibody was a protective factor of distant metastasis of PTC with an OR value of 0.403 (95% CI 0.216-0.622, p < 0.001). Additionally, subgroup analysis demonstrated single TgAb positivity and combined positivity of TgAb and TPOAb were shown to be related to less distant metastatic disease. Positive thyroid auto-antibody status could be a risk factor of more metastatic cervical lymph nodes while a protective factor of distant metastatic disease in PTC patients. The association between thyroid autoimmunity and thyroid cancer can be patient and antibody specific. A systemic immunosupression status may exist in PTC patients with distant metastasis.

A case of familial dysalbuminemic hyperthyroxinemia (FDH) in Japan: FDH as a possible differential diagnosis of syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH)

Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant condition and is the most commonly inherited euthyroid hyperthyroxinemia in Caucasians. However, it is extremely rare in Asian populations. A 30-year-old Japanese woman, who was incidentally found to have apparent thyroid dysfunction, was admitted to our hospital in 2004. She had extremely elevated serum free thyroxine (FT4), moderately elevated free triiodothyronine (FT3), and normal thyroid-stimulating hormone (TSH). Clinical thyroid examination revealed no abnormalities other than small goiter. Anti-thyroglobulin antibody titer was positive, but titers of other anti-thyroid antibodies, including antithyroid peroxidase antibody, TSH receptor antibodies, and thyroid-stimulating antibody, were negative. Levels of FT3, FT4, and TSH were similar when measured by three different laboratory kits, and FT4 was still high when measured by equilibrium dialysis. By affinity chromatography, FT4, TT4, and albumin were extracted to the same fraction, and the levels of FT4 and TT4 were extremely high. By combination of reversed phase liquid chromatography and mass spectrometry techniques, the amino acid sequence of human serum albumin was determined. The patient was found to be a heterozygote for p.R218P mutation in the gene for human serum albumin and was diagnosed as FDH. This patient, who harbored the p.R218P mutation in the albumin gene, is the fifth case report of FDH in Japan. This condition is characterized by extremely high serum FT4 and moderately high serum FT3 levels. Although rare, FDH should be considered in the differential diagnosis for syndrome of inappropriate secretion of TSH (SITSH) in Japan.

Unfavorable Course of Subclinical Hypothyroidism in Children with Hashimoto's Thyroiditis Compared to Those with Isolated Non-Autoimmune Hyperthyrotropinemia.

Subclinical hypothyroidism (SCH) is a common problem in pediatric population, and the natural history of SCH varies depending on its etiology. Whether Hashimoto’s thyroiditis (HT) negatively affects the natural course of SCH was investigated in pediatric patients without concomitant diseases. Predictors for levothyroxine medication were also evaluated. Medical records of 109 children with SCH (91 girls, 5−18 years) diagnosed between 2005 and 2014 were retrospectively reviewed. Patients were classified into HT (n = 37) and isolated non-autoimmune hyperthyrotropinemia (iso-NAHT, n = 72). During median 2 years of follow-up, only 10.1% of SCH patients eventually initiated levothyroxine, and HT patients showed a higher probability of requiring levothyroxine medication than iso-NAHT patients (21.6% vs. 4.2%). Underlying HT independently predicted deterioration of thyroid function, leading to levothyroxine medication (hazard ratios [HRs], 4.6 vs. iso-NAHT, P = 0.025). High titers of anti-thyroglobulin antibodies (TGAbs) predicted later medication in the HT group (HRs, 28.2 vs. normal TGAbs, P = 0.013). Most pediatric SCH showed benign and self-remitting courses. Underlying HT significantly increases the risk for levothyroxine medication, especially with high titers of TGAbs.

Serum BAFF and thyroid autoantibodies in autoimmune thyroid disease

BackgroundThis study investigated the association of serum B-lymphocyte activating factor (BAFF) levels with autoimmune thyroid disease (AITD) in a Chinese population. Materials and methodsWe enrolled 221 patients with AITD [170 patients with Graves' disease (GD), 51 patients with Hashimoto's thyroiditis (HT)], and 124 healthy controls. Serum BAFF levels, thyroid function and thyroid autoantibody (TAb) levels, including of thyroid-stimulating hormone receptor antibody (TSHRAb), anti-thyroid peroxidase antibody (Anti-TPO Ab), and antithyroglobulin antibody (ATA), were measured at baseline. ResultsSerum BAFF levels were higher in the GD, HT, and AITD groups than in the control group. Significant correlations were observed between BAFF and TSHRAb levels (r=0.238, p=0.018), between BAFF and Anti-TPO Ab levels (p=0.038), and between BAFF and ATA titers (p=0.025) in women but not in men. In addition, serum BAFF levels were significantly associated with free thyroxine (r=0.430, p=0.004) and TSHRAb (r=0.495, p=0.001) levels in women with active GD but not in those with inactive GD. ConclusionsSerum BAFF levels are increased in GD, HT, and AITD. The correlation between serum BAFF and TAb levels exhibits a dimorphic pattern, particularly in active GD.

