scholarly journals O29 Pharmacometric modelling of free thyroxine dynamics after initiation of antithyroid drug treatment in children with Graves’ disease: a tool for personalized drug dosing in children

2019 ◽  
Vol 104 (6) ◽  
pp. e13.1-e13
Author(s):  
G Koch ◽  
V Gotta ◽  
C Ollagnier ◽  
D Konrad ◽  
C Flück ◽  
...  
Keyword(s):  
Side Effects ◽  
Laboratory Data ◽  
Antithyroid Drug ◽  
Normal Growth ◽  
Thyroid Stimulating Hormone ◽  
Free Thyroxine ◽  
Model Parameters ◽  
Graves Disease ◽  
Study Cohort ◽  
Radioiodine Ablation

BackgroundThyroid hormones are essential for normal growth and puberty in children and adolescents. Graves’ disease (GD) is a rare autoimmune disorder associated with thyroid hormone over-production and occurs in 0.5–2:100’000 children (mostly females) in Europe. In contrast to adults, first line treatment of GD is long-term antithyroid drug (ATD) therapy, and radioiodine ablation is usually being reserved for patients after puberty. However, treatment of acquired hyperthyroidism with ATD is difficult since 1) paediatric patients differ considerable in age, weight and diseases severity and 2) minimal ATD dose should be used to avoid mild side effects (occurring in 6–35% of patients), and rare severe side effects such as agranulocytosis and liver failure.MethodsLongitudinal clinical and laboratory data from a Swiss multicentre cohort were analysed retrospectively. Non-linear mixed effects modelling was applied to characterize dynamics of free thyroxine (FT4) during the first 3 months of treatment with carbimazole. Sex, co-medications such as propranolol, and thyroid stimulating hormone receptor antibody were tested as covariates on model parameters. Reference range for FT4 was derived from target levels in clinical practice (12–22 pmol/L).ResultsStudy cohort comprised 45 children with GD, 78% females, median age 12.2 years (IQR = [8.7,13.6])) with a total of 181 visits. FT4 baseline at diagnosis of GD was 62.3 pmol/L (IQR = [45.7, 86.7]). None of the tested factors showed significant covariate effects. The model allows individual simulations of optimal ATD dosing strategies (starting and maintenance dose) for different GD severities, ages and weights at start of therapy. Personalized dosing examples will be presented.ConclusionsDeveloped pharmacometric model is able to predict dynamics of FT4 in children with GD depending on four parameters: ATD dose/kg/d, age, weight and disease severity, and can be applied to personalize dosing regimen to avoid over- or under dosing.Disclosure(s)Nothing to disclose

scholarly journals Carbimazole induced rhabdomyolysis

2021 ◽  
Vol 2021 ◽  
Author(s):  
Niamh O’Donnell ◽  
Aisling McCarthy ◽  
Ken Thong
Keyword(s):  
Adverse Effect ◽  
Creatine Kinase ◽  
Side Effects ◽  
Temporal Relationship ◽  
Early Recognition ◽  
Antithyroid Drug ◽  
Graves Disease ◽  
List Type ◽  
Musculoskeletal Complaints ◽  
Learning Points

Summary Carbimazole is a commonly used antithyroid drug (ATD), which is associated with several well-established side effects. However, Carbimazole-induced rhabdomyolysis is rarely reported in the literature. We report a 27-year-old male who presented with upper limb myalgia and significantly raised creatine kinase elevation, 1-month post commencement of Carbimazole for Graves’ disease. Carbimazole was ceased with subsequent clinical and biochemical improvement. Though the pathophysiology remains unclear, we hope to raise awareness regarding this rare adverse effect with a view to promote early recognition and prompt discontinuation of the offending medication caused by a commonly used medication in endocrinology. Learning points Musculoskeletal complaints can relate to unidentified and untreated hyperthyroidism. However one must be mindful that the treatment for these disorders can too induce myopathies. ATD-induced myopathy should be considered when there is a temporal relationship between introduction of ATDs and the onset of symptoms. If ATD-induced myopathy is being considered, other causes of myopathy should still be outruled. Prompt discontinuation of potentially offending medications may provide resolution of symptoms and avoid significant consequences.

