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Cureus Mar 2024This case report explores a rare presentation of restless legs syndrome (RLS) in a 59-year-old female with a history of Graves' disease (GD), highlighting the diagnostic...
This case report explores a rare presentation of restless legs syndrome (RLS) in a 59-year-old female with a history of Graves' disease (GD), highlighting the diagnostic challenges and the importance of considering thyroid dysfunctions in RLS. The patient, previously diagnosed and treated for GD, presented with acute nocturnal discomfort in her lower limbs, along with symptoms of fatigue, weight loss, and palpitations. Physical examinations and thyroid function tests indicated a recurrence of GD. Her RLS symptoms notably resolved following the treatment of GD with methimazole, pointing towards secondary RLS induced by GD. This case emphasizes the necessity of a comprehensive diagnostic approach in RLS, particularly in differentiating it from mimicking conditions including leg cramps, arthritis, peripheral neuropathy, and drug-induced akathisia, and identifying underlying etiologies like thyroid dysfunctions. The resolution of RLS symptoms after GD treatment underlines the potential link between thyroid dysfunctions, iron metabolism, and the dopaminergic system in RLS pathophysiology.
PubMed: 38694425
DOI: 10.7759/cureus.57354 -
Toxicology Jun 2024Thyroid hormone (TH) system disrupting compounds can impair brain development by perturbing TH action during critical life stages. Human exposure to TH system disrupting...
Thyroid hormone (TH) system disrupting compounds can impair brain development by perturbing TH action during critical life stages. Human exposure to TH system disrupting chemicals is therefore of great concern. To better protect humans against such chemicals, sensitive test methods that can detect effects on the developing brain are critical. Worryingly, however, current test methods are not sensitive and specific towards TH-mediated effects. To address this shortcoming, we performed RNA-sequencing of rat brains developmentally exposed to two different thyroperoxidase (TPO) inhibiting compounds, the medical drug methimazole (MMI) or the pesticide amitrole. Pregnant and lactating rats were exposed to 8 and 16 mg/kg/day(d) MMI or 25 and 50 mg/kg/d amitrole from gestational day 7 until postnatal day 16. Bulk-RNA-seq was performed on hippocampus from the 16-day old male pups. MMI and amitrole caused pronounced changes to the transcriptomes; 816 genes were differentially expressed, and 425 gene transcripts were similarly affected by both chemicals. Functional terms indicate effects from key cellular functions to changes in cell development, migration and differentiation of several cell populations. Of the total number of DEGs, 106 appeared to form a consistent transcriptional fingerprint of developmental hypothyroidism as they were similarly and dose-dependently expressed across all treatment groups. Using a filtering system, we identified 20 genes that appeared to represent the most sensitive, robust and dose-dependent markers of altered TH-mediated brain development. These markers provide inputs to the adverse outcome pathway (AOP) framework where they, in the context of linking TPO inhibiting compounds to adverse cognitive function, can be used to assess altered gene expression in the hippocampus in rat toxicity studies.
Topics: Animals; Female; Hippocampus; Male; Methimazole; Pregnancy; Rats; Iodide Peroxidase; Transcriptome; Antithyroid Agents; Prenatal Exposure Delayed Effects; Gene Expression Regulation, Developmental; Enzyme Inhibitors
PubMed: 38685447
DOI: 10.1016/j.tox.2024.153822 -
Medicines (Basel, Switzerland) Apr 2024The human leucocyte antigen (HLA) allele variability was studied in cohorts of patients with idiosyncratic drug-induced liver injury (iDILI). Some reports showed an... (Review)
Review
The human leucocyte antigen (HLA) allele variability was studied in cohorts of patients with idiosyncratic drug-induced liver injury (iDILI). Some reports showed an association between HLA genetics and iDILI, proposing HLA alleles as a potential risk factor for the liver injury. However, the strength of such assumptions heavily depends on the quality of the iDILI diagnosis, calling for a thorough analysis. Using the PubMed database and Google Science, a total of 25 reports of case series or single cases were retrieved using the terms HLA genes and iDILI. It turned out that in 10/25 reports (40%), HLA genetics were determined in iDILI cases, for which no causality assessment method (CAM) was used or a non-validated tool was applied, meaning the findings were based on subjective opinion, providing disputable results and hence not scoring individual key elements. By contrast, in most iDILI reports (60%), the Roussel Uclaf Causality Assessment Method (RUCAM) was applied, which is the diagnostic algorithm preferred worldwide to assess causality in iDILI cases and represents a quantitative, objective tool that has been well validated by both internal and external DILI experts. The RUCAM provided evidence-based results concerning liver injury by 1 drug class (antituberculotics + antiretrovirals) and 19 different drugs, comprising 900 iDILI cases. Among the top-ranking drugs were amoxicillin-clavulanate (290 cases, HLA A*02:01 or HLA A*30:02), followed by flucloxacillin (255 cases, HLA B*57:01), trimethoprim-sulfamethoxazole (86 cases, HLA B*14:01 or HLA B*14:02), methimazole (40 cases, HLA C*03:02), carbamazepine (29 cases, HLA A*31:01), and nitrofurantoin (26 cases, HLA A*33:01). In conclusion, the HLA genetics in 900 idiosyncratic drug-induced liver injury cases with evidence based on the RUCAM are available for studying the mechanistic steps leading to the injury, including metabolic factors through cytochrome P450 isoforms and processes that activate the innate immune system to the adaptive immune system.