Thyroid hormones and complement parameters in hereditary angioedema with C1-inhibitor deficiency

BackgroundThyroid hormones control and up-regulate the synthesis of many plasma proteins. ObjectiveTo explore possible associations between thyroid hormone and complement levels in patients with hereditary angioedema resulting from the deficiency of the C1-inhibitor (C1-INH-HAE). MethodsIn this case-control study, serum thyrotropin, free triiodothyronine (FT3), and free thyroxine (FT4) levels, anti–thyroid peroxidase and antithyroglobulin antibody titers, and C1-INH concentrations were measured in 117 euthyroid patients with C1-INH-HAE and compared with their clinical properties. The control group comprised 150 healthy, age- and sex-matched, euthyroid individuals. ResultsThe thyrotropin and antithyroglobulin levels were similar between the patients and the controls. Significantly lower FT3 (P < .001) and FT4 (P = .002) levels, as well as higher anti–thyroid peroxidase titers (P < .001), were seen in the patients with C1-INH-HAE. The proportion of patients with reduced C1-INH activity was greater among those with below-median FT4 levels than among those with above-median values (P = .02). Patients who experienced more edematous attacks per year had lower FT4 levels (within the normal range) than those afflicted by fewer episodes (P = .01). The FT3 and FT4 levels were significantly higher in patients undergoing long-term danazol therapy than in those who did not receive this drug (P = .01 and P = .02, respectively). The proportion of patients with FT4 levels in the below-median range was higher in the subset with increased d-dimer concentration (P = .009). ConclusionMinor variations of the thyroid hormone levels (within the reference range) can influence the function of C1-INH in C1-INH-HAE. Our findings suggest a role for the endocrine system in the pathophysiology of C1-INH-HAE.

Factors contributing to surgical outcomes of transaxillary robotic thyroidectomy for papillary thyroid carcinoma.

Transaxillary robotic thyroidectomy is considered a technically feasible and safe treatment option for patients with low-risk papillary thyroid carcinoma (PTC). The aim of the present study was to determine the factors that contribute to the perioperative surgical outcomes of robotic thyroidectomy and to suggest guidelines for patient selection to be used by surgeons inexperienced in the technique. We reviewed the records of 275 patients with PTC who underwent robotic total thyroidectomy using a gasless, transaxillary single-incision approach at Yonsei University Health System, South Korea, between January 2011 and May 2012. The association between surgical outcomes and clinicopathologic factors was assessed using linear and logistic regression analysis. The contributing factors for surgical outcomes of robotic thyroidectomy were categorized as patient factors, including gender and body mass index (BMI), and thyroid-specific factors, including thyroid gland size, coexistent thyroiditis, tumor size, and serum anti-thyroglobulin antibody and anti-microsomal antibody titers. Of these, male gender, a large thyroid gland, and thyroiditis significantly increased the total operation time. Male gender, thyroiditis, and overweight BMI increased the working space time, and a large thyroid gland and overweight BMI affected the console time. A large thyroid gland and histological thyroiditis were associated with increased intraoperative blood loss. There was no association between postoperative complications and clinicopathologic parameters. Male gender, overweight BMI, a large thyroid gland, and coexistent thyroiditis adversely affected the surgical outcome of robotic thyroidectomy. Surgeons inexperienced in the technique should avoid or carefully approach individuals with these factors.

Clinical Aggressiveness and Long-Term Outcome in Patients with Papillary Thyroid Cancer and Circulating Anti-Thyroglobulin Autoantibodies

The association between papillary thyroid cancer (PTC) and Hashimoto's thyroiditis is widely recognized, but less is known about the possible link between circulating anti-thyroglobulin antibody (TgAb) titers and PTC aggressiveness. To shed light on this issue, we retrospectively examined a large series of PTC patients with and without positive TgAb. Data on 220 TgAb-positive PTC patients (study cohort) were retrospectively collected in 10 hospital-based referral centers. All the patients had undergone near-total thyroidectomy with or without radioiodine remnant ablation. Tumor characteristics and long-term outcomes (follow-up range: 2.5-24.8 years) were compared with those recently reported in 1020 TgAb-negative PTC patients with similar demographic characteristics. We also assessed the impact on clinical outcome of early titer disappearance in the TgAb-positive group. At baseline, the study cohort (mean age 45.9 years, range 12.5-84.1 years; 85% female) had a significantly higher prevalence of high-risk patients (6.9% vs. 3.2%, p<0.05) and extrathyroidal tumor extension (28.2% vs. 24%; p<0.0001) than TgAb-negative controls. Study cohort patients were also more likely than controls to have persistent disease at the 1-year visit (13.6% vs. 7.0%, p=0.001) or recurrence during subsequent follow-up (5.8% vs. 1.4%, p=0.0001). At the final follow-up visit, the percentage of patients with either persistent or recurrent disease in the two cohorts was significantly different (6.4% of TgAb-positive patients vs. 1.7% in the TgAb-negative group, p<0.0001). At the 1-year visit, titer normalization was observed in 85 of the 220 TgAb-positive individuals. These patients had a significantly lower rate of persistent disease than those who were still TgAb positive (8.2% vs. 17.3%. p=0.05), and no relapses were observed among patients with no evidence of disease during subsequent follow-up. PTC patients with positive serum TgAb titer during the first year after primary treatment were more likely to have persistent/recurrent disease than those who were consistently TgAb-negative. Negative titers at 1 year may be associated with more favorable outcomes.

CA19-9-producing lung metastasis after surgery for papillary thyroid carcinoma: report of a case

Measuring tumor marker levels following cancer treatment can be useful. Although serum thyroglobulin is a useful marker after total thyroidectomy for papillary thyroid carcinoma (PTC), it is not a reliable marker for patients with a high titer of anti-thyroglobulin antibodies or when transformation to undifferentiated carcinoma has occurred. The female patient in this case report underwent total thyroidectomy and oral I-131 therapy for PTC at the age of 47 years, followed by cervical lymph node and lung resections for metastases, 3 and 11 years later, respectively. She also received oral I-131 therapy and external beam radiotherapy for mediastinal lymph node metastases. The lymphadenopathy lesions progressed and multiple lung metastases were detected when she was 61 years of age. She died at the age of 62 years. The serum CA19-9 level had gradually increased in association with enlargement of the recurrent lesions and immunostaining of CA19-9 in the pulmonary metastasis was intense. Thus, we consider that measuring the level of serum CA19-9 is an effective tool for evaluating disease status after surgery for PTC.