Thyroid storm is a rare, life-threatening endocrine emergency that can cause multiorgan dysfunction, although acute liver failure (ALF) remains an uncommon manifestation. A 52-year-old woman with Graves' disease who had discontinued methimazole presented with three days of nausea, vomiting, diarrhea, melena, generalized weakness, and chest pain. She was lethargic and tachycardic, with a diffusely enlarged thyroid gland, warm skin, bilateral hand tremors, and hypoglycemia. Laboratory testing demonstrated severe thyrotoxicosis, marked hepatocellular injury with an aspartate aminotransferase concentration of 1,059 units per liter (U/L) and an alanine aminotransferase concentration of 955 U/L, and an international normalized ratio of 7.8. Echocardiography showed a left ventricular ejection fraction of 25%-30%, while coronary angiography was normal, and evaluation for viral, autoimmune, and structural hepatobiliary disease was unrevealing. Treatment with hydrocortisone, propranolol, and methimazole resulted in clinical improvement and substantial biochemical recovery, with normalization of the hepatic and thyroid biochemical parameters at two-month follow-up. This case emphasizes the importance of considering thyroid storm in patients with ALF and promptly evaluating both thyroid-mediated and hemodynamic contributors to hepatic injury.

Retrospective review of our OB ultrasound database identified 17 fetuses with enlarged thyroid. Fourteen had a maternal risk factor, most commonly current or prior Graves' thyroiditis. In addition to the enlarged thyroid, abnormalities were identified in 6/17 (35.3%) fetuses. Treatment included adjusting the dose of propylthiouracil, methimazole, or levo-thyroxine, intraamniotic thyroxine, or nothing. Follow-up showed stable fetal thyroid size in 9 and decreased size in 5. Imagers should be aware that fetal goiter can result from maternal hyper- or hypothyroidism. Careful assessment and monitoring of mother and fetus are needed to determine the appropriate cause and treatment of fetal goiter.

BACKGROUND Thyrotoxicosis is associated with well-recognized and clinically significant complications, including congestive heart failure and cardiac arrhythmias. The relationship between hyperthyroidism and hepatic dysfunction is complex, with several proposed pathophysiological mechanisms; however, direct cholestatic injury is frequently overlooked. Although mild liver enzyme elevation is common in hyperthyroidism, clinically overt jaundice is rare. Nevertheless, increasing evidence from case reports and case series suggests that thyrotoxicosis, especially Graves disease, can result in cholestatic-pattern jaundice. This temporal association is supported by substantial improvements in jaundice and liver biochemistry after antithyroid therapy. CASE REPORT A 62-year-old woman presented with a 1-month history of right upper quadrant abdominal pain, unintentional weight loss, and jaundice. Laboratory evaluation demonstrated cholestatic-pattern liver injury, and abdominal ultrasound revealed a solitary gallstone without evidence of acute or chronic cholecystitis. Abdominal computed tomography demonstrated right-sided heart failure with pericardial and bilateral pleural effusions and congestive hepatopathy. Endoscopic retrograde cholangiopancreatography showed no filling defects, excluding biliary obstruction. Because the patient had persistent sinus tachycardia, thyroid function tests were performed. The findings were consistent with primary hyperthyroidism and elevated thyroid-stimulating hormone receptor antibodies); thyroid ultrasound and scintigraphy results supported toxic multinodular goiter. Treatment with methimazole led to dramatic improvement of the jaundice. Given the possibility of competing etiologies, thyrotoxicosis was considered the most likely contributing factor to cholestatic jaundice onset. CONCLUSIONS This case highlights the importance of considering hyperthyroidism in the differential diagnosis of jaundice, particularly in diagnostically challenging cases.

Chemicals released into aquatic environments are detected in surface waters globally, and some can disrupt thyroid hormone (TH) signaling in fishes. A key protein in this pathway is thyroperoxidase (TPO), which catalyzes synthesis of THs. Inhibition of TPO is associated with decreased THs, leading to a variety of adverse outcomes. However, there is uncertainty regarding species-specific sensitivities to inhibition of TPO among fishes and whether inhibitors in mammals share that activity in fishes. Therefore, the present study applied the Amplex UltraRed TPO assay to compare in vitro sensitivities across five phylogenetically diverse fishes, namely red drum (Sciaenops ocellatus), sheepshead minnow (Cyprinodon variegatus), American eel (Anguilla rostrata), southern flounder (Paralichthys lethostigma), and spotted gar (Lepisosteus oculatus). The reference inhibitor, methimazole, and five environmentally relevant chemicals were evaluated to represent a range of potencies reported in the ToxCast mammalian-based assays. Methimazole inhibited TPO activity in all five species, with sensitivities within an order of magnitude. All evaluated chemicals, except dichlorvos, inhibited TPO activity, with all five species having similar sensitivities. Potency relative to methimazole varied across the tested chemicals, with the average potency ranking across species being methimazole > bisphenol A > chlorophene > chlorpyrifos > triclocarban > dichlorvos. Chemicals identified as TPO inhibitors in mammalian-based assays shared inhibitory activity across fishes, and relative potencies were conserved between mammals and fishes. This sensitivity was consistent across phylogenetically diverse species and is supported by the high level of conservation of TPO structure and function across vertebrate taxa. Taken together, these findings suggest that toxicity data from model fishes can be extrapolated to native species and mammalian-based ToxCast data can confidently be used as a source for predicting relative potencies of chemicals for inhibiting TPO of fishes in support of more objective ecological risk assessments.

