Reversal of Abnormal CD4+ T Cell Metabolism Alleviates Thyroiditis by Deactivating the mTOR/HIF1a/Glycolysis Pathway.

Background: Hashimoto's thyroiditis (HT) is an autoimmune disease that features activation of thyroid antigen-specific helper T cells. HT patients have increased Th1 and Th17 T cell subsets. Glycolysis supports chronic activation of Th1 and Th17 T cells, but how this contributes to HT remains unknown. Methods: The metabolism of CD4+ T cells from 30 HT patients and 30 healthy controls was evaluated by determining the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR). Mice in a subacute thyroiditis (SAT) model were treated with 2DG, metformin, or combination. Metrics of mTOR/HIF-1α/HK2/glycolysis were measured by western blot and Seahorse assay methods. The severity of SAT was measured by flow cytometry and HE staining. Results: CD4+ T cells from HT patients had enhanced ECAR and OCR. Levels of Glut1, HK2, PKM2, and LDHA in cultured HT CD4+ T cells were elevated. The expression of HK2 and PKM2 in cultured SAT CD4+ T cells was elevated compared with the control group. Activation of the mTOR and HIF-1α pathways was significant in SAT mice, and expression of HIF-1α in the 2DG treated group was reduced. Treatment with 2DG and/or metformin significantly decreased the ratio of Th17 and Th1 T cells. Conclusions: Thyroiditis results in elevation of the mTOR/HIF-1α/HK2/glycolysis pathway in CD4+ T cells. The activation of this pathway is reduced by treatment with 2DG and metformin, which also reverted imbalances in CD4+ T cell differentiation.

Thyroid complications of SARS and coronavirus disease 2019 (COVID-19).

We have reviewed the available literature on thyroid diseases and coronavirus disease 2019 (COVID-19), and data from the previous coronavirus pandemic, the severe acute respiratory syndrome (SARS) epidemic. We learned that both SARS and COVID-19 patients had thyroid abnormalities. In the limited number of SARS cases, where it was examined, decreased serum T3, T4 and TSH levels were detected. In a study of survivors of SARS approximately 7% of the patients had hypothyroidism. In the previous evaluation evidence was found that pituitary function was also affected in SARS. Others suggested a hypothalamic-pituitary-adrenal axis dysfunction. One result published recently indicates that a primary injury to the thyroid gland itself may play a key role in the pathogenesis of thyroid disorders in COVID-19 patients, too. Subacute thyroiditis, autoimmune thyroiditis and an atypical form of thyroiditis are complications of COVID-19. Thyroid hormone dysfunction affects the outcome by increasing mortality in critical illnesses like acute respiratory distress syndrome, which is a leading complication in COVID-19. Angiotensin-converting enzyme 2 is a membrane-bound enzyme, which is also expressed in the thyroid gland and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses it for docking, entering as well as replication. Based on the available results obtained in the SARS-CoV-2 pandemic, beside others, we suggest that it is necessary to monitor thyroid hormones in COVID-19.

Detection of SARS-COV-2 receptor ACE-2 mRNA in thyroid cells: a clue for COVID-19-related subacute thyroiditis.

PURPOSE: SARS-COV-2 is a pathogenic agent belonging to the coronavirus family, responsible for the current global world pandemic. Angiotensin-converting enzyme 2 (ACE-2) is the receptor for cellular entry of SARS-CoV-2. ACE-2 is a type I transmembrane metallo-carboxypeptidase involved in the Renin-Angiotensin pathway. By analyzing two independent databases, ACE-2 was identified in several human tissues including the thyroid. Although some cases of COVID-19-related subacute thyroiditis were recently described, direct proof for the expression of the ACE-2 mRNA in thyroid cells is still lacking. Aim of the present study was to investigate by RT-PCR whether the mRNA encoding for ACE-2 is present in human thyroid cells. METHODS: RT-PCR was performed on in vitro ex vivo study on thyroid tissue samples (15 patients undergoing thyroidectomy for benign thyroid nodules) and primary thyroid cell cultures. RESULTS: The ACE-2 mRNA was detected in all surgical thyroid tissue samples (n = 15). Compared with two reporter genes (GAPDH: 0.052 ± 0.0026 Cycles-1; ß-actin: 0.044 ± 0.0025 Cycles-1; ACE-2: 0.035 ± 0.0024 Cycles-1), the mean level of transcript expression for ACE-2 mRNA was abundant. The expression of ACE-2 mRNA in follicular cells was confirmed by analyzing primary cultures of thyroid cells, which expressed the ACE-2 mRNA at levels similar to tissues. CONCLUSIONS: The results of the present study demonstrate that the mRNA encoding for the ACE-2 receptor is expressed in thyroid follicular cells, making them a potential target for SARS-COV-2 entry. Future clinical studies in patients with COVID-19 will be required for increase our understanding of the thyroid repercussions of SARS-CoV-2 infection.

