Current status of the thyroid hormone measurement items in patients receiving levothyroxine monotherapy by the management based on the thyroid tissue volume.

We and other investigators reported that mild TSH suppression with levothyroxine (LT4) was needed to achieve normal free triiodothyronine (FT3) levels and metabolic euthyroid state in athyreotic patients. Consequently, management methods based on thyroid tissue volume have been implemented for patients receiving LT4 at the Kuma Hospital. This retrospective study examined the composition of the thyroid hormone measurement items (serum-free thyroxine [FT4], FT3, and FT4 + FT3) in patients receiving LT4 monotherapy. According to the etiology of hypothyroidism, 36% of the 25,523 patients included in this study underwent total thyroidectomy (TT). Thirteen percent and 14% had undergone 131I treatment for hyperthyroidism (RIT) and partial thyroidectomy (PT), respectively. Moreover, 37% of patients had received non-invasive treatment (NIT). The proportion of patients who underwent only FT3 measurements was higher (TT, 93%; RIT, 61%) in the first two groups, whereas the proportion of patients who underwent only FT4 measurements was higher (PT, 50%; NIT, 65%) in the remaining two groups. Only FT3 measurements were performed in 58% of patients. Only FT4 measurements were performed in 34% of patients. The serum TSH levels were suppressed in nearly half of the patients (46%). Thus, FT3 was the major thyroid hormone measured in patients receiving LT4 treatment, and the serum TSH levels were suppressed in nearly half of the patients. This may be attributed to the management guidelines at our hospital, a specialized facility for thyroid disease, wherein half of the patients present are athyreotic or have atrophic thyroid glands after TT or RIT.

Nodule-specific NRF2-targeted upregulation in patients with KEAP1 mutations and familial nontoxic multinodular goiter.

CONTEXT: Kelch-like ECH-associated protein 1 (KEAP1) is associated with nuclear factor erythroid-2 related factor 2 (NRF2) and promotes NRF2 degradation in normal conditions. Genetic abnormality in KEAP1 is a rare disease and presents with familial multinodular goiter. OBJECTIVE: This study assessed the clinical and molecular findings concerning nodular formation in the thyroid gland of patients harboring KEAP1 germline mutations. METHODS: Next-generation sequencing analysis targeting goiter-associated genes was performed on 39 patients with familial multinodular goiter. The expression of NRF2-targeted genes from surgical thyroid specimens of patients with KEAP1 mutations were analyzed using a whole transcript expression array and immunohistochemistry. RESULTS: We found five probands with pathogenic heterozygous mutations in KEAP1 (p.Q86*, p.L136P, p.V411fs, p.R415C, and p.R483H), which had no meaningful concomitance with mutations of other goiter-associated genes in germline and somatic levels. Their common histopathological features showed multinodular goiters in the entire thyroid gland with few degenerative lesions or complications of malignancy and slow proliferation indicating < 1% at the Ki-67 labeling index. Among 42 NRF2-targeted genes, antioxidant genes were most frequently upregulated (11/12) in the nodule, followed by detoxification genes (6/11). Immunohistochemical analysis showed relatively high expression of glutathione peroxidase 2 and NAD(P)H quinone oxidoreductase 1 (representative NRF2-targeted genes) in the nodules of various patients harboring KEAP1 mutations. CONCLUSION: KEAP1 germline heterozygous mutations exert excessive NRF2 activity in the thyroid gland and may confer cytoprotective effects even under abundant reactive oxygen species associated with thyroid hormone production, resulting in thyroid hyperplasia with scarce degradation.

Familial Nonautoimmune Hyperthyroidism Due to a TSH Receptor Gene Pathogenic Variant.