Graves' disease can be managed with antithyroid drugs (ATDs), radioactive iodine (RAI), or surgery. When ATDs are ineffective or poorly tolerated, RAI or surgery may be indicated. Methimazole (MMI) and propylthiouracil (PTU) are commonly used, sometimes with adjunctive agents such as potassium iodide (KI), β-blockers, or corticosteroids. Although ATDs are essential in management, rare but severe allergic reactions may occur, necessitating careful monitoring. We report a case of refractory Graves' disease with a history of ATD-induced hemophagocytic syndrome and multiple drug allergies. A 43-year-old woman was diagnosed with Graves' disease after presenting with thyrotoxicosis and was treated with MMI and KI. Following an increase in the MMI dosage, she developed a rash and was switched to PTU. Although the rash resolved, she developed fever requiring hospitalization. During admission, shock and abnormal vital signs prompted suspicion of PTU-induced hemophagocytic lymphohistiocytosis. Immunosuppressive therapy, plasma exchange, temporary hemodialysis, and corticosteroids led to improvement. She was discharged on corticosteroids, but thyroid function worsened during tapering, making ATDs unsuitable. Sixteen months later, RAI therapy was attempted; thyroid function worsened, and KI was continued. Eighteen months later, she was rehospitalized for fatigue; increasing corticosteroids improved thyroid hormone levels. Due to multiple drug allergies, a drug-induced lymphocyte stimulation test was performed preoperatively and was positive for levothyroxine (LT4), although patch and oral provocation tests were negative, confirming LT4 safety. After stabilization, total thyroidectomy was performed; postoperatively, she received powdered LT4 and calcium supplementation. The course was uneventful, without allergic manifestations, and she was discharged in good condition. This case highlights the risk of severe hematologic complications from PTU and demonstrates that, with careful preoperative evaluation and individualized perioperative management, safe surgical treatment of refractory Graves' disease is possible.

Graves disease is the most common cause of hyperthyroidism in children. Although neutropenia and thrombocytopenia have been reported in adults with untreated Graves disease, these complications are rare in children. Here, we report a pediatric case of Graves disease complicated by agranulocytosis and thrombocytopenia at diagnosis. A 12-year-old girl presented with increased appetite, irritability, fever, and petechiae. Laboratory examination revealed thyrotoxicosis, and this was associated with agranulocytosis and thrombocytopenia. There was no history of antithyroid drug use. The diagnosis of Graves disease was established based on positive thyroid-stimulating hormone receptor antibodies and thyroid scintigraphy findings. After initiation of a β-blocker and potassium iodide, neutrophil and platelet counts gradually improved in association with the resolution of thyrotoxicosis, which allowed the subsequent introduction of methimazole. The β-blocker and potassium iodide were sequentially discontinued. Blood cell counts remained within the normal range thereafter, and thyroid function has remained well controlled with methimazole monotherapy. This case suggests that thyrotoxicosis itself is associated with cytopenia and provides valuable insight for clinicians when selecting a therapeutic strategy for Graves disease complicated by cytopenia.

It is critical to exploit a sensitive, selective, and portable strategy for the credible detection of methimazole (MMI) for human health. Herein, high-entropy Prussian blue analogues (HE-PBAs) nanozyme were successfully fabricated by a facile co-precipitation strategy. The as-synthesized HE-PBAs possess robust peroxidase (POD)-like activity, which can trigger the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to oxidized TMB (oxTMB) with the assistance of H2O2, generating a conspicuous chromogenic transition from colorless to blue. However, MMI can reduce oxTMB and consume the ROS, including •OH and O2[•-], thereby suppressing the intrinsic POD-mimicking catalytic performance of HE-PBAs. Such an inhibitory effect reduces the absorbance of the sensing system and enables the gradual fading of the blue chromogenic signal. Based on this competitive inhibition mechanism, a novel colorimetric sensing platform was constructed for quantitative MMI determination. The developed sensor achieves high sensitivity toward MMI with a detection limit of 0.032 μM. Considering its simple operation and superior sensing performance, a portable and user-friendly sensor was also designed for visual sensing of MMI by combining a common smartphone. Moreover, this colorimetric sensor has been successfully applied for MMI detection in commercial cosmetic samples, demonstrating its potential practicality. This work not only provides a cheap, user-friendly, and portable sensing platform for visual detection of MMI in resource-limited settings, but also offers a rational design strategy for HEzymes.

