Clinical Manifestation of Subacute Thyroiditis Triggered by SARS-CoV-2 Infection Can Be HLA-Dependent.

In the last two years, we have been struggling with the pandemic of SARS-CoV-2, the virus causing COVID-19. Several cases of subacute thyroiditis (SAT) have already been described as directly related to SARS-CoV-2 infection. The clinical course of SAT induced by SARS-CoV-2 can be entirely different from the classic SAT course, and one of the most important differences is a very rapid SAT onset observed in some patients, especially a phenomenon of the simultaneous presence of both diseases. The aim of this report is to compare HLA profile and clinical course of SAT in four patients, in whom SAT was considered as triggered by COVID-19, with special attention paid to the differences between a patient with rare simultaneous presence of SAT and COVID-19, and patients with longer time lag between the diseases. The unusual phenomenon of simultaneous occurrence of COVID-19 and SAT induced by SARS-CoV-2 infection can be HLA-dependent and related to the presence of homozygosity at HLA-B*35. Additionally, the clinical course of SAT triggered by COVID-19 can be HLA-related in regard to the risk of recurrence, and to a variety of other aspects, including severity of thyrotoxicosis.

The relationship between serum calprotectin levels and disease activity in patients with subacute thyroiditis.

OBJECTIVE: Increased calprotectin (S100A8/A9) levels have been demonstrated in many acute and chronic inflammatory processes. Subacute thyroiditis is an inflammatory disease of the thyroid gland. In our study, we investigated the value of this inflammation marker in the diagnosis and follow-up of subacute thyroiditis. PATIENTS AND METHODS: Patients with subacute thyroiditis admitted to our clinic between November 2018 and January 2020 were included in the study. In the acute phase of the disease, fT4 (free thyroxin), TSH (Thyroid Stimulant Hormone), CRP (C Reactive Protein), ESR (Erythrocyte Sedimentation Rate), ALT (Alanine Aminotransferase), AST (Aspartate Aminotransferase), Creatinine, WBC (White Blood Cell), Absolute Lymphocyte and Neutrophil Count (ALC, ANC) parameters were detected and recorded. After complete resolution of the disease, the same laboratory parameters and acute phase reactants were again detected. Additionally, Calprotectin determination was performed in the acute phase and recovery period. Persistent hypothyroidism was determined by 6th-month TSH levels. RESULTS: Thirty-six patients were included in the study. Along with the classical acute phase reactants and ANC, there was a significant increase in the Calprotectin levels in the acute inflammatory phase of the disease compared to the recovery period (96. 92-37.98, p<0.001). Neither classical acute phase reactants and nor calprotectin were found to have a significant effect on the development of permanent hypothyroidism. Calprotectin did not correlate with other acute phase reactants, absolute neutrophil count and TSH levels in both the acute phase and resolution period. CONCLUSIONS: Calprotectin appears to be an important marker in the diagnosis and follow-up of subacute thyroiditis.

Strong Correlation between HLA and Clinical Course of Subacute Thyroiditis-A Report of the Three Siblings.

Subacute thyroiditis (SAT) is a thyroid inflammatory disease with susceptibility associated with the presence of human leukocyte antigen (HLA)-B*35, -B*18:01, -DRB1*01 and -C*04:01. Previous viral infection is considered as a triggering factor in genetically predisposed individuals. The influence of HLA on the SAT course was previously suggested. We aim to present the three siblings-female twins and their brother-with very close onset but different clinical courses of SAT, which appeared to be HLA-dependent. The HLA profile in the reported three siblings is strongly correlated with both SAT and Graves' disease (GD), however the coexistence of particular sets of high risk and protective alleles seems to be crucial for the GD development and the SAT course. The co-occurrence of HLA-DRB1*15:01 and/or -B*07:02, possibly together with the lack of HLA-A*01:01 and -B*41:01 seems to be key factors protecting against the development of GD with high TRAb levels, as well as against the recurrent SAT course and steroid dependence.

