日本甲状腺学会、日本内分泌学会:甲状腺眼症診療の手引き 2020年度版、メディカルレビュー社、2020.
Kashiwai T, Hidaka Y, Takano T, Tatsumi KI, Izumi Y, Shimaoka Y, Tada H, Takeoka K, Amino N.
Practical treatment with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves' disease.
Endocr J. 2003 Feb;50(1):45-9. doi: 10.1507/endocrj.50.45.
Abstract/Text
Although many researchers have reported clinical and laboratory parameters for prediction of remission in Graves' disease during or after anti-thyroid drug therapy, there is no reliable one to assure the complete remission. We prospectively examined a practical therapy with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves' disease. Fifty-seven patients with Graves' disease were treated with anti-thyroid drugs at the initial dose of 30 mg/day of methimazole (MMI) or 300 mg/day of propylthiouracil (PTU). Then, doses were gradually decreased, and finally discontinued when the patients were able to maintain euthyroid (normal FT4 and TSH) for at least 6 months with the minimum maintenance dose (MMI 5 mg every other day or PTU 50 mg every other day). After discontinuation of drugs, FT4, FT3, TSH and TSH-binding inhibitory immunoglobulin (TBII) were measured every one to two months for the first 6 months and every 3-4 months for the next 18 months to confirm continuous remission. After 2 years of drug cessation, 46 (81%) of 57 patients were in remission and the other 11 patients had relapsed into thyrotoxicosis. At the time of drug discontinuation, the serum concentration of FT4, FT3 and TSH, titers of anti-thyroglobulin antibodies and anti-thyroid microsomal antibodies, goiter size were not different between the remission and relapse groups. At the time of drug cessation, the activities of TBII and thyroid-stimulating antibodies (TSAb) overlapped between the two groups, although they were significantly lower in the remission group than in the relapse group (p<0.01). Forty percent (4/10) of TBII positive patients and 71% (23/32) of TSAb positive patients continued to be in remission. On the other hand, thyrotoxicosis relapsed in 5 (11%) of 47 TBII negative and 2 (8%) of 25 TSAb negative patients. These data indicate that minimum maintenance therapy to keep euthyroid (normal FT4 and TSH) for 6 months is a practical measure for 81% prediction of remission in Graves' disease. The measurement of TBII or TSAb gave little additional information for predicting remission.
Yoshimura Noh J, Miyazaki N, Ito K, Takeda K, Hiramatsu S, Morita S, Miyauchi A, Murakami T, Inomata K, Noguchi S, Satoh T, Amino N.
Evaluation of a new rapid and fully automated electrochemiluminescence immunoassay for thyrotropin receptor autoantibodies.
Thyroid. 2008 Nov;18(11):1157-64. doi: 10.1089/thy.2008.0119.
Abstract/Text
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.
Suzuki N, Noh JY, Hiruma M, Kawaguchi A, Morisaki M, Ohye H, Suzuki M, Matsumoto M, Kunii Y, Iwaku K, Yoshihara A, Watanabe N, Sugino K, Ito K.
Analysis of Antithyroid Drug-Induced Severe Liver Injury in 18,558 Newly Diagnosed Patients with Graves' Disease in Japan.
Thyroid. 2019 Oct;29(10):1390-1398. doi: 10.1089/thy.2019.0045. Epub 2019 Oct 1.
Abstract/Text
Background: The prevalence of antithyroid drug (ATD)-related drug-induced liver injury (DILI) has been reported to vary among patients in several countries. The purpose of this study was to summarize the prevalence of liver injury induced by ATD and to determine the actual prevalence of severe liver injury. Methods: The medical records of 18,558 patients who were newly diagnosed with Graves' disease between January 2005 and December 2016 were retrospectively reviewed. Severe DILI was defined as alanine aminotransferase (ALT) 8 times higher than the upper limit of normal (ULN) or total bilirubin (T-bil) 3 times higher than the ULN. The most severe DILI was defined as ALT higher than 20 times the ULN or T-bil higher than 10 times the ULN. Results: A total of 461 subjects (470 cases) were analyzed, and they consisted of 10 males and 451 females, with a median age of 37 years (range 10-82 years). Nine of 461 patients had severe DILI with both drugs. The total prevalence of severe DILI in this study was 2.5%, and the prevalence of DILI by drug was 1.4% with metimazole (MMI) (n = 198) and 6.3% with propylthiouracil (PTU) (n = 272) (p < 0.001). The prevalence of the most severe ATD-related DILI was 0.22% (n = 40), and the prevalence for each drug was 0.08% with MMI (n = 11) and 0.68% with PTU (n = 29). The median time to DILI development was 30 days (range 7-314 days), and all patients recovered from DILI, with no fatalities. The prevalence of MMI-related DILI was significantly age dependent (p < 0.001). Conclusions: Though there were no fatalities in this study, the prevalence of PTU-related severe DILI was significantly higher than that of MMI-related severe DILI.