Thyroid hormone (TH) signaling is critical for normal testis development; however, the molecular mechanisms linking developmental hypothyroidism to adverse testis outcomes remain poorly understood. Improved mechanistic insight is needed to support predictive approaches in chemical risk assessment. Here, we build on previous work to define a molecular signature in testes from hypothyroid rats induced by three thyroperoxidase (TPO)-inhibiting chemicals: the pharmaceuticals propylthiouracil (PTU), and methimazole (MMI), and the pesticide amitrole (AMI). Transcriptomic data for MMI and AMI were obtained from a previously published study. For the PTU study, pregnant Sprague-Dawley rat dams were exposed by oral gavage to PTU (1.25 or 2.5 mg/kg bw/day) from gestational day (GD) 7 to pup day (PD) 28. Reproductive toxicity endpoints were assessed, and testes were collected from offspring on GD21, PD16, and PD78 for bulk RNA barcoding and sequencing (BRBseq). Comparative transcriptomic analysis across PTU, MMI, and AMI revealed substantial transcriptional disruption, with effects that were both age- and chemical-dependent. Notably, at PD16, there was an overlap of 278 differentially expressed genes between the three chemicals, a finding that was preserved when applying a previous bioinformatic pipeline. The shared transcriptional changes were associated with biological processes related to cell cycle regulation, developmental growth, and pathways involved in Sertoli cell proliferation, germ cell development, and testis morphogenesis. Collectively, these findings support the existence of a TH-mediated molecular signature that aligns with the classical morphologic phenotype of hypothyroid testis and underscores its potential value for the development of alternative, mechanism-based test methods for regulatory purposes.

Nose-to-brain infection represents a non-hematogenous route by which pathogens invade the central nervous system via neural pathways. The olfactory and trigeminal systems are implicated in this process, but the molecular mechanisms underlying lethal pathology remain incompletely understood. We hypothesized that trigeminal TRPV1 and downstream STAT3 signaling contribute to disease progression during pneumococcal nose-to-brain infection. A murine intranasal infection model using Streptococcus pneumoniae was established with methimazole-induced olfactory epithelial damage and/or resiniferatoxin-mediated trigeminal TRPV1 ablation. We assessed bacterial burden and survival. Spatial transcriptomic analysis of coronal head sections containing the nasal cavity and olfactory bulb was performed to identify region-specific transcriptional responses. Olfactory epithelial damage significantly increased pneumococcal invasion into the olfactory bulb, but ablation of trigeminal TRPV1 improved survival. Spatial transcriptomic analysis identified a distinct transcriptional cluster enriched in methimazole-treated mice that was localized to the olfactory epithelium and adjacent olfactory bulb. The cluster exhibited a STAT3-centered transcriptional regulatory network and enrichment of inflammatory and tissue remodeling pathways. These features suggest the formation of a localized inflammatory niche associated with olfactory epithelial damage. Olfactory epithelial damage and trigeminal TRPV1 activation were suggested to exacerbate nose-to-brain infection cooperatively through STAT3-mediated inflammatory signaling. This TRPV1-STAT3 axis could be a key mechanism linking sensory neuronal activation to lethal neuroinflammation. Targeting this pathway could provide a novel therapeutic strategy for preventing severe central nervous system complications associated with respiratory infections.IMPORTANCEPneumococcal infection can spread from the nasal cavity to the brain via neural pathways, leading to severe and often fatal disease. However, the mechanisms that drive disease severity have been poorly understood. Using a mouse model, we show that damage to the olfactory epithelium establishes a local inflammatory niche, while activation of the trigeminal nerve amplifies deleterious immune responses. We identify a key signaling pathway that links sensory nerve activation to excessive inflammation in the brain. These findings suggest that targeting host responses, rather than the bacteria alone, may mitigate severe complications of pneumococcal infection. This study provides new insight into the contribution of sensory systems to infection outcomes and highlights potential strategies for therapeutic intervention.