Two-Years Prospective Follow-Up Study of Subacute Thyroiditis.

Purpose: The aim of the present prospective follow-up study was to explore the early indicators of hypothyroidism and the final changes in thyroid volume in subacute thyroiditis (SAT) patients. Methods: We enrolled 61 SAT patients and followed them up for 2 years to assess the incidence of hypothyroidism and changes in thyroid volume. Binary logistic regression and receiver operating characteristic (ROC) curves were used for data analysis. Results: During the 2 years follow-up period, we found that the volumes of the thyroid gland in SAT patients at 1 and 2 years were significantly smaller than those in the healthy control group, which were significantly smaller compared to the initial thyroid volumes after SAT onset (p < 0.001). Also, the thyroid volumes of SAT patients with hypothyroidism were significantly smaller than those of SAT patients without hypothyroidism. The early maximum thyroid-stimulating hormone (TSH) values (within 3 months after SAT onset) were closely related to the incidence of hypothyroidism at 2 years. The OR value was 1.18 (95% CI = 1.01-1.38, p = 0.032). The early maximum TSH value had a maximum area under the ROC curve (AUC) of 0.866 for the development of hypothyroidism 2 years after SAT onset vs. euthyroidism (p < 0.001). Conclusions: The thyroid volumes of patients increased significantly after the onset of SAT, while during the follow-up these volumes decreased; the thyroid volumes at 1 and 2 years were significantly smaller than those of normal healthy subjects, especially in SAT patients with hypothyroidism. Furthermore, the early maximum TSH value could be used as an effective indicator of the development of hypothyroidism 2 years after the onset of SAT.

Hepcidin and Iron Homeostasis in Patients with Subacute Thyroiditis and Healthy Subjects.

PURPOSE: Hepcidin is an acute-phase protein involved also in regulation of iron homeostasis. The aim of the study was to prospectively assess for the first time the hepcidinEL concentration in patients with subacute thyroiditis (SAT), to identify biochemical determinants of hepcidinEL concentration and evaluate the potential role of hepcidin in SAT diagnosis and monitoring. METHODS: Out of 40 patients with SAT initially recruited, restrictive inclusion criteria fulfilled 21 subjects aged 45 ± 10 years and 21 healthy control subjects (CS). HepcidinEL concentration, thyroid status, and iron homeostasis were evaluated at SAT diagnosis and following therapy and compared with CS. RESULTS: The median hepcidinEL concentration at SAT diagnosis is higher than that in CS (48.8 (15.9-74.5) ng/mL vs. 18.2 (10.2-23.3) ng/mL, p = 0.009) and is significantly lower after treatment (4.0 (1.2-10.0) ng/mL, p = 0.007) compared with CS. The ROC analysis for hepcidinEL at SAT diagnosis revealed that area under the curve (AUC) is 0.735 (p = 0.009), and the cut-off for hepcidinEL concentration is 48.8 ng/mL (sensitivity 0.52 and specificity 0.95). HepcidinEL in SAT patients correlated with CRP (r = 0.614, p = 0.003), ferritin (r = 0.815, p < 0.001), and aTPO (r = -0.491, p = 0.024). On multiple regression, the correlation between hepcidinEL and ferritin was confirmed (p < 0.001). CONCLUSIONS: SAT is accompanied by a significant increase in hepcidin, which reflects an acute-phase inflammatory process. Parameters of iron homeostasis improved significantly while inflammatory indices got lower following recovery. The potential role of hepcidin as a predictive factor of the risk of SAT relapse needs to be assessed in studies on larger groups of SAT patients.