Yoshiuchi K, Kumano H, Nomura S, Yoshimura H, Ito K, Kanaji Y, Kuboki T, Suematsu H.
Psychosocial factors influencing the short-term outcome of antithyroid drug therapy in Graves' disease.
Psychosom Med. 1998 Sep-Oct;60(5):592-6. doi: 10.1097/00006842-199809000-00014.
Abstract/Text
OBJECTIVE: Although psychological stress and smoking have been proposed as factors contributing to Graves' disease, their independent roles in the course of this disease have not been determined. We assessed the association between the course of Graves' disease and psychosocial factors by using multivariate analysis.
METHODS: We investigated the association between the short-term outcome of Graves' disease (assessed 12 months after the beginning of antithyroid drug therapy) and stressful life events, daily hassles, smoking, drinking habits, coping skills, and social support (before and 6 months after beginning therapy) in 230 patients (182 women and 48 men) with newly diagnosed Graves' disease, using a logistic regression model.
RESULTS: After adjustment for smoking, coping skills, and thyroid function, daily hassles scores in women at 6 months after beginning therapy were significantly associated with a hyperthyroid state 12 months after beginning therapy. The relative risk was 3.9 for women with higher daily hassles scores compared with women with lower daily hassles scores (95% confidence interval, 1.1 to 13.2; p < .05). Smoking was not significantly associated with a hyperthyroid state 12 months after beginning therapy in either women or men.
CONCLUSIONS: Chronic psychological stress is associated with the course of Graves' disease in women.
Vestergaard P.
Smoking and thyroid disorders--a meta-analysis.
Eur J Endocrinol. 2002 Feb;146(2):153-61. doi: 10.1530/eje.0.1460153.
Abstract/Text
BACKGROUND: Smoking has been associated with Graves' disease, but it remains unclear if the association is present in other thyroid disorders.
OUTCOME VARIABLES: Graves' disease, Graves' ophthalmopathy, toxic nodular goitre, non-toxic goitre, post-partum thyroid disease, Hashimoto's thyroiditis, or hypothyroidism.
MATERIAL AND METHODS: A search of MEDLINE identified 25 studies on the association between smoking and thyroid diseases.
RESULTS: In Graves' disease eight studies were available showing an odds ratio (OR) of 3.30 (95% confidence interval (CI): 2.09-5.22) in current smokers compared with never smokers. In ex-smokers there was no significant excess risk of Graves' disease (OR=1.41, 95% CI: 0.77-2.58). The OR associated with ever smoking in Graves' ophthalmopathy (4.40, 95% CI: 2.88-6.73, six studies) was significantly higher than in Graves' disease (1.90, 95% CI: 1.42-2.55, two-sided P-value <0.01). Ever smoking was not associated with toxic nodular goitre (OR=1.27, 95% CI: 0.69-2.33, three studies), while there was an increased risk of non-toxic goitre in smokers if men were excluded (OR=1.29, 95% CI: 1.01-1.65, eight studies). The risk associated with smoking was significantly lower in men than in women for both Graves' disease and non-toxic goitre. Hashimoto's thyroiditis and post-partum thyroid dysfunction were also associated with smoking while the association with hypothyroidism did not reach statistical significance.
CONCLUSIONS: Cessation of smoking seems associated with a lower risk of Graves' disease than current smoking. Smoking increases the risk of Graves' ophthalmopathy beyond the risk associated with Graves' disease alone. Smoking cessation may lead to a decrease in morbidity from Graves' disease, especially in women.
Sato S, Noh JY, Sato S, Suzuki M, Yasuda S, Matsumoto M, Kunii Y, Mukasa K, Sugino K, Ito K, Nagataki S, Taniyama M.
Comparison of efficacy and adverse effects between methimazole 15 mg+inorganic iodine 38 mg/day and methimazole 30 mg/day as initial therapy for Graves' disease patients with moderate to severe hyperthyroidism.
