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  • Author: Eijun Nishihara x
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Hirotoshi Nakamura Kuma Hospital, Kobe, Japan

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Akane Ide Kuma Hospital, Kobe, Japan

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Takumi Kudo Kuma Hospital, Kobe, Japan

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Eijun Nishihara Kuma Hospital, Kobe, Japan

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Mitsuru Ito Kuma Hospital, Kobe, Japan

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Akira Miyauchi Kuma Hospital, Kobe, Japan

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Objective: Finding agranulocytosis (AG) at an early stage is important to improve outcome, but periodic granulocyte count monitoring is not generally recommended for patients with Graves' disease, because AG develops suddenly. Method: At the Kuma Hospital, Graves' patients under antithyroid drug (ATD) treatment in an outpatient clinic have a granulocyte count examination during each visit, and if it is <1,000/μl, a warning is immediately sent to the patient's physician. We evaluated the usefulness of this system. Results: We investigated 25 AG and 33 granulocytopenia (GP) cases over a recent 5-year period, excluding patients who developed AG or GP at another hospital and were referred to us for treatment. Among the 25 AG patients, 16 patients (64%; 9 asymptomatic and 7 very mild symptomatic cases) were discovered by the periodic granulocyte count examination at an outpatient clinic. The remaining 9 patients visited the Kuma Hospital or other hospitals because of infection symptoms. Most of the AG patients were given granulocyte colony-stimulating factor injections immediately and were admitted if a prompt increase in granulocytes could not be obtained. The final treatments for Graves' disease were <sup>131</sup>I-radioisotope therapy (19 patients), thyroidectomy (2 patients), inorganic iodine (1 patient), or another ATD (1 patient). Among the 33 GP patients, 31 (94%), including 20 asymptomatic cases, were discovered during periodic granulocyte count monitoring. Most of them stopped ATD, and other treatments for Graves' disease were selected. Conclusion: Periodic monitoring of granulocyte counts is useful for identifying AG and GP patients with no or minimum infection symptoms.

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Eijun Nishihara Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Nobuyuki Amino Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Takumi Kudo Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Kazuyoshi Kohsaka Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Mitsuru Ito Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Shuji Fukata Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Mitsushige Nishikawa Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Hirotoshi Nakamura Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Akira Miyauchi Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Background: Subacute thyroiditis is generally believed to be induced by viral infection, and little attention has been paid to anti-thyroid antibodies. Objectives: Our study aimed to assess the prevalence of anti-thyroid antibodies in patients with subacute thyroiditis. Methods: Anti-thyroglobulin (TgAb) and anti-thyroid peroxidase antibodies (TPOAb) were measured with 4 different immunoassay kits currently used in 40 patients in the early phase of subacute thyroiditis. Results: The proportion of samples positive for TgAb was 52.5 ± 13.7% (mean of 4 kits), which was significantly (p < 0.05) higher than that positive for TPOAb (15.6 ± 6.5%). The prevalence of positive TgAb alone (negative TPOAb) was also significantly higher than that of TPOAb alone (negative TgAb). TgAb titers decreased or disappeared within 4 months to 6 years in 6 patients. Conclusions: Patient samples were moderately positive for TgAb initially, but the titer decreased or disappeared afterwards in subacute thyroiditis.

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Hirosuke Danno Division of Internal Medicine, Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan

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Eijun Nishihara Division of Internal Medicine, Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan

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Kazuyoshi Kousaka Division of Internal Medicine, Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan

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Tomohiko Nakamura Division of Internal Medicine, Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan

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Toshihiko Kasahara Division of Internal Medicine, Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan

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Takumi Kudo Division of Internal Medicine, Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan

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Mitsuru Ito Division of Internal Medicine, Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan

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Shuji Fukata Division of Internal Medicine, Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan

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Mitsushige Nishikawa Division of Internal Medicine, Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan

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Akira Miyauchi Division of Surgery and Director, Center for Excellence in Thyroid Care, Kuma Hospital, Kobe, Japan

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Introduction: Marine-Lenhart syndrome (MLS) is now understood to be a combination of Graves’ disease and autonomously functioning thyroid nodule(s) (AFTNs). The prevalence of the syndrome and suitable treatments for those living in iodine-sufficient areas are uncertain. Objectives: We aimed to investigate the prevalence, treatment, and prognosis of MLS in Japan, an iodine-sufficient area. Methods: This study involved patients who visited our hospital between February 2005 and August 2019. Among patients with both thyrotoxicosis and thyroid nodule(s) larger than 10 mm, MLS and isolated AFTNs were diagnosed based on serum thyroid-stimulating hormone receptor antibody levels and scintigraphy using radioiodine or technetium-99m and thyroid uptake. Results: Twenty-two patients were found to have MLS, compared to 372 with isolated AFTNs and 8,343 with Graves’ disease, during the period. Therefore, the rate of MLS cases was 0.26% among all patients with Graves’ disease (22/8,343). Treatments and outcomes were assessed for cases of MLS (n = 18) and isolated AFTNs (n = 269). Antithyroid drugs (ATDs) were withdrawn in 27.8% of cases in the MLS group and 10.3% in the isolated AFTN group. There was no significant difference in the clinical outcome after ATD withdrawal between the 2 groups. However, the rate of hypothyroidism after radioactive iodine (RAI) administration was significantly higher in the MLS group than in the isolated AFTN group (42.9 vs. 9.0%, p = 0.005) despite similar doses of RAI. Conclusions: The prevalence of MLS among patients with Graves’ disease was 0.26% in Japan. RAI therapy induces hypothyroidism more frequently than in those with AFTNs probably because RAI is taken up in the surrounding Graves’ tissues.