PubMed: 38667507
DOI: 10.3390/medicines11040009 -
Physiological Reports Apr 2024Thyroid hormones regulate metabolic rate, nutrient utilization, growth, and development. Swine are susceptible to thyroid suppression in response to disease or...
Thyroid hormones regulate metabolic rate, nutrient utilization, growth, and development. Swine are susceptible to thyroid suppression in response to disease or environmental conditions, but the physiological impact of such disruption has not been established. The objective of this study was to evaluate the impact of hypothyroidism induced with the antithyroid medication methimazole (MMI). 10 mg/kg MMI significantly decreased circulating triiodothyronine (T3) for the duration of treatment but had only a transient effect on circulating thyroxine (T4). Thyroid tissue weight was significantly increased by more than 3.5-fold in response to MMI treatment. Histologically, the eosinophilic colloid was largely absent from the thyroid follicle which displayed a disorganized columnar epithelium consistent with goiter. MMI induced hypothyroidism has no effect on growth rate over 28 days. Hepatic expression of genes associated with thyroid metabolism (DIO1, DIO2, and DIO3), lipid utilization (CD36, FASN, and ACACA), apoptosis (TP53, PERP, SIVA1, and SFN) and proliferation (CDK1, CDK2, CDK4, and CDKN1A) were unaffected by treatment. Collectively these results demonstrate that MMI induces mild systemic hypothyroidism and pronounced goiter, indicating a strong homeostatic central regulation within the hypothalamic pituitary thyroid axis. This combined with limited peripheral effects, indicates resilience to hypothyroidism in modern swine.
Topics: Animals; Methimazole; Hypothyroidism; Swine; Antithyroid Agents; Thyroid Gland; Female; Triiodothyronine; Liver; Thyroxine; Male
PubMed: 38658325
DOI: 10.14814/phy2.16007 -
Endocrine Connections Jun 2024While subclinical or overt hypothyroidism are common in Down syndrome (DS); Graves' disease (GD) is rare (ranges 0.6-3%). We aimed to evaluate the clinical features,...
While subclinical or overt hypothyroidism are common in Down syndrome (DS); Graves' disease (GD) is rare (ranges 0.6-3%). We aimed to evaluate the clinical features, course, and treatment of GD in children with DS and compare them with those without DS. Among 161 children with GD, 13 (8 female, 5 male) had DS (8%). Data were collected retrospectively from patients' medical records. The mean age at diagnosis was 10.6 ± 4.5 years, with a female-to-male ratio 1.6:1. The main symptoms were weight loss (n = 6), increased irritability (n = 3), and increased sweating (n = 3). None had orbitopathy. Seven of 11 patients with a thyroid ultrasound at diagnosis had a goitre. On admission, all had thyroid-stimulating hormone (TSH) <0.01 mU/L (normal range (NR): 0.51-4.30), free triiodothyronine, free thyroxine (mean ± s.d .), and thyrotrophin receptor antibodies (median, range) were 22.2 ± 10.2 pmol/L (NR: 3.5-8.1), 50.2 ± 18.7 pmol/L (NR 12.6-20.9), and 17.0 (2.89-159.0) U/L (NR <1), respectively. Patients were treated either with methimazole (n = 10) or carbimazole (n = 3), a dose of 0.54 ± 0.36 mg/kg/day. The treatment was 'block and replace' in ten patients and 'dose titration' in three patients, with a mean duration of 43.4 ± 11.0 months. Of 13 patients, four are still receiving primary treatment, three are in remission, one patient had two medically treated recurrences, three underwent surgery without complications, and two patients were lost to follow-up. Our data show that the clinical course of GD in patients with DS was similar to those without DS and suggest that a prolonged medical therapy should be the preferred option.
PubMed: 38657665
DOI: 10.1530/EC-24-0032 -
Journal of Medical Cases Apr 2024In pediatric-aged patients, hyperthyroidism generally results from the autoimmune disorder, Graves' disease (GD). Excessive levels of thyroid hormones (triiodothyronine...