Thyroid. 2015 Jan;25(1):43-50. doi: 10.1089/thy.2014.0084.
Abstract/Text
BACKGROUND: Methimazole (MMI) is usually used at an initial dose of 30 mg/day for severe Graves' disease (GD) hyperthyroidism, but adverse effects are more frequent at this dose than at MMI 15 mg/day.
OBJECTIVES: We designed a regimen to address the lack of a primary therapeutic effect of the MMI 15 mg/day by combining it with inorganic iodine at 38.2 mg/day. Our aim was to compare the two regimens (MMI 15 mg+inorganic iodine at 38.2 mg/day (M15+I) vs. MMI 30 mg/day (M30)) in terms of therapeutic effect, adverse effects, and remission rate.
DESIGN AND PATIENTS: In a prospective study, 310 patients with untreated GD (serum free thyroxine (fT4) ≥5 ng/dL) were assigned to one of the two regimens. Potassium iodide was discontinued in the M15+I group as soon as the serum fT4 level was within the reference range (0.8-1.6 ng/dL).
RESULTS: Percentages of patients achieving an fT4 level within reference range in ≤30, ≤60, or 90 days on the study treatment regimens were 45.3%, 73.9%, and 82.0% respectively for the M15+I group, and 24.8%, 63.1%, and 75.2% respectively for the M30 group. Hence, the proportions of patients achieving this goal in ≤30 or ≤60 days were significantly larger in the M15+I group. Adverse effects that required discontinuation of MMI were more frequent in the M30-treated than in the M15+I-treated group (14.8% vs. 7.5%; p=0.0387). The remission rates in the M15+I and M30 groups were 19.9% and 14.8%-higher in the former, but the difference did not reach statistical significance.
CONCLUSION: The results of this study raise the possibility that M15+I is superior to M30 as a primary treatment for moderate to severe hyperthyroidism caused by GD.
Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K, Kosuga Y, Suzuki M, Matsumoto M, Kunii Y, Watanabe N, Mukasa K, Ito K, Ito K.
Treatment of graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation.
J Clin Endocrinol Metab. 2012 Jul;97(7):2396-403. doi: 10.1210/jc.2011-2860. Epub 2012 Apr 30.
Abstract/Text
BACKGROUND: Several reports have suggested that propylthiouracil (PTU) may be safer than methimazole (MMI) for treating thyrotoxicosis during pregnancy because congenital malformations have been associated with the use of MMI during pregnancy.
OBJECTIVES: We investigated whether in utero exposure to antithyroid drugs resulted in a higher rate of major malformations than among the infants born to a control group of pregnant women.
METHODS: We reviewed the cases of women with Graves' disease who became pregnant. The pregnancy outcomes of 6744 women were known, and there were 5967 live births. MMI alone had been used to treat 1426 of the women, and 1578 women had been treated with PTU alone. The 2065 women who had received no medication for the treatment of Graves' disease during the first trimester served as the control group. The remaining women had been treated with potassium iodide, levothyroxine, or more than one drug during the first trimester. The antithyroid drugs were evaluated for associations with congenital malformations.
RESULTS: The overall rate of major anomalies in the MMI group was 4.1% (50 of 1231), and it was significantly higher than the 2.1% (40 of 1906) in the control group (P = 0.002), but there was no increase in the overall rate of major anomalies in the PTU group in comparison with the control group (1.9%; 21 of 1399; P = 0.709). Seven of the 1231 newborns in the MMI group had aplasia cutis congenita, six had an omphalocele, seven had a symptomatic omphalomesenteric duct anomaly, and one had esophageal atresia. Hyperthyroidism in the first trimester of pregnancy did not increase the rate of congenital malformation.
CONCLUSIONS: In utero exposure to MMI during the first trimester of pregnancy increased the rate of congenital malformations, and it significantly increased the rate of aplasia cutis congenita, omphalocele, and a symptomatic omphalomesenteric duct anomaly.
Hiraiwa T, Ito M, Imagawa A, Takamatsu J, Kuma K, Miyauchi A, Hanafusa T.
Restriction of dietary Iodine does not ameliorate the early effect of anti-thyroid drug therapy for Graves' disease in an area of excessive iodine intake.
J Endocrinol Invest. 2006 Apr;29(4):380-4. doi: 10.1007/BF03344113.