TNF-alpha is upregulated in subacute thyroiditis and stimulates expression of miR-155-5p in thyroid follicle cells.

Tumor necrosis factor alpha (TNF-α) regulates the expression of proinflammatory cytokines and apoptosis in thyroids. miR-155-5p is upregulated in circulating microvesicles in patients with autoimmune thyroiditis. However, the function and molecular mechanisms of TNF-α and miR-155-5p in the initiation and progression of subacute thyroiditis are largely unknown. Herein, we determined serum TNF-α levels in subacute thyroiditis patients and normal healthy controls by ELISA assay. Proliferation and apoptosis of rat thyroid follicle FRTL-5 cells were determined by MTT, TUNEL, and annexin V staining assays. Protein levels and phosphorylation status were assessed by immunoblotting. miR-155-5p expression was determined by the real-time quantitative PCR. Serum TNF-α was significantly upregulated in patients with subacute thyroiditis compared to that in normal healthy controls. In rat thyroid follicle FRTL-5 cells, TNF-α treatment led to a reduction of cell proliferation and an induction of apoptosis. It also increased IL-6 expression and phosphorylation of JAK2 and STAT3. Importantly, we demonstrated that serum miR-155-5p was upregulated in subacute thyroiditis patients and TNF-α stimulated the expression of miR-155-5p in FRTL-5 cells. We found that miR-155-5p inhibited the proliferation and induced apoptosis of FRTL-5 cells and increased the expression of IL-6 in FRTL-5 cells. Our results demonstrated that serum TNF-α and miR-155-5p were upregulated in patients with subacute thyroiditis, and TNF-α inhibited proliferation and induced apoptosis of rat thyroid follicle FRTL-5 cells via modulating the IL-6-JAK2/STAT3 pathway and miR-155-5p signaling. Our findings suggest that miR-155-5p might be a novel biomarker of subacute thyroiditis.

Increased pertechnetate and radioiodine uptake in the thyroid gland with subacute thyroiditis and concurrent Graves' disease.

OBJECTIVE: A 61 years old woman presented with low grade fever and weight loss for a month. Thyroid function tests showed hyperthyroidism: increased technetium-99m pertechnetate ((99m)Tc O(-)4) and radioiodine ((131)I) uptake and elevated thyroid stimulating hormone receptor antibodies (TSHRAb). She also had high erythrocyte sedimentation rate. Fine-needle aspiration (FNA) biopsies of left thyroid lobe revealed subacute thyroiditis (SAT). Simultaneous occurrence of SAT and Graves' disease (GD) was diagnosed. The patient was in good physical condition after two doses of betamethasone and daily administration of low dose antithyroid drugs. CONCLUSION: This case indicated that the measurement of TSHRAb is useful in understanding the clinical course of patients with SAT when thyroid function tests including the (99m)Tc and (131)I uptake are not compatible with the diagnosis. In such cases, GD should be suspected. The mechanism of high (99m)Tc and/or (131)I uptake in patients with simultaneous SAT and GD may be due to the inflammatory process which was detected by FNA in a small part of the left thyroid lobe inducing the stimulating effects of elevated TSHRAb on the undamaged follicular cells.

Patterns of thyroid radioiodine uptake: Jordanian experience.