In pediatric-aged patients, hyperthyroidism generally results from the autoimmune disorder, Graves' disease (GD). Excessive levels of thyroid hormones (triiodothyronine and thyroxine) result in irritability, emotional lability, nervousness, tremors, palpitations, tachycardia, and arrhythmias. The risk of morbidity and mortality is increased when surgical intervention is required in patients with hyperthyroidism due to the potential for the development of thyroid storm (TS). A 3-year, 1-month-old child with a past medical history of GD presented for total thyroidectomy when pharmacologic control with methimazole was not feasible due to intolerance following development of a serum sickness-like illness. Prior to surgery, his thyrotoxicosis symptoms worsened with fever, tachycardia, diaphoresis, and hypertension. He subsequently developed TS and was admitted to the pediatric intensive care unit where management included hydrocortisone, potassium iodide, and β-adrenergic blockade with esmolol and propranolol. Thyroid studies improved prior to surgery, and a total thyroidectomy was successfully completed. Corticosteroid therapy was slowly tapered as an outpatient, and he was discharged home on hospital day 9. Following discharge, his signs and symptoms of thyrotoxicosis resolved, and he was started on oral levothyroxine replacement therapy. The remainder of his postoperative and post-discharge course were unremarkable. Only two case reports of perioperative pediatric TS have been published in the past 20 years. Our case serves as an important reminder of the signs of TS in children and to outline the treatment options in a pediatric patient, especially in those unable to tolerate first-line pharmacologic therapies such as methimazole or propylthiouracil.
PubMed: 38646421
DOI: 10.14740/jmc4197 -
IBRO Neuroscience Reports Jun 2024Ginsenoside Rg1(Rg1), a monomer of a tetracyclic triterpenoid derivative, possesses diverse medicinal properties attributed to its unique chemical structure and may have...
Protective role of the ginsenoside Rg1 against methimazole-induced gestational hypothyroidism on reflexive behaviors, conditioned fear and cortical antioxidant levels in mice offspring.
Ginsenoside Rg1(Rg1), a monomer of a tetracyclic triterpenoid derivative, possesses diverse medicinal properties attributed to its unique chemical structure and may have beneficial effects on fetal development. This study aimed to investigate the protective effects of prenatal exposure to Rg1 against Methimazole-induced gestational hypothyroidism on reflexive behaviors, conditioned fear, and cortical antioxidant levels in mouse offspring.40 female virgin mice and 12 male NMRI mice were assigned to four groups: group 1 served as the control, group 2 received Methimazole(MMI) at a concentration of 0.02% in their drinking water, group 3 received Rg1(150 mg/kg), and group 4 received both MMI and Rg1.Groups of 2-4 were administered the substances from days 1-9 of gestation. After delivery, pups were selected, and reflexive motor behaviors and conditioned fear were assessed. Additionally, levels of brain tissue catalase(CAT), malondialdehyde(MDA), superoxide dismutase(SOD), and glutathione peroxidase(GPx) levels were measured. Furthermore, postpartum immobility time in the forced swimming test (FST), tail suspension test (TST), and the number of squares crossed in the open field test (OFT)were determined. The results demonstrated that maternal exposure to Rg1 improved ambulation score, hind-limb suspension score, grip strength, front-limb suspension, hind-limb foot angle, negative geotaxis, surface righting, and conditioned fear in hypothyroidism-induced offspring(<0.05). Rg1 decreased immobility time in the FST, and TST, and increased the number of squares crossed in the OFT in postpartum hypothyroidism-induced mice(<0.05). Moreover, Rg1 reduced brain tissue MDA levels and increased brain tissue CAT, SOD, and GPx levels in mice and their offspring(<0.05). These findings indicate that Rg1 mitigated postpartum depression in mice and improved reflexive motor behaviors in their pups.
PubMed: 38634016
DOI: 10.1016/j.ibneur.2024.03.010 -
Cureus Apr 2024Insulin autoimmune syndrome (IAS) or Hirata disease is a rare condition presenting as recurrent hypoglycemia, and associated with elevated insulin levels in the presence...