scholarly journals Graves Disease in Childhood

2021 ◽  
Author(s):  
Madhukar Mittal ◽  
Vanishri Ganakumar
Keyword(s):  
Thyroid Hormone ◽  
Side Effects ◽  
Age Of Onset ◽  
Severe Disease ◽  
Clinical Manifestations ◽  
Thyroid Stimulating Hormone ◽  
Graves Disease ◽  
Older Children ◽  
Prepubertal Children ◽  
Pediatric Age Group

Graves’ disease (GD) is an autoimmune disease caused by autoantibodies against thyroid stimulating hormone receptor (TSH-R), resulting in stimulation of thyroid gland and overproduction of thyroid hormones resulting in clinical manifestations. It is uncommon in children and is 6 times more prevalent in females. The symptomatology, clinical and biochemical severity are a function of age of onset of disease. Prepubertal children tend to present with weight loss and bowel frequency, associated with accelerated growth and bone maturation. Older children are more likely to present with the classical symptoms of thyrotoxicosis like palpitations, tremors and heat intolerance. Prepubertal children tend to have a more severe disease, longer duration of complaints and higher thyroid hormone levels at presentation than the pubertal and postpubertal children. The non-specificity of some of the symptoms in pediatric age group can lead to children being initially seen by other specialities before being referred to endocrinology. Management issues are decided based on patient’s priorities and shared decision making between patient and treating physician. Radioactive Iodine Ablation is preferred when there is relatively higher value placed on Definitive control of hyperthyroidism, Avoidance of surgery, and potential side effects of ATDs. Similarly Antithyroid drugs are chosen when a relatively higher value is placed on possibility of remission and avoidance of lifelong thyroid hormone treatment, Avoidance of surgery, Avoidance of exposure to radioactivity. Surgery is preferred when access to a high-volume thyroid surgeon is available and a relatively higher value is on prompt and definitive control of hyperthyroidism, avoidance of exposure to radioactivity and avoidance of potential side effects of ATDs. Continental differences with regards to management do exist; radio-iodine ablation being preferred in North America while Anti-thyroid drug treatment remains the initial standard care in Europe.

scholarly journals Fine mapping MHC associations in Graves’ disease and its clinical subtypes in Han Chinese

2018 ◽  
Vol 55 (10) ◽  
pp. 685-692 ◽  
Author(s):  
Xun Chu ◽  
Minjun Yang ◽  
Zhen-Ju Song ◽  
Yan Dong ◽  
Chong Li ◽  
...  
Keyword(s):  
Amino Acid ◽  
Molecular Mechanisms ◽  
Amino Acid Level ◽  
Antithyroid Drug ◽  
Amino Acid Position ◽  
Thyroid Stimulating Hormone ◽  
Han Chinese ◽  
Graves Disease ◽  
Hla Genes ◽  
Antithyroid Drug Therapy

BackgroundThe classical human leucocyte antigen (HLA) genes were the most important genetic determinant for Graves’ disease (GD). The aim of the study was to fine map causal variants of the HLA genes.MethodsWe applied imputation with a Pan-Asian HLA reference panel to thoroughly investigate themajor histocompatibility complex (MHC) associations with GD down to the amino acid level of classical HLA genes in 1468 patients with GD and 1490 controls of Han Chinese.ResultsThe strongest finding across the HLA genes was the association with HLA-DPβ1 position 205 (Pomnibus=2.48×10−33). HLA-DPA1*02:02 was the strongest association among the classical HLA alleles, which was in perfect linkage disequilibrium with HLA-DPα1 residue Met11 (OR=1.90, Pbinary=1.76×10−31). Applying stepwise conditional analysis, we identified amino acid position 205 in HLA-DPβ1, position 66 and 99 in HLA-B and position 28 in HLA-DRβ1 explain majority of the MHC association to GD risk. We further evaluated risk of two clinical subtypes of GD, namely persistent thyroid stimulating hormone receptor antibody -positive (pTRAb+) group and ‘non-persistent TRAb positive’ (pTRAb−) group after antithyroid drug therapy. We found that HLA-B residues Lys66-Arg69-Val76 could drive pTRAb− GD risk alone, while HLA-DPβ1 position 205, HLA-B position 69 and 199 and HLA-DRβ1 position 28 drive pTRAb+ GD risk. The risk heterogeneity between pTRAb+ and pTRAb− GD might be driven by HLA-DPα1 Met11.ConclusionsFour amino acid positions could account for the associations of MHC with GD in Han Chinese. These distinct HLA association patterns indicated the two subtypes have distinct molecular mechanisms of pathogenesis.