Abstract/Text
The close relationship between iodine intake and the effects of anti-thyroid drugs (ATD) for Graves' disease (GD) has been well established. However, it remains unknown whether restriction of dietary iodine improves the effect of ATD. This study aimed to clarify this issue in Japanese patients with GD who routinely ingest large amounts of dietary iodine. We performed a prospective clinical study in 81 patients with newly diagnosed GD who were divided into an iodine restricted group and a control group. Urinary iodine, thyroid hormones and TSH receptor antibody were measured during the first 8 weeks of ATD therapy. Urinary iodine concentrations in the iodine restricted group were significantly lower than in the control group (p=0.043). However, there were no significant differences in the decrease of thyroid hormones and TSH receptor antibody between the two groups. Restriction of dietary iodine does not ameliorate the effect of ATD therapy for GD in an area of excessive iodine intake.
Yoshimura Noh J, Inoue K, Suzuki N, Yoshihara A, Fukushita M, Matsumoto M, Imai H, Hiruma S, Ichikawa M, Koshibu M, Sankoda A, Hirose R, Watanabe N, Sugino K, Ito K.
Dose-dependent incidence of agranulocytosis in patients treated with methimazole and propylthiouracil.
Endocr J. 2024 Jul 12;71(7):695-703. doi: 10.1507/endocrj.EJ24-0135. Epub 2024 May 3.
Abstract/Text
Agranulocytosis is a serious adverse effect of methimazole (MMI) and propylthiouracil (PTU), and although there have been reports suggesting a dose-dependent incidence in relation to both drugs, the evidence has not been conclusive. The objective of our study was to determine whether the incidences of agranulocytosis induced by MMI and PTU exhibit dose-dependency. The subjects were 27,784 patients with untreated Graves' disease, 22,993 of whom were on an antithyroid drug treatment regimen for more than 90 days. Within this subset, 18,259 patients had been treated with MMI, and 4,734 had been treated with PTU. The incidence of agranulocytosis according to dose in the MMI group was 0.13% at 10 mg/day, 0.20% at 15 mg/day, 0.32% at 20 mg/day, and 0.47% at 30 mg/day, revealing a significant dose-dependent increase. In the PTU group, there were 0 cases of agranulocytosis at doses of 125 mg/day and below, 0.33% at 150 mg/day, 0.31% at 200 mg/day, and 0.81% at 300 mg/day, also revealing a significant dose-dependent increase. The incidence of agranulocytosis at MMI 15 mg and PTU 300 mg, i.e., at the same potency in terms of hormone synthesis inhibition, was 0.20% and 0.81%, respectively, and significantly higher in the PTU group. Our findings confirm a dose-dependent increase in the incidence of agranulocytosis with both drugs, but that at comparable thyroid hormone synthesis inhibitory doses PTU has a considerably higher propensity to induce agranulocytosis than MMI does.
Tajiri J, Noguchi S, Murakami T, Murakami N.
Antithyroid drug-induced agranulocytosis. The usefulness of routine white blood cell count monitoring.
Arch Intern Med. 1990 Mar;150(3):621-4. doi: 10.1001/archinte.150.3.621.
Abstract/Text
This study was aimed at establishing the importance of routine monitoring of white blood cell counts in patients with Graves' disease receiving antithyroid drug treatment. In the 12-year period from 1975 to 1987, 15,398 patients with Graves' disease receiving treatment with antithyroid drugs were seen at our clinic. Of these, 55 (0.4%) were found to have agranulocytosis. Agranulocytosis was defined as a granulocyte count of 0.5 x 10(9)/L or less. In only 12 of the 55 patients was agranulocytosis detected after the occurrence of infection (symptomatic; classic agranulocytosis). The remaining 43 patients were asymptomatic when agranulocytosis was detected during routine white blood cell count monitoring. However, 14 of these 43 patients became symptomatic several days after withdrawal of antithyroid drug treatment despite antimicrobial treatment (asymptomatic to symptomatic). Twenty-nine patients who were treated appropriately had no symptom of infection throughout the course of the disease, despite the absence of or an extremely small number of granulocytes in circulation (asymptomatic). These results suggest that a "routine monitoring" of the white blood cell count could be the most effective way of predicting and detecting agranulocytosis due to antithyroid drug treatment.