UNLABELLED: This study aimed to determine the reference range of 24-h radioiodine uptake in euthyroid Jordanians, as well as the reference ranges for patients with diffuse and nodular hyperthyroidism. In addition, radioiodine uptake ranges were determined for those patients with Hashimoto's thyroiditis and early-phase subacute thyroiditis. METHODS: The medical records of 285 Jordanian patients referred for (131)I thyroid scintiscans and 24-h radioiodine uptake tests were reviewed. The patients were referred because of a presumed-certain thyroid disorder. The patients included those who were euthyroid or who had Graves' disease, toxic nodules, Hashimoto's thyroiditis, or subacute thyroiditis. Mean radioiodine uptake and the 95% confidence interval were determined in each group. A comparison was made between groups. RESULTS: Mean uptake (+/-SD) for the euthyroid group, toxic-nodule group, and Hashimoto's thyroiditis group was 15% +/- 7%, 19% +/- 9%, and 19% +/- 15%, respectively, and these values were not significantly different from each other (P > 0.05). Mean uptake for the subacute thyroiditis group and Graves' disease group was 3% +/- 4% and 40% +/- 14%, respectively, and both values were significantly different from other groups (P < 0.05). CONCLUSION: The reference range of radioiodine uptake in Jordan is comparable to that reported in North America and Europe because Jordanians likely have a sufficient daily intake of stable iodine. Radioiodine uptake discriminates between euthyroid patients, subacute thyroiditis patients, and Graves' disease patients. Radioiodine uptake in toxic-nodule patients is diagnostic only if combined with image findings. Mean radioiodine uptake in Hashimoto's thyroiditis is higher than the euthyroid mean but has a wide range.

A critical role for TRAIL in resolution of granulomatous experimental autoimmune thyroiditis.

Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by mouse thyroglobulin (MTG)-sensitized splenocytes activated in vitro with MTG and IL-12. Thyroid lesions reach maximal severity 20 days after cell transfer, and usually resolve or progress to fibrosis by day 60 depending on the extent of thyroid damage at day 20. Our previous studies indicated that neutralization of TNF-alpha or FasL had no effect on G-EAT induction, but neutralization of TNF-alpha promoted, while neutralization of FasL inhibited, G-EAT resolution. TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily. This study was undertaken to define the role of endogenous TRAIL in G-EAT development and/or resolution. Neutralization of endogenous TRAIL had little effect on G-EAT induction, but significantly inhibited G-EAT resolution and increased thyroid fibrosis. This correlated with higher expression of pro-inflammatory cytokines and preferential expression of the pro-apoptotic molecule TRAIL, and anti-apoptotic molecules FLIP and Bcl-xL on inflammatory cells in thyroids of anti-TRAIL-treated recipients. The results suggest that endogenous TRAIL is not required for G-EAT development in recipients, but is critical for G-EAT resolution. Endogenous TRAIL might promote resolution, at least in part, through modulation of the balance between pro- and anti-inflammatory cytokines, and the expression pattern of pro- and anti-apoptotic molecules of thyroid epithelial cells (TECs) and inflammatory cells.

Expression of transgenic FLIP on thyroid epithelial cells inhibits induction and promotes resolution of granulomatous experimental autoimmune thyroiditis in CBA/J mice.

Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by transfer of thyroglobulin-primed in vitro activated splenocytes. Thyroid lesions reach maximal severity 20 d later, and inflammation resolves or progresses to fibrosis by d 60, depending on the extent of thyroid damage at d 20. Depletion of CD8+ T cells inhibits G-EAT resolution. We showed that expression of Fas-associated death domain-like IL-1beta-converting enzyme inhibitory protein (FLIP) transgene (Tg) on thyroid epithelial cells (TECs) of DBA/1 mice had no effect on G-EAT induction but promoted earlier resolution of G-EAT. However, when CBA/J wild-type donor cells were transferred to transgenic CBA/J mice expressing FLIP on TECs, they developed less severe G-EAT than FLIP Tg- littermates. Both strains expressed similar levels of the FLIP Tg, but endogenous FLIP was up-regulated to a greater extent on infiltrating T cells during G-EAT development in DBA/1 compared with CBA/J mice. After transient depletion of CD8+ T cells, FLIP Tg+ and Tg- CBA/J recipients both developed severe G-EAT at d 20. Thyroid lesions in CD8-depleted Tg+ recipients were resolving by d 60, whereas lesions in Tg- littermates did not resolve, and most were fibrotic. FLIP Tg+ recipients had increased apoptosis of CD3+ T cells compared with Tg- recipients. The results indicate that transgenic FLIP expressed on TECs in CBA/J mice promotes G-EAT resolution, but induction of G-EAT is inhibited unless CD8+ T cells are transiently depleted.

Technetium-99 m sestamibi imaging in patients with subacute thyroiditis.