Familial nonautoimmune hyperthyroidism (NAH) is a rare type of autosomal dominant hyperthyroidism caused by constitutively active pathogenic variants of the thyrotropin receptor (TSHR) gene. Although affected family members present with varied levels of hyperthyroid features, even when the same pathogenic variant is present, total thyroidectomy followed by radioiodine therapy is recommended for long-term management. Herein, we present the case of an 18-year-old proband and her family members with NAH (TSHR-I640V), who presented with diverse thyroid dysfunctions: fluctuations between euthyroid and subclinical hyperthyroidism, mild hyperthyroidism, and overt hyperthyroidism. Almost all affected adult family members, except the proband, showed no progression of hyperthyroidism or thyroid enlargement. A family history of thyrotropin receptor antibodies (TRAb)-negative hyperthyroidism is important for the identification of NAH in adults before TSHR genetic testing can be performed. Ablative therapy is not necessary when familial NAH presents with late-onset mild hyperthyroidism without coexisting diseases.

Generation of a mouse model of thyroid storm and preliminary investigation of the therapeutic effects of ghrelin.

BACKGROUND: Thyroid storm (TS), a life-threatening condition that can damage multiple organs, has limited therapeutic options. Hypercytokinemia is a suggested background, but the pathological condition is unclear and there are no appropriate animal models. We aimed to develop a TS mouse model by administration of triiodothyronine and lipopolysaccharide, and then to examine the effects of ghrelin on this model. METHODS: We evaluated the use of serum IL-6 levels as a representative marker of hypercytokinemia in patients with TS. To establish the mouse model, preliminary experiments were conducted to determine the non-lethal doses of triiodothyronine and lipopolysaccharide when administered individually. As a TS model, C57BL/6 mice were administered with triiodothyronine 1.0 mg/kg (subcutaneously, once daily for seven consecutive days) and lipopolysaccharide 0.5 mg/kg (intraperitoneally, on day 7) to develop a lethal model with approximately 30% survival on day 8. We assessed the survival ratio, mouse sepsis scores and blood biomarkers (IL-6, metanephrine, alanine aminotransferase) and evaluated the effects of ghrelin 300 µg/kg on these parameters in TS model. RESULTS: Serum IL-6 was increased in patients with TS compared with those with Graves' disease as the diseased control (18.2 vs. 2.85 pg/mL, P < .05, n = 4 each). The dosage for the murine TS model was triiodothyronine 1.0 mg/kg and lipopolysaccharide 0.5 mg/kg. The TS model group had increased mouse sepsis score, serum IL-6, metanephrine and alanine aminotransferase. In this model, the ghrelin improved the survival rate to 66.7% (P < .01, vs. 0% [saline-treated group]) as well as the mouse sepsis score, and it decreased the serum IL-6 and metanephrine. CONCLUSION: We established an animal model of TS that exhibits pathophysiological states similar to human TS with induction of serum IL-6 and other biomarkers by administration of T3 and LPS. The results suggest the potential effectiveness of ghrelin for TS in humans.

Diagnostic significance of clay-like materials aspirated from thyroid nodules.

Objective: The simplest way to determine the adequacy of aspirated materials is the on-site gross visual assessment of aspirated materials. However, few studies have examined the gross findings of thyroid aspirates. This study aimed to clarify the diagnostic significance of clay-like material aspirated from thyroid nodules. Material and Methods: We reviewed 69,848 thyroid nodules that underwent aspiration cytology at Kuma Hospital between January 2007 and August 2021. Among them, 355 (0.5%) nodules with aspirated materials described as clay-like materials were retrospectively examined. Results: Among 355 nodules, 322 (90.7%) were categorized as cystic fluid or benign. The aspirated materials were mainly composed of non-epithelial components, including colloid or proteinaceous materials, foamy histiocytes, and degenerative red blood cells. In original ultrasound reports, the incidence of intermediate and high suspicion was 11.0%. Malignant cells were observed in 21 nodules (5.9%), one-third of which were papillary thyroid carcinomas. The materials aspirated from papillary and follicular thyroid carcinomas exhibited necrotic carcinoma cells derived from infarcted areas. The overall risk of malignancy was 3.9%. The risk of malignancy in nodules interpreted as highly suspicious on ultrasound examination was 37.5%. Conclusion: As clay-like materials aspirated from thyroid nodules were considered sufficient specimens, the recognition contributes to avoiding unnecessary second punctures. The presence of clay-like materials was indicative of the colloid and/or blood components of benign cystic lesions, or, more rarely, of infarcted carcinoma. The ultrasound examination results tended to overestimate nodules. We should reaffirm that on-site gross visual assessment of aspirated materials is a fast and reasonably accurate predictor of the on-site adequacy of the samples.