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

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

Neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and platelet-tolymphocyte ratio in different etiological causes of thyrotoxicosis

Background/aim: The most common causes of thyrotoxicosis include Graves' disease (GD), toxic multinodular goiter (TMNG), toxic adenoma (TA), and subacute granulomatous thyroiditis (SAT). In our study, we aimed to see whether neutrophil­to­lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet­to­lymphocyte ratio (PLR), and mean platelet volume (MPV) may be helpful in the differential diagnosis of these diseases. Materials and methods: We retrospectively analyzed the hospital records of the Endocrinology Clinic of our hospital between 2016 and 2019. We included data from 66 GD, 37 TA, and 35 SAT patients. We compared the data with those of 35 healthy subjects as controls. Results: NLR, MLR, and PLR were found to be higher in the SAT group when compared to other groups. The post hoc analysis of comparison of NLR, MLR, and PLR in each group showed that NLR and PLR were significantly different in the SAT group when compared to the GD, TA, and controls groups (P < 0.001, P = 0.003, and P < 0.001 for NLR respectively and P < 0.001 for PLR in all groups). MPV levels were different between groups (P = 0.007). However, the intergroup analysis (Tukey's test) failed to show a statistically significant difference for any of the groups. In patients with SAT, PLR and NLR were significantly higher than in the GD, TA, and control groups. MLR was also higher in SAT when compared to other groups, but the difference was not statistically significant. Conclusion: High PLR and NLR may be helpful to differentiate SAT from GD and TA, the other common causes of thyrotoxicosis.

Granulomatous Thyroiditis: A Case Report and Literature Review.

BACKGROUND: Granulomatous disease in the thyroid gland has been linked to viral, bacterial and autoimmune etiologies. The most common granulomatous disease of the thyroid is subacute granulomatous thyroiditis, which is presumed to have a viral or post-viral inflammatory cause. Bacterial etiologies include tuberculosis, actinomycosis, and nocardiosis, but are extremely rare. Disseminated actinomycosis and nocardiosis more commonly affect organ-transplant patients with the highest susceptibility within the first year after transplant surgery. CASE: A 45-year-old African American male, who received his third kidney transplant for renal failure secondary to Alport Syndrome, presented with numerous subcutaneous nodules and diffuse muscle pain in the neck. Further workup revealed bilateral nodularity of the thyroid. Fine needle aspiration of these nodules demonstrated suppurative granulomatous thyroiditis. Subsequent right thyroid lobectomy showed granulomatous thyroiditis with filamentous micro-organisms, morphologically resembling Nocardia or Actinomyces. CONCLUSION: Disseminated granulomatous disease presenting in the thyroid is very rare, and typically afflicts immune-compromised patients. The overall clinical, cytologic and histologic picture of this patient strongly points to an infectious etiology, likely Nocardia, in the setting of recent organ transplantation within the last year.

Comparison of thyroglobulin and thyroid peroxidase antibodies measured by five different kits in autoimmune thyroid diseases.

It is generally believed that the detection of thyroid peroxidase antibodies (TPOAb) is superior to that of thyroglobulin antibodies (TgAb) for the diagnosis of Hashimoto's thyroiditis. However, limited data are available on the comparison of TgAb and TPOAb prevalence as a diagnostic measurement for Hashimoto's thyroiditis using sensitive immunoassays. We herein used five different current immunoassay kits (A-E) to compare the prevalence of TgAb and TPOAb in Hashimoto's thyroiditis (n = 70), Graves' disease (n = 70), painless thyroiditis (n = 50), and healthy control subjects (n = 100). In patients with Hashimoto's thyroiditis, positive TgAb was significantly more frequent than positive TPOAb in kits A-D (mean ± SD of the four kits: 98.6 ± 1.7 vs 81.4 ± 2.0%). In patients with Graves' disease, TgAb prevalence was almost equivalent to that of TPOAb in five kits. Patients with painless thyroiditis exhibited positive TgAb significantly more frequently than positive TPOAb in kits A-D (73.5 ± 4.1 vs 33.0 ± 3.4%). The prevalence of TgAb alone was significantly higher than that of TPOAb alone in both Hashimoto's thyroiditis and painless thyroiditis in kits A-D. In kit E, TgAb and TPOAb prevalence did not differ significantly for any disease, and TgAb distribution was different from other kits. In conclusion, the prevalence of TgAb was higher than that of TPOAb in patients with Hashimoto's thyroiditis and painless thyroiditis using commercially available kits. We suggest that TgAb immunoassay is the first choice of screening test for thyroid autoimmune abnormalities in Japan.

