Analysis of 754 Cases of Antithyroid Drug-Induced Agranulocytosis Over 30 Years in Japan

Nakamura, Hirotoshi; Miyauchi, Akira; Miyawaki, Natsuko; Imagawa, Jun-ichi

doi:10.1210/jc.2013-2569

Cited by 129 publications

(153 citation statements)

References 15 publications

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“…No study gives exact information on the frequency of side effects when low-dose antithyroid drugs are used to treat subclinical hyperthyroidism. In large studies, the risk of agranulocytosis from methimazole use (all doses) was approximately 0.1-0.3% (120,121,122) and liver failure was less common (122). Such side effects mostly develop during the initial months of the therapy (120,121,122).…”

Section: Side Effects Of Subclinical Hyperthyroidism Therapymentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Subclinical thyrotoxicosis: prevalence, causes and choice of therapy

Carlé¹,

Andersen

Boelaert

et al. 2017

European Journal of Endocrinology

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Subclinical thyrotoxicosis is a condition affecting up to 10% of the population in some studies. We have reviewed literature and identified studies describing prevalences, causes and outcomes of this condition. Treatment should be considered in all subjects if this biochemical abnormality is persistent, especially in case of symptoms of thyrotoxicosis or in the presence of any complication. In particular, treatment should be offered in those subclinically thyrotoxic patients with a sustained serum TSH below 0.1 U/L. However it is important to recognise that there are no large controlled intervention studies in the field and thus there is no high quality evidence to guide treatment recommendations. In particular, there is no evidence for therapy and there is weak evidence of harm from thyrotoxicosis if serum TSH is in the 0.1-0.4 IU/L range. In this review, we describe the different causes of subclinical thyrotoxicosis, and how treatment should be tailored to the specific cause. We advocate radioactive iodine treatment to be the first-line treatment in majority of patients suffering from subclinical thyrotoxicosis due to multinodular toxic goitre and solitary toxic adenoma, but we do generally not recommend it as the first-line treatment in patients suffering from subclinical Graves' hyperthyroidism. Such patients may benefit mostly from antithyroid drug therapy. Subclinical thyrotoxicosis in early pregnancy should in general be observed, not treated. Moreover, we advocate a general restriction of therapy in cases where no specific cause for the presumed thyroid hyperactivity has been proven. Allan Carlé, MD, PhD, is a senior researcher, Aalborg University Hospital, Aalborg, Denmark. His research has focused on nosological classification of various subtypes of hypothyroidism. He has explored the field of hypoand hyper-thyroidism with special focus on the occurrence in the population, biochemical findings at diagnosis, the symptom presentation across gender and age, the magnitude of avoiding referral bias in population-based studies, and he has studied several risk factors for both hyper-and hypo-thyroidism. The research frame has been DanThyr (The Danish Investigation on Iodine Intake and Thyroid Diseases).

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Section: Side Effects Of Subclinical Hyperthyroidism Therapymentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Subclinical thyrotoxicosis: prevalence, causes and choice of therapy

Carlé¹,

Andersen

Boelaert

et al. 2017

European Journal of Endocrinology

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“…In particular treatment of GD is not satisfactory, anti-thyroid medications such as Methimazole are associated with serious side effects including liver dysfunction and agranulocytosis (32,33); thyroidectomy is associated with potential surgical risks; and radioactive iodine was shown to worsen or trigger de novo Graves ophthalmopathy (34). Treatment of HT is relatively straightforward, but up to 15% of HT patients remain symptomatic even after thyroid functions are normalized (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis

Menconi

Osman

et al. 2016

Journal of Biological Chemistry

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We previously showed that an HLA-DR variant containing arginine at position 74 of the DR␤1 chain (DR␤1-Arg74) is the specific HLA class II variant conferring risk for autoimmune thyroid diseases (AITD). We also identified 5 thyroglobulin (Tg) peptides that bound to DR␤1-Arg74. We hypothesized that blocking the binding of these peptides to DR␤1-Arg74 could block the continuous T-cell activation in thyroiditis needed to maintain the autoimmune response to the thyroid. The aim of the current study was to identify small molecules that can block T-cell activation by Tg peptides presented within DR␤1-Arg74 pockets. We screened a large and diverse library of compounds and identified one compound, cepharanthine that was able to block peptide binding to DR␤1-Arg74. We then showed that Tg.2098 is the dominant peptide when inducing experimental autoimmune thyroiditis (EAT) in NOD mice expressing human DR␤1-Arg74. Furthermore, cepharanthine blocked T-cell activation by thyroglobulin peptides, in particular Tg.2098 in mice that were induced with EAT. For the first time we identified a small molecule that can block Tg peptide binding and presentation to T-cells in autoimmune thyroiditis. If confirmed cepharanthine could potentially have a role in treating human AITD. Autoimmune thyroid diseases (AITD),2 Graves disease (GD), and Hashimoto thyroiditis (HT), are among the most common autoimmune disorders, afflicting up to 5% of the United States population (1). They are characterized by infiltration of the thyroid by lymphocytes reactive to thyroid antigens and production of thyroid-specific antibodies (2). Complex interaction of genetic susceptibility factors, environmental triggers, and epigenetic alterations leads to the breakdown of tolerance, resulting in AITD (3-5). Currently, there is no satisfactory therapy except for hormone replacement therapy in HT or thyroid suppression or ablation in GD (6 -10). To develop new therapies for AITD a better understanding of their etiology is needed. We have been studying the etiology of AITD using a reverse-genetics approach, i.e. dissecting the mechanisms causing disease through unbiased genetic screening studies. These studies led to the identification of a specific HLA-DR pocket sequence that is strongly associated with AITD (11). The presence of arginine at position 74 of the DR␤ chain renders the individual highly susceptible to AITD, whereas glutamine at position 74 is protective (12). These data were confirmed by other groups (13). The presence of DR␤1-Arg74 (from here on we refer to the HLA-DR3 containing arginine at position 74 as HLA-DR␤1-Arg74) results in a more positively charged P4 pocket. With this structural change in the pocket, the selectivity and binding of pathogenic peptides is affected, conferring higher risk for disease (12).Besides the HLA genes, two thyroid-specific genes, the thyroglobulin (Tg) and thyrotropin receptor (TSHR) genes also contribute to the etiology of AITD (2). Thyroglobulin is the most abundant thyroidal protein (14), and it is the precursor to ...