To determine if subacute thyroiditis (SAT) is associated with changes in the regional perfusion of the thyroid gland, we performed Tc-99 m sestamibi scans on eleven patients with SAT who had painful goiter and clinical thyrotoxicosis. Eleven patients had Tc-99 m pertechnetate and Tc-99 m sestamibi scintigraphy during the acute stage of SAT. The thyroid uptake ratio of sestamibi was compared with the laboratory data and color Doppler ultrasonography. Tc-99 m pertechnetate scintigraphy in the thyroid was markedly reduced during the acute stage of SAT. Conversely, Tc-99 m sestamibi showed diffuse increased uptake in the thyroid region, suggesting increased perfusion. On the other hand, there was near absence of vascularization in the acute phase and slight increase in the recovery phase by color Doppler ultrasonography. The clearance rate of Tc-99 m sestamibi during the early phase (from 10 min to 1 h) was decreased in the acute stage of SAT. The sestamibi uptake ratio correlated with serum immunosuppressive acidic protein (IAP) in the acute stage of SAT and the sestamibi uptake ratio in the recovery stage of SAT was correlated with serum thyrotropin levels. Tc-99 m sestamibi uptake in the early phase in the acute stage of SAT may reflect the inflammatory process associated with SAT.

Cellular composition of subacute thyroiditis. an immunohistochemical study of six cases.

To clarify the cellular composition of subacute thyroiditis, histologic and immunohistochemical studies were performed. Histologically, the lesion presented a patchy distribution of non-caseous granulomas comprising colloid, small lymphocytes, neutrophils, macrophages with or without epithelioid features, and multinucleated giant cells of foreign body type. In addition, numerous plasmacytoid monocytes were closely associated with the granulomas. The giant cells were CD68+, thyroglobulin- and cytokeratin-. Usually, small lymphocytes in the granulomas are CD3+, CD8+, CD45RO+ cytotoxic T-cells. In the non-granulomatous lesion, the follicles were often infiltrated by CD8+ T-lymphocytes, plasmacytoid monocytes and histiocytes, resulting in disrupted basement membrane and rupture of the follicles. Lymphoid follicles with or without active germinal centers were not observed. Moreover, no residual follicular dendritic cell networks were detected by CD23 and CAN.42 immunostains. In the interfollicular area, scattered plasma cells were observed among infiltrating cells. Neither human herpes virus 8 nor EBER-positive cells were detected in the six patients. The findings of our study suggest that cellular immune response may play an important role in the pathogenesis of subacute thyroiditis.

Immunohistochemical expression of growth factors in subacute thyroiditis and their effects on thyroid folliculogenesis and angiogenesis in collagen gel matrix culture.

The inflammatory-mechanistic basis of subacute thyroiditis remains unclear. To elucidate the roles of vascular endothelial cell growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor-BB (PDGF), transforming growth factor-beta1 (TGF-beta1) and epidermal growth factor (EGF) in the inflammatory process, their immunoexpression was examined in biopsy specimens of ten cases. At the granulomatous stage, all cases expressed VEGF, bFGF, PDGF, and TGF-beta1 in monocytes/macrophages infiltrating into follicle lumina, and in both epithelioid histiocytes and multinucleated giant cells of the granulomas. In fibroblasts and endothelial cells around the granulomas, all cases displayed VEGF, bFGF, and PDGF, but TGF-beta1 was detected only in fibroblasts in two cases. No cases expressed EGF in any of the above cell types. At the regenerative stage, all cases expressed VEGF, bFGF, and EGF in regenerating thyrocytes, whereas three and no cases displayed PDGF and TGF-beta1, respectively. Ten, seven and six cases expressed PDGF in fibroblasts, endothelial cells, and monocytes, respectively. In these cell types, all cases expressed VEGF and bFGF, whereas no cases displayed TGF-beta1 and EGF. To estimate the roles of these growth factors in thyroid tissue regeneration, their effects on thyroid folliculogenesis and angiogenesis were examined using collagen gel culture of thyrocytes and endothelial cells, respectively. Cell proliferation was also studied by bromodeoxyuridine (BrdU) uptake. EGF decreased follicle formation and TGF-beta1 drastically inhibited it, but the others had no effect. VEGF showed the greatest effect on vessel formation, although all of the others promoted it. EGF and VEGF or bFGF caused the highest BrdU uptake in thyrocytes and endothelial cells, respectively. The data suggest firstly, that at the granulomatous stage of subacute thyroiditis, growth factor-rich monocytes/macrophages infiltrating into follicle lumina trigger the granulomatous reaction, and VEGF, bFGF, PDGF, and TGF-beta1 produced by the stromal cell types tested mediate the reaction; secondly, that at the regenerative stage, EGF serves follicle regeneration through its mitogenic effect on thyrocytes, although some cofactors with EGF are involved in folliculogenesis and the decreased expression of TGF-beta1, a fibrogenic factor, contributes to thyroid tissue repair; and thirdly, that VEGF and bFGF are more responsible for the angiogenesis at both stages than the other factors studied.