Clinicopathological characteristics of methotrexate-related lymphoproliferative disorder of the thyroid: A study of 11 patients.

Methotrexate (MTX) is a well-known agent that can potentially cause lymphoproliferative disorder (LPD), known as MTX-related LPD (MTX-LPD). Only two cases of thyroid MTX-LPD have been reported to date. This study aimed to report 11 cases of MTX-LPDs arising in the thyroid gland and discuss their clinicopathological characteristics. Of the 747 patients with cytologically suspected lymphoma, 11 had received MTX. The mean age of the patients with MTX-LPD was 70.2 years (range: 51-82 years), and all were female. The duration of MTX administration ranged from 5 to 31 years (mean: 19.5 years). Nine patients (81.8 %) tested positive for anti-thyroglobulin antibody and/or anti-thyroid peroxidase antibody. In three patients, the tumor decreased in size or disappeared without surgery or chemotherapy after withdrawal of MTX therapy. Histologically, all eight nodules examined were B-cell lymphomas, and seven were mucosa-associated lymphoid tissue (MALT) lymphomas. Epstein-Barr virus-encoded small RNA in situ hybridization showed negative results for all six nodules examined. All five patients who were followed-up at our hospital exhibited progression-free survival for >3 years without chemotherapy. Six patients were transferred to other hospitals, and their follow-up details are unknown. MTX-LPDs occurring in the thyroid are characterized by a high female predominance, positivity for anti-thyroid autoantibodies, high prevalence of MALT lymphomas, negativity for Epstein-Barr virus, and good outcomes without chemotherapy. We recommend that patients with thyroid lymphoma should be checked for a history of MTX.

Availability of Serum Levels of Carbohydrate Antigen 19-9 (CA19-9) as a Surrogate Tumor Marker for Papillary Thyroid Carcinoma.

Introduction: Thyroglobulin (Tg) is a very sensitive and specific marker in patients who have undergone total thyroidectomy for papillary thyroid carcinoma (PTC). However, the presence of a Tg antibody (TgAb) interferes with Tg immunometric assays, making Tg levels unreliable indicators. There are currently no other tumor markers to monitor in patients with PTC whose serum is TgAb-positive. Thus, we investigated whether carbohydrate antigen 19-9 (CA19-9) can be used as a tumor marker for PTC. Methods: We retrospectively analyzed 196 consecutive patients with PTC (maximum diameter ≥ 2 cm). The serum CA19-9 and Tg values of each patient were obtained before and 0.5-1 month postsurgery. Immunohistochemical staining for PTC was performed using an antibody against CA19-9. Results: High pre-surgery serum levels of CA19-9 were observed in 6.1% of the patients. Postsurgery, serum CA19-9 levels in all 196 patients decreased considerably and were within the normal range. CA19-9 expression was detected in 28 of 62 PTCs (45.2%) and was detected at various degrees and ranges in conventional PTC histology. Conclusions: Although further studies with longer follow-ups are necessary, serum CA19-9 levels may serve as a surrogate tumor marker for PTC in place of serum Tg levels sin some patients.