Noh JY, Yasuda S, Sato S, Matsumoto M, Kunii Y, Noguchi Y, Mukasa K, Ito K, Ito K, Sugiyama O, Kobayashi H, Nihojima S, Okazaki M, Yokoyama S.
Clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis caused by antithyroid drugs.
J Clin Endocrinol Metab. 2009 Aug;94(8):2806-11. doi: 10.1210/jc.2008-2700. Epub 2009 Jun 2.
Abstract/Text
CONTEXT: The clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis caused by antithyroid drugs are still unclear because most reports describe only a small number of patients.
OBJECTIVE: The objective was to analyze a large number of patients with MPO-ANCA-associated vasculitis to determine the time of onset, the drug and dose taken, the clinical symptoms, the relationship between the clinical symptoms and the MPO-ANCA titer, and the incidence.
DESIGN: We analyzed 92 patients in whom the adverse reaction of MPO-ANCA-associated vasculitis was reported to Chugai Pharmaceutical, a company that markets antithyroid drugs.
RESULTS: Of the 92 patients, 41 (44.6%) had single-organ failure, 32 (34.8%) had two-organ failure, 13 (14.1%), had three-organ failure, and two (2.2%) had four-organ failure. The number of organs involved was unknown in the other four patients (4.3%). The median time of onset was 42 months (range, 1-372 months) after starting drug treatment. The median dose at onset of MPO-ANCA-associated vasculitis was 15 mg/d (range, 2.5-45 mg/d) for methimazole and 200 mg/d (50-450 mg/d) for propylthiouracil. The severity and number of organs involved were not correlated with the MPO-ANCA titer. The incidence was between 0.53 and 0.79 patients per 10,000, and the ratio of the estimated incidences for methimazole and propylthiouracil was 1:39.2.
CONCLUSIONS: The time of onset of MPO-ANCA-associated vasculitis and the dose at onset varied. The severity and number of organs involved were not correlated with the MPO-ANCA titer, indicating a need for vigilance even when the MPO-ANCA titer is only weakly positive.
日本甲状腺学会・日本内分泌学会・厚生労働省「ホルモン受容機構異常に関する調査研究」班、臨床重要課題「バセドウ病悪性眼球突出症の診断基準と治療指針」作成委員会(編):甲状腺眼症診療の手引き メディカルレビュー社、2020.
日本甲状腺学会:甲状腺ホルモン不応症診療の手引き、南江堂、2023.
Nishihara E, Fukata S, Hishinuma A, Amino N, Miyauchi A.
Prevalence of thyrotropin receptor germline mutations and clinical courses in 89 hyperthyroid patients with diffuse goiter and negative anti-thyrotropin receptor antibodies.
Thyroid. 2014 May;24(5):789-95. doi: 10.1089/thy.2013.0431. Epub 2014 Jan 24.
Abstract/Text
BACKGROUND: We studied the frequency of thyrotropin (TSH) receptor mutations in hyperthyroid patients with diffuse goiter and negative TSH receptor antibodies (TRAb), and the clinical pictures of the hyperthyroid patients in the presence and absence of mutations.
PATIENTS AND METHODS: From 2003 through 2012, 89 hyperthyroid patients with diffuse goiter and negative TRAb based on a second- or third-generation assay underwent sequence analysis of the TSH receptor gene from peripheral leukocytes. The outcome of hyperthyroidism in patients with a TSH receptor mutation and their affected family members was compared with that in patients without any mutation after a 1-10-year follow-up.
RESULTS: Germline mutations of the TSH receptor occurred in 4 of the 89 patients (4.5%), including 3 definitive constitutively activating mutations (L512Q, E575K, and D617Y). The main difference in the clinical outcome of hyperthyroidism was that no patients with a TSH receptor mutation achieved euthyroidism throughout the follow-up, while 23.5% of patients without any mutation entered remission. The progression from subclinical to overt hyperthyroidism was not significantly different between patients with or without a mutation. Meanwhile, 10.3% of TRAb-negative patients without any TSH receptor mutation developed TRAb-positive Graves' hyperthyroidism during the follow-up.
CONCLUSIONS: The prevalence of nonautoimmune hyperthyroidism with TSH receptor mutations is lower than that of latent Graves' disease in TRAb-negative patients with hyperthyroidism. However, all affected patients with a TSH receptor mutation showed persistent hyperthyroidism regardless of subclinical or overt hyperthyroidism throughout the follow-up.