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Eijun Nishihara Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Yoshitaka Hobo ASKA Pharmamedical Co., Ltd. Fujisawa, Japan

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Akira Miyauchi Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Yasuhiro Ito Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Miyoko Higuchi Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Mitsuyoshi Hirokawa Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Mitsuru Ito Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Shuji Fukata Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Mitsushige Nishikawa Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Takashi Akamizu Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

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Objective

This study aimed to elucidate disproportionately low serum thyroglobulin (Tg) values in Tg antibody (TgAb)-positive patients with structural recurrence of papillary thyroid carcinoma (PTC) using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Design

A retrospective study was performed on 176 patients in whom Tg and TgAb levels were measured between 2016 and 2021. Several comprehensive analyses of Tg-LC-MS/MS with an electrochemiluminescence immunoassay for Tg (Tg-ECLIA) were conducted using serum samples.

Methods

TgAb-positive patients who underwent total thyroidectomy with multiple lung metastases due to PTC were evaluated using Tg-LC-MS/MS and Tg-ECLIA. Tg expression in lymph node metastases and metastatic lesions was evaluated by immunohistochemistry and Tg levels of aspiration washouts were also evaluated. Two in vitro assays were performed to elucidate TgAb interference.

Results

Tg concentrations of negative TgAb in both assays were similar (R2= 0.99; n  = 52). Patients with structural recurrence showed higher Tg values with Tg-LC-MS/MS than with Tg-ECLIA. The undetectable proportion was significantly lower with Tg-LC-MS/MS (31.6%, 6/19) than with Tg-ECLIA (68.4%, 13/19; P  = 0.023). The spike-recovery rate and Tg concentrations determined by the serum mixture text (n  = 29) were significantly reduced to 75.0% (118.3–88.7%) and 81.3% (107.0–87.0%), respectively, with TgAb using Tg-ECLIA (both P  < 0.001) confirming assay interference but not using Tg-LC-MS/MS (91.8–92.3%, P  = 0.77 and 98.4–100.8%, P  = 0.18, respectively).

Conclusions

TgAb had no effect on the Tg-LC-MS/MS assay but yielded 19–25% lower values in Tg-ECLIA. Tg-LC-MS/MS is preferable for monitoring serum Tg levels in TgAb-positive patients, although those with structural recurrence often had disproportionally low Tg values.

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Naohiro Araki Diagnostic Division, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan

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Mitsuru Iida Diagnostic Division, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan

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Nobuyuki Amino Department of Internal Medicine, Kuma Hospital, Kobe, Japan

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Shinji Morita Department of Internal Medicine, Kuma Hospital, Kobe, Japan

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Akane Ide Department of Internal Medicine, Kuma Hospital, Kobe, Japan

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Eijun Nishihara Department of Internal Medicine, Kuma Hospital, Kobe, Japan

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Mitsuru Ito Department of Internal Medicine, Kuma Hospital, Kobe, Japan

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Jun Saito Department of Medicine, Yokohama Rosai Hospital, Yokohama, Japan

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Tetsuo Nishikawa Department of Medicine, Yokohama Rosai Hospital, Yokohama, Japan

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Kiyonori Katsuragi Diagnostic Division, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan

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Akira Miyauchi Department of Internal Medicine, Kuma Hospital, Kobe, Japan

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Background: Thyroid-stimulating antibodies (TSAb) are known to be responsible for hyperthyroidism in Graves' disease (GD). The conventional methods to measure TSAb depend on cell-based assays that require cumbersome procedures and a sterilized tissue culture technique. The aim of the present study was to develop a ready-to-use cell-based assay for measuring TSAb activity without requiring sterilized conditions. Methods: We developed a new assay kit using a frozen Chinese hamster ovary cell line expressing the thyroid-stimulating hormone receptor, cyclic adenosine monophosphate (cAMP)-gated calcium channel and aequorin, tentatively named the aequorin TSAb assay. Activated stimulatory G-protein-coupled adenylate cyclase increases intracellular cAMP, which then binds to the cyclic nucleotide-gated calcium channel. Activation of this channel allows Ca<sup>2+</sup> to enter the cell, and the influx of Ca<sup>2+</sup> can be measured with aequorin, which is quantified by a luminometer. Results can be obtained in only 4 h without sterilized conditions. TSAb activities were expressed by international units using the NIBSC 08/204 standard. Results: Positive results of aequorin TSAb were obtained in 197 of 199 (98.9%) of untreated patients with GD. Only 1 of 42 (2.3%) patients with painless thyroiditis had a weakly positive aequorin TSAb. All 45 patients with subacute thyroiditis and 185 normal subjects showed negative aequorin TSAb. As for chronic thyroiditis, all 52 euthyroid patients showed negative aequorin TSAb, but 8 of 50 (16.0%) hypothyroid patients had a positive reaction. However, these positive reactions were not induced by serum thyroid-stimulating hormone (TSH) and were thought to be induced by the stimulating activity of anti-TSH receptor immunoglobulins. Conventional porcine TSAb and Elecsys thyroid-stimulating hormone receptor antibodies were positive in 69.3 and 95.5% of GD, respectively. Conclusion: The aequorin TSAb assay was positive in 98.9% of GD and was more sensitive than the conventional assay. This assay can be conducted in only 4 h without sterilized conditions and is practically useful in general clinical laboratories.

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