Utility of solid area diameter in management of cystic papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) with marked cystic formation (CPTC) is not a subtype of PTC, and its clinical characteristics have not been fully investigated. This study aimed to clarify the clinical and pathological characteristics of CPTC and propose important indicators for its clinical management. Thirty-three CPTC nodules with cystic areas occupying >50% of their volume were examined. Two matched controls (MCs) were prepared, one with tumor diameter matched for whole tumor diameter (WTD) of CPTCs and the other with tumor diameter matched for solid area diameter (SAD) of CPTCs. The mean age of patients with CPTC was 55.2 years significantly older than that in SAD-MCs. Of the CPTCs, 69.7% were classified as highly suspicious by ultrasonography, and the prevalence was lower than that in WTD-MCs (88.9%) and SAD-MCs (91.5%). Total thyroidectomy was performed in 69.7% of CPTC cases, which was significantly less frequent than that in WDT-MCs (91.7%) and similar to that in SAD-MCs (76.1%). Histologically, CPTCs exhibited two characteristic findings: invasion from the solid area into the surrounding normal thyroid tissue and granulation tissue around the cystic wall. The frequencies of the cases with pathological lateral node metastasis, extrathyroidal extension, and Ki-67 labeling index ≥5% in CPTCs were significantly lower than those in WTD-MCs and relatively similar to those in SAD-MCs. In the surgical strategy and prognosis of CPTC, the evaluation of tumor size should be based on SAD rather than on WTD. We advocate measuring not only WTD but also SAD in CPTC.

Calcium oxalate crystals as a cause of multiple punctate echogenic foci in benign thyroid lesions.

PURPOSE: Multiple punctate echogenic foci (MPEF) on thyroid ultrasonography reflects psammoma bodies in papillary thyroid carcinomas. However, MPEF is also observed in benign thyroid lesions. The aim of this study was to determine the origin of MPEF in patients with benign thyroid lesions. METHODS: We enrolled 26 patients with Graves' disease (GD) and 24 with follicular nodular disease (FND) who exhibited MPEF and underwent surgery. As controls, we enrolled 40 patients with GD and 32 with FND, but without MPEF, who underwent surgery. RESULTS: MPEF was observed in both lobes in 80.8% of GDs with MPEF, but was limited to a single lobe in the remaining cases. MPEF was diffusely distributed in 72.3% of the cases and focally distributed in the remaining cases. On ultrasonography, most (92.3%) FNDs with MPEF were solid lesions, and seven nodules (26.9%) were interpreted as intermediate suspicion and their frequencies were higher than in those without MPEF (p < 0.01). Microscopically, calcium oxalate (CaOx) crystals were observed more frequently in GDs and FNDs with MPEF (100% and 88.5%, respectively) than in those without MPEF (p < 0.001). These differences were particularly significant for CaOx crystals > 100 µm. In GD cases, large CaOx crystals were observed more frequently in the lobes with MPEF than in those without (p < 0.05). No psammoma bodies were present in any of the cases. CONCLUSION: Appearance of MPEF in GDs and FNDs is not because of psammoma bodies; it is attributable to CaOx crystals larger than 100 µm. Therefore, MPEF is not an indicator of malignancy.

Prospective Multicenter Registry-Based Study on Thyroid Storm: The Guidelines for the Management from Japan are Useful.

CONTEXT: The mortality rate in thyroid storm (TS) has been reported to be higher than 10%. OBJECTIVE: We aimed to evaluate the effectiveness of the 2016 guidelines for the management of TS proposed by the Japan Thyroid Association and Japan Endocrine Society. DESIGN: Prospective registry-based study through a secure web platform. SETTING: Prospective multicenter registry. PATIENTS AND MEASUREMENTS: Patients with new-onset TS were registered in the Research Electronic Data Capture (REDCap). On day 30 after admission, clinical information and prognosis of each patient were added to the platform. On day 180, the prognosis was described. RESULTS: This study included 110 patients with TS. The median of Acute Physiology and Chronic Health Evaluation (APACHE) II score was 13, higher than the score in the previous nationwide epidemiological study, 10 (p = 0.001). Nonetheless, the mortality rate at day 30 was 5.5%, approximately half compared with 10.7% in the previous nationwide survey. Lower body mass index, shock and lower left ventricular ejection fraction were positively associated with poor prognosis at day 30, while the lack of fever ≥ 38℃ was related to the outcome. The mortality rate in patients with an APACHE II score ≥12 for whom the guidelines were not followed was significantly higher than the rate in patients for whom the guidelines were followed (50% vs. 4.7%) (p = 0.01). CONCLUSIONS: Prognosis seemed better than in the previous nationwide survey, even though disease severity was higher. The mortality rate was lower when the guidelines were followed. Thus, the guidelines are useful for managing TS.