Graves' disease is an autoimmune disorder and represents the most prevalent cause of hyperthyroidism. Its pathogenesis involves a complex interplay of immunological mechanisms, with a central role attributed to stimulating autoantibodies directed against the thyroid-stimulating hormone receptor (TSHR) expressed on thyroid follicular cells. The differential diagnosis of hyperthyroidism is of paramount importance, including other causes of thyrotoxicosis such as autonomously functioning thyroid adenoma, toxic nodular goitre, various forms of inflammatory or destructive thyroiditis and factitious thyrotoxicosis. The cornerstone of initial therapy for Graves' disease is the administration of antithyroid drugs (ATDs), whereas radioiodine ablation and total thyroidectomy constitute important therapeutic options, primarily in cases of disease recurrence or when serious adverse events related to ATDs occur. During recent decades, prolonged low-dose ATD regimens have demonstrated comparable safety profiles whilst offering superior efficacy relative to the conventional 18-month treatment course. Emerging therapeutic approaches involve immunomodulatory strategies targeting B lymphocytes, IgG recycling pathways and TSHR itself. Furthermore, the induction of immune tolerance to TSHR represents a promising future direction. This review aims to provide a comprehensive overview of the differential diagnosis of thyrotoxicosis as well as current and evolving therapeutic strategies for the management of hyperthyroidism in Graves' disease.

Methimazole has effects in the production of thyroid hormone and is useful in treating conditions related to thyroid hormone, especially thyrotoxicosis. It is considered a thyroid blocking agent. This activity reviews the indications, interaction, adverse effects, and other pharmacodynamic and pharmacokinetic factors of methimazole, and highlights the role of the interprofessional team in improving care for patients receiving methimazole for conditions where it has an indicated therapeutic value.

Hypothyroidism is associated with cardiovascular complications, including supraventricular arrhythmias. Thus, this study investigated functional and morphological alterations in the atrial of hypothyroid rats and evaluated the effects of acute ranolazine treatment on arrhythmia susceptibility. Hypothyroidism was induced in Wistar rats with methimazole (0.02 % in drinking water) for 28 days. The experimental approach included in vivo electrocardiography (ECG), ex vivo assessment of atrial contractility and arrhythmia induction by burst pacing, histological analyses, PCR, and immunofluorescence. Hypothyroid rats exhibited reduced heart rate, prolonged P-wave duration, and increased PR interval, indicating impaired atrial function. Ex vivo atrial preparations also showed increased susceptibility to arrhythmias, characterized by a higher number and longer duration of arrhythmic episodes following burst pacing. Acute ex vivo administration of the antiarrhythmic drug ranolazine significantly reduced arrhythmias susceptibility. Histological analysis revealed myocardial disorganization, and increased vacuolization in hypothyroid rat atria. In addition, Cx43 expression was markedly reduced, potentially contributing to impaired intercellular electrical coupling and increased arrhythmogenic susceptibility. Overall, these findings demonstrate that hypothyroidism induces significant electrophysiological, structural and contractile atrial remodeling, resulting in increased susceptibility to atrial arrhythmia. These findings highlight the importance of thyroid hormone signaling in maintaining atrial electrical stability and suggest that targeting electrical instability with ranolazine may have therapeutic potential in hypothyroid cardiac remodeling.

Hyperthyroidism in pregnancy most commonly results from gestational transient thyrotoxicosis (GTT), though Graves' disease and, less frequently, toxic nodular disease also occurs. Differentiating these conditions requires integration of clinical findings, trimester-specific thyroid function test thresholds, and thyroid-stimulating immunoglobulin measurement when an autoimmune etiology is suspected. Untreated or inadequately managed overt maternal hyperthyroidism that is not due to GTT is associated with significant maternal and fetal complications, including preeclampsia, thyroid storm, growth restriction, and fetal or neonatal thyrotoxicosis. Graves' disease management requires a delicate balance between achieving maternal euthyroidism and minimizing fetal drug exposure. Propylthiouracil is preferred during the first trimester to reduce teratogenic risk. If antithyroid drug (ATD) therapy is still required beyond 16 weeks of gestation, the decision to continue propylthiouracil or switch to methimazole should be guided by shared decision-making between the patient and clinician. The use of the lowest effective ATD dose and close biochemical monitoring remain fundamental principles. Beta-adrenergic blockade may provide short-term symptomatic relief, whereas iodides are reserved for selected patients who are intolerant to ATDs. Thyroidectomy is typically reserved for patients with refractory hyperthyroidism or contraindications to ATDs and is preferably performed during the second trimester of pregnancy. Postpartum relapse of Graves' disease is common. Methimazole is considered safe during lactation at low doses, with no adverse effects on infant growth or neurodevelopment, while radioactive iodine therapy remains contraindicated. Collectively, contemporary evidence emphasizes early diagnosis, individualized therapy, and multidisciplinary care as central to optimizing maternal and fetal outcomes in hyperthyroidism during the reproductive years.