[Silent thyroiditis and subacute thyroiditis].

Silent thyroiditis and subacute thyroiditis are important causes of transient thyrotoxicosis from rapidly progressive tissue injury, followed by the release of thyroid hormone into the circulation. The most striking differences between them are severe pain and extreme tenderness in the thyroid region. Although the etiology of these diseases is not clarified, silent thyroiditis is basically occurred in autoimmune thyroiditis. The most difficult differential diagnosis of silent thyroiditis is Graves' disease. TSH receptor antibody (TRAb) is useful, but TRAb is rarely positive in silent thyroiditis. A low thyroid radioiodine uptake value is most useful in identified silent thyroiditis.

Thyroglobulin autoantibodies of patients with subacute thyroiditis are restricted to a major B cell epitope.

BACKGROUND: Thyroglobulin autoantibodies (TgAb) can develop in patients with subacute thyroiditis (SAT). AIM: Comparison of the epitope pattern of TgAb of patients with SAT, Hashimoto's thyroiditis (HT) [autoimmune thyroid disease (AITD)] and non-toxic multinodular goiter (NTMG) (non-AITD). SUBJECTS AND METHODS: Serum TgAb from 10 patients with SAT, 45 with HT, and 19 with NTMG were evaluated. Serum TgAb binding to Tg was inhibited by 4 recombinant human TgAb-Fab, recognizing Tg epitope regions A, B, C, and D. The ability of single TgAb-Fab to inhibit the binding of serum TgAb to Tg was evaluated in enzymelinked immunosorbent assay. RESULTS: Levels of inhibition were different for all TgAb-Fab in the 3 groups of patients. Inhibition by region A TgAb-Fab in SAT [50.5 (30.3-62.5)%] (median and 25th to 75th percentiles) was similar to HT [49.0 (38.0-69.5)%] and significantly higher than in NTMG [25.0 (14.0-37.0)%]; by region B TgAb-Fab in SAT [0.0 (0.0-12.5)%] was significantly lower than in HT [28.0 (9.5-48.0)%] and similar to NTMG [9.0 (4.8-20.5)%]; by region C TgAb-Fab in SAT [9.5 (0.0-25.8)%] were similar to HT [23.0 (9.5-41)%] and NTMG [6.5 (1.7-21.5)%]; and by region D TgAb-Fab in SAT [0.0 (0.0-8.0)%] were lower than in HT [12.0 (1.0-28.5)%] and similar to NTMG [1.0 (0.0-5.0)%]. CONCLUSIONS: The epitope pattern of TgAb of SAT is restricted to the A region that is immunodominant in AITD and non-AITD. In the majority of patients with SAT, the autoimmune phenomena represent a non-specific and transient response to the release of thyroid antigens, rather than the expression of thyroid autoimmunity.

Simultaneous occurrence of subacute thyroiditis and Graves' disease.