Comparison of pathophysiology in subclinical hyperthyroidism with different etiologies.

Subclinical hyperthyroidism (SHyper) is defined as normal levels of free thyroxine (fT4) and free triiodothyronine (fT3) with suppressed levels of TSH. Previous studies have reported the individual pathophysiology of endogenous SHyper patients and athyreotic patients receiving TSH suppression therapy with levothyroxine; however, apparently no studies have compared the two conditions. Five-hundred-forty untreated endogenous SHyper patients and 1,024 patients receiving TSH suppression therapy who underwent total thyroidectomy for papillary thyroid carcinoma were sampled. Thyroid hormone profiles and peripheral indices related to thyrotoxicosis were investigated in endogenous SHyper patients, athyreotic patients receiving TSH suppression therapy, and healthy participants. Endogenous SHyper patients showed significantly higher thyroid hormone levels (fT4 [p < 0.001] and fT3 [p < 0.001]), and peripheral indices showed a significant tendency towards thyrotoxicosis (strong TSH suppression: alkaline phosphatase [ALP, p < 0.001], creatinine [Cre, p < 0.001], pulse rate [p < 0.05]; and mild TSH suppression: Cre [p < 0.05]) than healthy participants. In contrast, athyreotic patients receiving TSH suppression therapy showed a significant tendency towards thyrotoxicosis than healthy participants only when TSH was strongly suppressed (fT3 [p < 0.001] and Cre [p < 0.001]). Endogenous SHyper patients showed significantly higher fT3 levels (p < 0.001) than athyreotic patients receiving TSH suppression therapy; however, there was a significant tendency towards thyrotoxicosis only when TSH was strongly suppressed (ALP [p < 0.05] and pulse rate [p < 0.05]). The effects of endogenous SHyper and TSH suppression therapy on target organ function are different. Although the serum thyroid hormone profile is similar to that of the thyrotoxic state, athyreotic patients receiving TSH suppression therapy with mildly suppressed serum TSH levels are not thyrotoxic.

Profiling of Unfolded Protein Response Markers and Effect of IRE1α-specific Inhibitor in Pituitary Neuroendocrine Tumor.

CONTEXT: Inositol-requiring enzyme 1α (IRE1α) and PKR-like ER kinase (PERK), which are endoplasmic reticulum (ER) membrane proteins, regulate the unfolded protein response (UPR). These molecules have recently gained attention as a novel therapeutic target in secretory tumors. The roles of the UPR in pituitary neuroendocrine tumors (PitNETs) are unclear. OBJECTIVE: To clarify UPR profiling of PitNETs and to investigate the effect of pharmacological modulation of UPR by KIRA8, a newly developed IRE1α-specific inhibitor. METHODS: In 131 patients with PitNETs, we evaluated RNA expression of UPR markers in PitNETs and their clinical phenotypes. Using GH3 cells, we examined the effects of KIRA8 and its combination with octreotide on UPR profiling, cell growth, and apoptosis. RESULTS: Cytoprotective adaptive-UPR (A-UPR) markers were more increased in functioning PitNETs (FPitNETs, n = 112) than in nonfunctioning PitNETs (NFPitNETs, n = 19), while there was no difference in proapoptotic terminal-UPR (T-UPR) markers. Similarly, overt somatotroph tumors (STs, acromegaly, n = 11) increased A-UPR compared with silent STs (n = 10). In STs, serum IGF-1 levels were inversely correlated with Txnip mRNA expression, a representative T-UPR marker. KIRA8 inhibited cell growth and facilitated apoptosis in GH3 cells with increased expressions of T-UPR markers, which was enhanced by the combination with octreotide. Octreotide increased mRNA expression of Txnip and Chop, but decreased spliced Xbp1 under ER stress. Octreotide is suggested to inhibit activation of IRE1α but to reciprocally induce T-UPR under PERK. CONCLUSION: UPR markers in FPitNETs are implicated as dominant A-UPR but blunted T-UPR. KIRA8, enhanced with octreotide, unbalances the UPR, leading to antitumor effects. Targeting IRE1α may provide a novel strategy to treat PitNETs.