Immunohistochemical analysis of Bcl-2, Bax, and Bak expression in thyroid glands from patients with subacute thyroiditis.

Bcl-2 family proteins are important regulators of apoptosis. To clarify a role of apoptosis and the expression of Bcl-2 family proteins in the pathogenesis of subacute thyroiditis (SAT), we evaluated the expression of Bcl-2, Bax, and Bak by immunohistochemistry and apoptosis by in situ end labeling of fragmented DNA in thyroid tissues from 11 patients with SAT. Apoptotic nuclei were found in granulomas, especially in macrophages/histiocytes and lymphocytes, and in the regenerating follicular cells, but were rarely found in the area of fibrosis. The mean (+/-SD) percentage of apoptotic follicular cells was significantly greater in SAT than that in controls (1.4 +/- 0.8% vs. 0.4 +/- 0.6%). Bcl-2, Bak, and Bax were strongly expressed in the granulomas and regenerating thyroid follicular cells from patients with SAT. Bcl-2 and Bak, but not Bax, were expressed in follicular cells from normal controls. The percentage of apoptotic cells and the expression of Bax in follicular cells did not correlate with age or serum levels of thyroid hormones, C-reactive protein, or thyroglobulin. These data suggest that apoptosis may be involved in the development of SAT and that Bax expression in regenerating thyrocytes may be important for the recovery of SAT.

Pertechnetate thyroid uptake is not always suppressed in patients with subacute thyroiditis.

The authors studied the clinical courses and immunologic aspects in 15 patients (age range, 32-69 years old; 14 women) with clinical features that were similar to subacute thyroiditis (SAT). In 2 patients (group A) whose thyrotropin-binding inhibitory immunoglobulins (TBII) and thyroid stimulating antibody (TSAb) showed strongly positive activity at the initial visit, Tc-99m pertechnetate thyroid uptake (Tc-99m uptake) was elevated (5.6% and 3.8%, respectively, normal; 0.7-3.0%). In 6 (group B) of 13 other patients, Tc-99m uptake was not completely suppressed (2 normal, 4 near normal) and imaging showed uptake in one lobe. In 7 (group C), however, there was no evidence of uptake in either lobe. Inflammatory process was localized in one lobe in all group B patients, and was in both lobes in all group C patients but one. Serum TSH levels were detectable in at least 4 patients (2 group B, 2 group C) low in all. There were no patients in both groups B and C in whom TBII and/or TSAb were detected at the initial visit. In SAT, marked suppression of Tc-99m uptake may be ascribed mainly to inflammatory follicular cell damage, but it is not always suppressed, owing to an association similar to Graves' disease and other unknown mechanism(s).

Studies of human peripheral blood mononuclear cells (PBMC) from patients with subacute thyroiditis in severe combined immunodeficient (SCID) mice: less production of human interferon gamma than that seen for Graves' disease.