BACKGROUND: Rare cases of Graves' disease occurring years after subacute thyroiditis (SAT) have been reported. Here, we present the first known case of simultaneous occurrence of Graves' disease and SAT. PATIENT FINDINGS: A 41-year-old woman presented with 10 days of neck pain, dysphagia, and hyperthyroid symptoms. Neck pain had initially started at the base of the right anterior neck and gradually spread to her upper chest, the left side of her neck, and bilateral ears. Physical examination revealed a heart rate of 110 beats/minute and a diffusely enlarged tender thyroid gland without evidence of orbitopathy. There was a resting tremor of the fingers and brisk deep tendon reflexes. Laboratory values: thyrotropin<0.01 mcIU/mL (nL 0.39-5.33), free thyroxine 2.0 ng/dL (nL 0.59-1.60), free T3 6.6 pg/mL (nL 2.3-4.2), thyroglobulin 20.1 ng/mL (nL 2.0-35.0), thyroglobulin antibody 843 IU/mL (nL 0-80), thyroperoxidase antibody 130 IU/mL (nL 0-29), thyroid stimulating hormone receptor antibody 22.90 IU/L (nL<1.22), thyroid stimulating immunoglobulins 299 units (nL<140), erythrocyte sedimentation rate 120 mm/h (nL 0-20), and C-reactive protein 1.117 mg/dL (nL 0-0.5). Human leukocyte antigen (HLA) typing revealed DRB1, DR8, B35, B39, DQB1, DQ4, and DQ5. A thyroid ultrasound showed an enlarged heterogeneous gland with mild hypervascularity. Fine-needle aspiration (FNA) biopsies of both thyroid lobes revealed granulomatous thyroiditis. The thyroid scan showed a diffusely enlarged gland and heterogeneous trapping. There was a focal area of relatively increased radiotracer accumulation in the right upper pole. The 5-hour uptake ((123)I) was 6.6% (nL 4-15). The patient was symptomatically treated. Over the next several weeks, she developed hypothyroidism requiring levothyroxine treatment. SUMMARY: This case illustrates a rare simultaneous occurrence of Graves' disease and SAT. Previous case studies have shown that Graves' disease may develop months to years after an episode of SAT. A strong family history of autoimmune thyroid disorders was noted in this patient. Genetic predilection was also shown by HLA typing. CONCLUSION: Although the occurrence of SAT with Graves' disease may be coincidental, SAT-induced autoimmune alteration may promote the development of Graves' disease in susceptible patients. Genetically mediated mechanisms, as seen in this patient by HLA typing and a strong family history, may also be involved.

Subacute thyroiditis and dyserythropoesis after influenza vaccination suggesting immune dysregulation.

Subacute thyroiditis (SAT) is an extremely rare complication of influenza vaccination. Several infectious agents have been related with SAT. It is also well known the association between HLA-B35 and the development of SAT. We describe a case of subacute thyroiditis and dyserythropoesis occurring shortly after administration of an influenza vaccine in a 55-year-old man with history of diabetes and psoriasis, family history of autoimmunity without clinical evidence of acute viral infection prior to the onset of symptoms. We propose that, the events occurring in the patient may be explained as result of complex interactions between the individual genetic background and environmental exposure to infectious agents that generated a pro-inflammatory status, where the vaccine was the trigger for the subsequent alterations in thyroid and bone marrow. These findings highlight the importance of immunogenetic factors involved in response to vaccination that is the central theme in the growing field of 'vaccinomics'.

Evaluation of a new rapid and fully automated electrochemiluminescence immunoassay for thyrotropin receptor autoantibodies.

BACKGROUND: Hyperthyroidism in Graves' disease is caused by autoantibodies to the TSH receptor (TSHR), and measurement of the TSHR autoantibody (TRAb) yields important information to diagnose and decide on the course of treatment of Graves' disease. We evaluated basic and clinical performance of a new, rapid, and fully automated electrochemiluminescence immunoassay Elecsys Anti-TSHR (Elecsys TRAb) for measuring serum TRAb. METHODS: For evaluation of basic performance of the assay, we carried out intra- and interassay precision studies using five serum pools and three serum pools, respectively, and the assay was compared with four commercial TRAb assays. Clinical performance of the assay was evaluated with sera from 298 patients with untreated Graves' disease, 220 patients with destructive (painless and subacute) thyroiditis, and 332 healthy volunteers. The optimal cutoff point, which was calculated by receiver operating characteristic (ROC) analysis with the above subjects, was then used to classify an independent sample set of 80 patients with untreated Graves' disease, and 152 patients with destructive thyroiditis. RESULTS: Intraassay coefficient of variation (CV) was 4.24% at 1.85 IU/L and interassay CV was 10.1% at 1.46 IU/L. All the correlation coefficient values calculated against four commercial assays were larger than 0.85. ROC analysis resulted in a specificity of 99.1% with a sensitivity of 97.0% at a decision limit of 1.86 IU/L from comparison with untreated Graves' disease and destructive thyroiditis. The cutoff point yielded a sensitivity of 87.5% and specificity of 96.7% with the independent sample set. CONCLUSION: In spite of the short measuring time of only 27 minutes, the assay showed the same or better results with the existing commercial products. The short measuring time would contribute to speedy, preconsultation diagnosis of thyroid disease, especially of Graves' disease.