Prevalence and diagnostic significance of non-invasive follicular thyroid neoplasm with papillary-like nuclear features in Japan-A multi-institutional study.

This multi-institutional study investigated non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) frequency and its diagnostic significance in Japan. We reviewed 4008 thyroid nodules resected in six institutions before NIFTP was proposed. Overall, 26 cases diagnosed as non-invasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) and 145 cases of follicular thyroid adenoma (FTA) were included. Of these nodules, 80.8% and 31.0%, respectively, were NIFTPs. In five institutions, NIFTPs were more commonly found in FTA than in PTC nodules. When NIFTP was included with PTC, the overall prevalence was 2.3%, with rates in five institutions below 5.0% (0.8%-4.4%). One NIFTP case with nuclear score 3 revealed nodal metastasis 2.5 years post-resection, and the carcinoma cells were immunohistochemically positive for BRAF. FTAs or NIFTPs with nuclear score 2 did not metastasize. NIFTP was more common among FTA than among PTC nodules, possibly due to underdiagnosis of PTC on nuclear findings. Considering the clinical findings, molecular pathogenesis, and therapeutic strategy in Japan, NIFTP with nuclear score 2 is not different from FTA, and use of this entity terminology is not meaningful. In contrast, NIFTP with nuclear score 3 has potential for metastasis and BRAFV600E mutation. Therefore, in NIFTP cases, nuclear scores 2 and 3 should be separately reported.

Interference against a newly labeled substance with ruthenium sulfonate complexes showing discrepant thyroid function test results.

We report here two patients exhibiting a combination of falsely elevated serum levels of free thyroxine (FT4), free triiodothyronine (FT3), and thyrotropin receptor antibodies (TRAb), measured using Elecsys assay kits (Roche Diagnostics GmbH). The first patient was a 74-year-old man misdiagnosed with Graves' disease and treated with methimazole. The second patient was a 48-year-old woman whose serum FT4 and FT3 concentrations were found to be high during a blood test. These patients denied taking biotin or any other supplements. Further detailed examination, including a heterophilic blocking tube test, revealed the presence of serum antibodies. The abnormal reactions were observed only using the improved assay kits using ruthenium (Ru) sulfonate instead of Ru as a chemiluminescent agent. Therefore, serum antibodies to the Ru sulfonate complex caused the pseudo-high levels of FT4, FT3, and TRAb. To our knowledge, this is the first report showing that antibodies to the Ru sulfonate complex in the electrochemiluminescence immunoassay can cause falsely elevated levels of the combination, leading to discrepant thyroid function test results. We emphasize that in cases of abnormal test results, alternative assay methods should be considered for further examination; unusual test results should not be impulsively interpreted, even when using revised assay kits.

Long-Term Disproportional TSH Hyposecretion in a Patient With Nonautoimmune Hyperthyroidism After Radioiodine Therapy.

Nonautoimmune hyperthyroidism (NAH), caused by constitutively active mutants of the thyrotropin receptor (TSHR) gene, is recommended to be treated with total thyroidectomy followed by radioiodine administration. Herein, we present a 39-year-old woman with sporadic NAH caused by a TSHR-L512Q mutation. At the age of 20 years, she presented with a large goiter of 370 mL, treated with thiamazole, and opted for radioiodine therapy as outpatient management. Over the next 17 years, she underwent 6 treatments of 13 mCi radioiodine each. She did not experience a relapse of hyperthyroidism, and thiamazole was reduced and later withdrawn during the final radioiodine treatment. The patient's goiter significantly reduced to 18 mL, and thyroid function tests showed that free thyroxine and free triiodothyronine levels were below the lower limit of the reference ranges, while TSH remained within the reference range for 20 months. Along with an almost normal TSH response to thyrotropin-releasing hormone stimulation, no pituitary atrophy was observed on magnetic resonance imaging. Contrary to the recommended treatment, this case showed that fractionated radioiodine therapy alone is effective in controlling thyroid function and in reducing goiter size. Low TSH levels during treatment should not be assessed as subclinical hyperthyroidism or as risk of relapse.