Human peripheral blood mononuclear cells (PBMC) from 2 patients with de Quervain's subacute thyroiditis (SAT), 2 with Graves' disease (GD), and 3 normal persons (N) were engrafted into severe combined immunodeficient (SCID) mice so as to study whether SAT PBMC would differ immunologically from GD PBMC in vivo. Human IgG was detected in all mice engrafted with PBMC from either group of patients or normal persons. Thyroid Stimulating Antibody (TSAb) was detected in the sera of mice with PBMC from SAT or GD patients, but not N. Thyroperoxidase (TPO)-antibody (Ab) and/or thyroglobulin (Tg)-Ab was detectable in the mice with GD PBMC only, but not in those with SAT or normal PBMC. The production of interferon gamma (IFN gamma) in mice engrafted with N PBMC was 8, 13 and 14 U/ml, similar to values found in sera of SCID mice with SAT PBMC (14 and 11 U/ml), i.e., much lower than that seen for GD PBMC (127 and 78 U/ml); this is consistent with the view that, compared to GD T lymphocytes, that there is probably a lower number of T lymphocytes sensitized to the thyrotrophin (TSH) receptor antigen in SAT patients. Another possibility is that the transient thyroidal antigenic release seen in the acute (hyperthyroid) phase may be insufficient for adequate T cell sensitization. Still other possibilities include the effect of more severe hyperthyroidism of GD on T cell sensitization, and CD4/CD8 cell ratios. In any event, these results are consistent with our previous view that antigenic release in SAT will not itself lead to autoimmune thyroid disease.

Non-suppressed thyroidal radioactive iodine uptake (RAIU) in thyrotoxic phase in a case of subacute thyroiditis with thyroid-stimulating antibodies (TSAb).

In this paper, we report a 49-year-old female with subacute thyroiditis who had thyroid-stimulating antibodies (TSAb) and thyroid-stimulation-blocking antibodies (TSBAb) in serum. Although she was in the thyrotoxic phase and TSH was suppressed in May, 1990, her radioactive iodine uptake (RAIU) was not suppressed (35.5%) and a thyroid scan disclosed a diffuse goiter with no defect. Serum assays revealed the presence of TSAb, but TSBAb were negative. In August, 1990, the right lobe became undetectable by thyroid scan when the RAIU was 20.7% with the TSH level remaining suppressed. At that time, TSAb were negative, while TSBAb were positive. When the RAIU was 31.1% in October, 1990, both thyroid lobes became visible and the TSH level was normalized. TSBAb became negative, and although TSAb reappeared it later became undetectable. These results indicate that the changes in the patient's thyroid scan and RAIU were attributable to the presence of TSAb.

An outbreak of thyrotoxicosis due to atypical subacute thyroiditis.

We describe an epidemic of self-limited (6 weeks) thyrotoxicosis which affected 12 index cases, 5 household contacts, and 6 retrospectively identified cases in July, August, and September, 1987 in the town of Winterswijk (28,011 inhabitants), The Netherlands. A small goiter was present in 9 of the 12 index patients, tender upon palpation in only 2. Signs and symptoms of thyrotoxicosis were accompanied by a low grade fever in combination with fatigue, headache, myalgia, and a fine desquamation of the palms and soles. The apparent incubation time between family members was 6 days. Thyroid technetium uptake was decreased in 10 of 11 tested patients. Laboratory findings included elevated sedimentation rates (up to 68 mm/h), increased liver enzymes, lymphopenia in 2 patients, and absence of thyroid autoantibodies. HLA-B35, associated with classical subacute thyroiditis, was found in 1 patient only. An etiological agent was not identified. No evidence was found for thyrotoxicosis factitia. After 10 months, all patients were euthyroid, without a goiter or thyroid autoantibodies. Thus, a new variant of thyroiditis, atypical subacute thyroiditis, was probably the cause of this unusual outbreak. It is unclear at present if this variant of thyroiditis is common in communities and represents a separate disease entity.

Recurrence of subacute thyroiditis over 10 years after the first attack in three cases.

We saw a total of 4 episodes of the recurrence of subacute thyroiditis in 3 patients out of 222. The recurrent episodes were similar to the first episodes of subacute thyroiditis. The titers of various viral antibodies were not increased significantly during the clinical course of the recurrence. Regarding the HLA typing, A26, B35 and C3 were positive in all 3 patients. The association between the occurrence of subacute thyroiditis and the presence of HLA-B35 and C3 has hitherto been reported, although the association of HLA-A26 with recurrent type of subacute thyroiditis was observed and described for the first time in this report. It is suggested that HLA-A26 may somehow be related to the predisposition to the recurrence of subacute thyroiditis which developed after more than 10 years.