Interleukin-10 promotes resolution of granulomatous experimental autoimmune thyroiditis.

Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by mouse thyroglobulin-sensitized splenocytes activated in vitro with mouse thyroglobulin and interleukin (IL)-12. Thyroid lesions reach maximal severity 20 days after cell transfer, and inflammation either resolves or progresses to fibrosis by day 60 depending on the extent of thyroid damage at day 20. Depletion of CD8(+) T cells inhibits G-EAT resolution. Our previous studies indicated that IL-10 was generally higher in G-EAT thyroids that resolved. Using both wild-type and IL-10(-/-) CBA/J mice, this study was undertaken to determine whether G-EAT resolution would be inhibited in the absence of IL-10. The results showed that either depletion of CD8(+) T cells or IL-10 deficiency increased fibrosis and inhibited resolution of inflammation. We also found a correlation between higher expression levels of proinflammatory cytokines and preferential expression levels of proapoptotic molecules, such as FasL and TRAIL, and antiapoptotic molecules, such as FLIP and Bcl-xL, in inflammatory cells from thyroids of both CD8-depleted and IL-10-deficient mice. Furthermore, many of the CD8(+) T cells were also IL-10(+). These results suggest that IL-10 plays an important role in G-EAT resolution and might promote resolution, at least in part, through its production in CD8(+) T cells. Further understanding of the mechanisms that promote the resolution of inflammation will facilitate the development of novel strategies for treating autoimmune diseases.

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.

Riedel's thyroiditis in a patient with recurrent subacute thyroiditis: a case report and review of the literature.

Riedel's thyroiditis is a rare form of chronic thyroiditis, characterised by a fibroinflammatory process that partially destroys the thyroid and often involves surrounding tissues. The relationship of Riedel's thyroiditis to other forms of thyroiditis is not clear. A case of Riedel's thyroiditis in a 51-year-old woman presenting with symptoms of subacute thyroiditis, is reported. She was diagnosed with subacute thyroiditis based on clinical manifestation and laboratory results. She was treated with glucocorticoids for six weeks, and then followed-up for 12 months. Three years later, she visited with tenderness and enlargement of thyroid mass, and laboratory and radiology findings suggested that she had a malignant thyroid tumor as well as subacute thyroiditis. After thyroidectomy, histopathologic findings showed that she had Riedel's thyroiditis in the presence of subacute thyroiditis. Until now, few cases of Riedel's thyroiditis in patients with a history of subacute thyroiditis have been reported in the literature. Although the etiology of Riedel's thyroiditis is unknown, it may develop in the course of subacute thyroiditis.

Familial occurrence of painful subacute thyroiditis associated with human leukocyte antigen-B35.

INTRODUCTION: Subacute thyroiditis (SAT) is a spontaneously remitting inflammatory disorder of the thyroid that is presumed to be virally induced in genetically predisposed individuals. A strong association has been suggested between human leukocyte antigen (HLA)-B35 and patients who developed SAT. However, familial occurrence of SAT associated with HLA-B35 is reported only rarely. CASE-REPORTS: We report three sibs, (two brothers and one sister) living in the same Lebanese town, who developed SAT during an 18-month-period. All tested positive for HLA-B35. DISCUSSION: The family described here represents the first Third World third familial report of SAT associated with HLA-B35. It highlights the probably underestimated importance of genetic predisposition to SAT in families.