Thyroid function, glycemic control, and diabetic nephropathy in patients with type 2 diabetes over 24 months: prospective observational study.

BACKGROUND: The higher prevalence of thyroid dysfunction in type 1 diabetes patients has been well established, whereas it is a matter of debate whether that is also observed in type 2 diabetes patients. This study was conducted to reveal whether higher prevalence of thyroid dysfunction is observed in patients with type 2 diabetes. METHODS: We examined thyroid functions and thyroid autoantibodies in 200 patients with type 2 diabetes and 225 controls, with 24 months follow up for those with type 2 diabetes. RESULTS: Serum free triiodothyronine (fT3) levels and fT3/free thyroxine (fT4) ratio were significantly lower, while fT4 levels were significantly higher in patients with type 2 diabetes. The number of patients with thyroid dysfunction or patients positive for thyroid autoantibodies were not different between the two groups. The fT3/fT4 ratio was positively and negatively correlated with serum c-peptide and HbA1c levels, respectively, suggesting that the difference can be attributable to insulin resistance and diabetic control. In the follow-up observation, we found no significant correlation between basal thyrotropin (TSH), fT3, fT4 or fT3/fT4 ratio with the amounts of changes of HbA1c levels at 12 or 24 months after the basal measurements. There was a negative relationship between TSH levels and eGFR at baseline measurements, but TSH levels did not seem to predict future decline of eGFR levels. No relationship was observed between urine albumin/ g‧cre levels and thyroid function. CONCLUSION: Thyroid dysfunction and thyroid autoantibodies were not different in prevalence between patients with type 2 diabetes and controls, although in patients with type 2 diabetes, the fT3/fT4 ratio was decreased. Basal thyroid function did not predict future diabetes control or renal function within 24 months of follow-up.

Recurrent laryngeal nerve's course running anteriorly to a thyroid tumor.

The thyroid gland's neurovascular relationship is commonly portrayed as the recurrent laryngeal nerve (RLN) coursing posteriorly to the thyroid gland. We report a rare case with the RLN running anteriorly to a thyroid tumor. A 56-year-old Japanese woman underwent a thyroidectomy for a benign thyroid tumor. Preoperatively, computed tomography confirmed that part of the tumor had extended into the mediastinum and was descending posteriorly up to the brachiocephalic artery. Intraoperatively, when the sternothyroid muscle was incised to expose the thyroid gland, a cord (nerve)-like structure was observed directly anterior to the thyroid tumor. Although the course of this cord-like structure was clearly different from the "traditional" course of the right RLN, the possibility that the structure was the RLN could not be excluded. The structure was traced back in order to preserve it; we saw that it entered the larynx at the lower margin of the cricothyroid muscle and approximately at the level of the cricothyroid junction through the back of the normal thyroid tissue. With intraoperative neuromonitoring, the structure was identified as the RLN. As a result, the course of the RLN run anterior to the tumor but then posterior to the 'normal thyroid' i.e. into it normal anatomical position. Had we assumed that the RLN was behind the thyroid tumor, we would have damaged the RLN. It would not be possible to diagnose this abnormal running course of the RLN reliably before surgery, but extra care should be taken in similar cases, that is, when a large thyroid tumor is descending posteriorly up to the brachiocephalic artery on the right side.

A case of immunoglobulin G4-related retroperitoneal fibrosis and hypophysitis with antecedent respiratory disease followed by spontaneous remission and recurrence.