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“…30,31 Antithyroid drugs are not effective in reducing thyroid hormone levels in exogenous thyroid hormone ingestion because endogenous thyroid hormone production is already suppressed. While propylthiouracil also reduces peripheral conversion of free thyroxine (T 4 ) to free triiodothyronine (T 3 ), there are other therapeutic alternatives for this, as described previously.…”

Section: Differences In Management From Endogenous Thyrotoxicosismentioning

confidence: 99%

Case report: clues to the diagnosis of an unsuspected massive levothyroxine overdose

Allen

Crawford

Conaglen

et al. 2015

CJEM

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There is currently little literature pertaining to levothyroxine overdose apart from minor or accidental overdoses in the pediatric population. In particular, there is little information available on how to confidently differentiate levothyroxine overdose from endogenous causes of thyrotoxicosis when there is no history available at the time of assessment.We report a levothyroxine (15,800 mcg) and citalopram (2,460 mg) overdose in a 55-year-old woman presenting with seizure and tachycardia in which the diagnosis was not initially suspected. Clinical data, including a long history of treated hypothyroidism and lack of a goiter; and biochemical findings, such as an incompletely suppressed thyroid-stimulating hormone (TSH) level, despite a markedly elevated free thyroxine level (FT 4 ), a normal sex hormone-binding globulin level at baseline, and an undetectable thyroglobulin, supported the diagnosis of thyrotoxicosis due to a massive exogenous thyroid hormone overdose. Treatment was given to decrease free triiodothyronine (FT 3 ) conversion and increase thyroid hormone clearance with dexamethasone and cholestyramine. The patient made a full recovery.Levothyroxine overdose can result in subtle symptoms and signs clinically, even when in massive quantities. This can make diagnosis challenging. Biochemical features, such as the pattern of thyroid hormone elevation and thyroglobulin levels, help differentiate exogenous thyroid hormone overdose from endogenous causes of thyrotoxicosis. RÉSUMÉLa documentation sur le surdosage de lévothyroxine est peu abondante, exception faite des surdosages mineurs ou accidentels chez les enfants; plus particulièrement, il manque d'information sur la manière de faire la distinction, en toute confiance, entre le surdosage de lévothyroxine et la thyrotoxicose d'origine endogène, dans les cas d'absence d'antécédents évocateurs au moment de l'évaluation.Sera exposé ici un cas de surdosage de lévothyroxine (15 800 μg) et de citalopram (2460 mg) chez une femme de 55 ans, prise de convulsions et de tachycardie, chez qui rien, au point de départ, ne laissait soupçonner le diagnostic. Toutefois, des données d'ordre clinique, notamment des antécédents d'hypothyroïdie traitée de longue date et l'absence de goitre; des résultats d'analyses biochimiques, par exemple la présence de thyréostimuline (TSH) partiellement supprimée malgré un taux nettement élevé de thyroxine libre (T 4 libre); un taux normal, au départ, de globuline de liaison aux hormones sexuelles et un taux indétectable de thyroglobuline, ont étayé le diagnostic de thyrotoxicose attribuable à un surdosage massif d'hormone thyroïdienne d'origine exogène. Le traitement, par la dexaméthasone et la cholestyramine, visait à abaisser la conversion de la triiodothyronine libre (T 3 libre) et à accroître la clairance de l'hormone thyroïdienne. La patiente s'est complètement rétablie.Le surdosage de lévothyroxine, même massif, peut se manifester par des signes et des symptômes cliniques peu prononcés, d'où la difficulté de poser le dia...

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Analysis of 754 Cases of Antithyroid Drug-Induced Agranulocytosis Over 30 Years in Japan

Abstract: This is the largest study of agranulocytosis. Agranulocytosis tends to occur abruptly within 3 months after initiation of ATD therapy, although it develops gradually in some patients. Providing every patient with sufficient information on agranulocytosis is critical.

Cited by 129 publications

References 15 publications

MANAGEMENT OF ENDOCRINE DISEASE: Subclinical thyrotoxicosis: prevalence, causes and choice of therapy

MANAGEMENT OF ENDOCRINE DISEASE: Subclinical thyrotoxicosis: prevalence, causes and choice of therapy

Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis

Case report: clues to the diagnosis of an unsuspected massive levothyroxine overdose

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