Insulin autoimmune syndrome (IAS) or Hirata disease is a rare condition presenting as recurrent hypoglycemia, and associated with elevated insulin levels in the presence of insulin autoantibodies (IAAs) in patients who were never exposed to exogenous insulin and with no evidence of pancreatic abnormalities. IAS is much more frequent in East Asians, especially the Japanese population, compared to the lower incidence in Caucasians. However, it can be associated with other autoimmune diseases or drug use like methimazole and alpha-lipoic acid (ALA). We report a case of a 47-year-old Caucasian male presenting with a 12-month history of worsening episodes of fasting and post-prandial hypoglycemia associated with symptoms of dizziness, tremors, palpitations, and unconsciousness associated with hypoglycemia. Symptoms resolved with the administration of carbohydrate-containing foods, establishing Whipple's triad. At an outside facility, he had initial labs that showed elevated insulin levels (141 µU/ml) with normal glucose, C-peptide, and proinsulin levels, but there was no availability of an IAA lab assay. Given his symptoms, severity, and frequency of hypoglycemia, he was admitted to the hospital for a 72-hour fast, which showed the lowest glucose level of 64 mg/dl with inappropriately high insulin of 22.2 µU/ml, low C-peptide of 0.57 ng/ml, and undetectable proinsulin of <1.6 pmol/L, but with IAA being >50 U/ml (0.0-0.4 U/ml). He was treated with intensive dietary counseling with a low-carbohydrate diet and prednisone 20 mg twice daily initially. Additionally, he could not tolerate octreotide, diazoxide, and acarbose due to side effects. He is currently on prednisone 10 mg daily and nifedipine with no further hypoglycemic episodes, but still has a high IAA of >50 U/ml and serum insulin levels of 70-112 µU/ml. Our case highlights the importance of recognizing hypoglycemia and checking for IAA levels as first-line diagnostic tests, in the absence of which there could be a delay in diagnosis and leading to unnecessary lab and imaging testing. Our case is unique since it happened in a Caucasian without any prior exposure to a triggering factor and has not undergone self-remission yet, which happens in most of IAS cases.
PubMed: 38623323
DOI: 10.7759/cureus.58270 -
Heliyon Apr 2024Thyroid storm (TS) leading to acute liver failure is rare but fatal in clinical practice and hepatic failure can remarkably limit medication options for TS. We...
Case report and literature review: A thyroid storm patient with severe acute hepatic failure treated by therapeutic plasma exchange and a double plasma molecular absorption system.
Thyroid storm (TS) leading to acute liver failure is rare but fatal in clinical practice and hepatic failure can remarkably limit medication options for TS. We successfully cured a patient with TS complicated with acute hepatic failure using therapeutic plasma exchange (TPE) and a double plasma molecular absorption system (DPMAS) and summarized the case characteristics of 10 similar critical patients reported worldwide. We recommend that patients with TS complicated with liver failure disuse propylthiouracil or methimazole. TPE should be utilized to rapidly decrease thyroid hormone levels, and DPMAS should be considered for supportive treatment in the presence of hepatic encephalopathy or dramatic bilirubin elevations.
PubMed: 38601545
DOI: 10.1016/j.heliyon.2024.e28867 -
Journal of Translational Medicine Mar 2024A subset of Graves' disease (GD) patients develops refractory hyperthyroidism, posing challenges in treatment decisions. The predictive value of baseline characteristics...
BACKGROUND
A subset of Graves' disease (GD) patients develops refractory hyperthyroidism, posing challenges in treatment decisions. The predictive value of baseline characteristics and early therapy indicators in identifying high risk individuals is an area worth exploration.
METHODS
A prospective cohort study (2018-2022) involved 597 newly diagnosed adult GD patients undergoing methimazole (MMI) treatment. Baseline characteristics and 3-month therapy parameters were utilized to develop predictive models for refractory GD, considering antithyroid drug (ATD) dosage regimens.
RESULTS
Among 346 patients analyzed, 49.7% developed ATD-refractory GD, marked by recurrence and sustained Thyrotropin Receptor Antibody (TRAb) positivity. Key baseline factors, including younger age, Graves' ophthalmopathy (GO), larger goiter size, and higher initial free triiodothyronine (fT3), free thyroxine (fT4), and TRAb levels, were all significantly associated with an increased risk of refractory GD, forming the baseline predictive model (Model A). Subsequent analysis based on MMI cumulative dosage at 3 months resulted in two subgroups: a high cumulative dosage group (average ≥ 20 mg/day) and a medium-low cumulative dosage group (average < 20 mg/day). Absolute values, percentage changes, and cumulative values of thyroid function and autoantibodies at 3 months were analyzed. Two combined predictive models, Model B (high cumulative dosage) and Model C (medium-low cumulative dosage), were developed based on stepwise regression and multivariate analysis, incorporating additional 3-month parameters beyond the baseline. In both groups, these combined models outperformed the baseline model in terms of discriminative ability (measured by AUC), concordance with actual outcomes (66.2% comprehensive improvement), and risk classification accuracy (especially for Class I and II patients with baseline predictive risk < 71%). The reliability of the above models was confirmed through additional analysis using random forests. This study also explored ATD dosage regimens, revealing differences in refractory outcomes between predicted risk groups. However, adjusting MMI dosage after early risk assessment did not conclusively improve the prognosis of refractory GD.
CONCLUSION
Integrating baseline and early therapy characteristics enhances the predictive capability for refractory GD outcomes. The study provides valuable insights into refining risk assessment and guiding personalized treatment decisions for GD patients.
Topics: Adult; Humans; Secondary Prevention; Prospective Studies; Reproducibility of Results; Hyperthyroidism; Antithyroid Agents; Graves Disease
PubMed: 38553734
DOI: 10.1186/s12967-024-05129-3