A 65-year-old man presented with apparent bronchopneumonia. After treatment with antibiotics, he showed eosinophilia. Computed tomography (CT) imaging revealed bilateral consolidation, ground-glass opacities with nodular consolidations, and pleural effusion. Lung biopsy showed organising pneumonia with lymphoplasmacytic infiltration in the alveolar septa and in the thickened pleura and interlobular septa. All pulmonary abnormalities spontaneously went into remission within 12 months. At 73 years old, a follow-up CT scan revealed small nodules in both lungs and the review of the head CT scan showed thickening of the pituitary stalk in studying prolonged headache. Two years later, he visited the hospital complaining of severe oedema on the lower extremities with high serum immunoglobulin (Ig)G4 186 mg/dl. A whole-body CT scan showed retroperitoneal mass surrounding aortic bifurcation and compressing inferior vena cava, pituitary stalk thickening and gland swelling, and enlarged pulmonary nodules. Anterior pituitary stimulation tests showed central hypothyroidism, central hypogonadism, and adult growth hormone deficiency with partial primary hypoadrenocorticism. Retroperitoneal mass biopsy showed storiform fibrosis and obliterative phlebitis with marked lymphoplasmacytic infiltration with moderate IgG4-positivity. Immunostaining of the former lung specimen revealed dense interstitial infiltration of IgG4-positive cells. These findings indicated metachronous development of IgG4-related disease in lung, hypophysis, and retroperitoneum, according to the recent comprehensive diagnostic criteria of IgG4-related disease. Glucocorticoid therapy ameliorated oedema, on the other hand, unmasked partial diabetes insipidus at the initial dose of the treatment. Hypothyroidism and retroperitoneal mass regressed at 6 months of the treatment. This case warns us that long-term follow-up from prodromal to remission is necessary for the treatment of IgG4-related disease.

Clinical, cytological, and pathological characteristics of metastatic renal cell carcinoma to the thyroid: A study of 14 cases at a Japanese single institution.

A preoperative diagnosis of metastatic renal cell carcinoma to the thyroid (MRCCT) is important for determining clinical management but is challenging even in cases with a clinical history of renal cell carcinoma (RCC). This study aimed to elucidate the clinical, cytological, and pathological characteristics of MRCCT. Fourteen MRCCT cases extracted from 18 320 malignant thyroid tumors were included in this study. Twelve MRCCT (85.7%) occurred as solitary lesions and the most frequently suspected lesions on ultrasonography were follicular tumors. On cytology, 46.2% of cases were reported as RCC or suspected RCC; a medical history of RCC and immunocytochemistry were helpful in interpretation. RCC metastasized to a follicular adenoma in 50.0% of the solitary lesions. MRCCTs with a long interval from the initial presentation, solitary lesion, and Ki-67 labeling index <10% showed significantly longer disease-free survival. MRCCT is characterized by a long interval from the initial presentation of RCC, appearance as a solitary nodule, ultrasonographic similarity to follicular tumors, sharing cytological findings with primary thyroid tumors, and high frequency of metastasis within follicular adenoma. A long interval from the initial presentation, occurrence as a solitary lesion, and low Ki-67 labeling index may be favorable prognostic factors.

Non-hyalinizing trabecular thyroid adenoma: a novel thyroid tumor with diagnostic pitfalls of hyalinizing trabecular adenoma and medullary thyroid carcinoma.

BACKGROUND: Only one thyroid follicular cell-derived tumor with a purely trabecular growth pattern has previously been described. This report aims to describe the histological, immunohistochemical, and molecular findings of our second case, propose a novel thyroid tumor, and discuss its diagnostic pitfalls. CASE PRESENTATION: A 68-year-old female presented with an encapsulated thyroid tumor composed of thin and long trabeculae. No papillary, follicular, solid, or insular patterns are observed. The tumor cells were elongated or fusiform and arranged perpendicular to the trabecular axis. No nuclear findings of papillary thyroid carcinoma and increased basement membrane material were found. Immunohistochemically, the tumor cells were positive for paired-box gene 8, thyroid transcription factor-1, and negative for thyroglobulin, calcitonin, and chromogranin A. Inter- and intra-trabecular accumulation of type IV collagen-positive materials was not demonstrated. None of PAX8/GLIS1 and PAX8/GLIS3 and mutations in BRAF, HRAS, KRAS, NRAS, TERT promoter, CTNNB1, PTEN, and RET were detected. CONCLUSIONS: We report our case as a novel disease entity called non-hyalinizing trabecular thyroid adenoma, which has the diagnostic pitfalls of hyalinizing trabecular tumor and medullary thyroid carcinoma.