scholarly journals MASSIVE THYMIC HYPERPLASIA SECONDARY TO GRAVES DISEASE

2020 ◽  
Vol 6 (3) ◽  
pp. e144-e146
Author(s):  
WingYee Wan ◽  
Jeffrey A. Colburn
Keyword(s):  
Computed Tomography ◽  
Thyroid Stimulating Hormone ◽  
Free Thyroxine ◽  
Thymic Hyperplasia ◽  
Anterior Mediastinal Mass ◽  
Graves Disease ◽  
Presenting Symptoms ◽  
Thyroid Stimulating Immunoglobulins ◽  
Computed Tomography Angiogram ◽  
Stimulating Hormone

Objective: Graves disease (GD) has a well-known association with thymic hyperplasia, which is seen histo-logically in up to 38% of patients with GD. However, there have only been approximately 100 documented cases of Graves-associated massive thymic hyperplasia. Potential mechanisms of thymic pathology are reviewed. Methods: A 24-year-old female presented to the emergency department with dyspnea, palpitations, tachycardia, anxiety, and weight loss. She was evaluated for hyperthyroidism using labs (thyroid-stimulating hormone, free thyroxine, thyroid-stimulating immunoglobulins) and imaging (radioactive iodine uptake [RAIU] scan), leading to treatment with radioiodine. A computed tomography angiogram of the chest was also performed to evaluate for pulmonary embolism given the patient's presenting symptoms. Results: Our patient was found to have undetectable thyroid-stimulating hormone, elevated free thyroxine (2.9 ng/dL), and elevated thyroid-stimulating immunoglobulins (399%). Diagnosis of GD was confirmed on RAIU scan. The computed tomography chest angiogram demonstrated a significant anterior mediastinal mass (7.9 × 6.9 × 6.3 cm). Treatment with radioiodine led to reduction of the mass by 76% in volume. Conclusion: While the patient's thyroid labs and RAIU scan were consistent with GD, the presence of massive thymic hyperplasia was atypical. However, the resolution of thymic hyperplasia after radioiodine therapy, without the use of thymectomy, was similar to other reported cases.

scholarly journals Predictors of time to remission and treatment failure in patients with Graves’ disease treated with propylthiouracil

2009 ◽  
Vol 32 (3) ◽  
pp. 199 ◽  
Author(s):  
Hakan Cinemre ◽  
Cemil Bilir ◽  
Feyzi Gokosmanoglu ◽  
Nermin Akdemir ◽  
Besir Erdogmus ◽  
...  
Keyword(s):  
Side Effects ◽  
Treatment Failure ◽  
Flow Rate ◽  
Free Thyroxine ◽  
Prolonged Treatment ◽  
Superior Thyroid Artery ◽  
Graves Disease ◽  
Long Term Treatment ◽  
Artery Flow

Purpose: Propylthiouracil is one of the thionamides used in the treatment of Graves’ disease. The drug has serious side effects and long-term treatment might be needed to achieve remission. We designed this study to evaluate the clinical and thyroid Doppler characteristics that might predict time to remission and treatment failure in propylthiouracil treated Graves’ patients. Methods: 26 patients, among 134 presenting to our university hospital outpatient clinic between Feb -July 2007 and with first time diagnosis of clinical thyroid dysfunction, were clinically and ultasonographically diagnosed with Graves’ disease. Doppler parameters, serum thyrotropin, free thyroxine and free triiodothyronine were measured at the beginning of the study and thyroid studies were repeated every 4 weeks until remission. Propylthiouracil 300 mg/day was started for each patient at the time of diagnosis and doses were titrated according to repeat thyroid studies. Patients were treated and followed up for 18 months. Results: Treatment failure was associated with smoking (P = 0.001) and male gender (P= 0.037). Stepwise multiple regression analysis revealed that age, free thyroxine and superior thyroid artery flow rate were predictors of time to remission (P= 0.001, 0.002 and 0.003, respectively). Conclusion: The time to remission in Graves patients treated with propylthiouracil can be predicted using age, serum free thyroxine and superior thyroid artery flow rate. This may help early consideration of alternative treatment for the patients requiring prolonged treatment for remission or for those who fail medical treatment. This would decrease unnecessary, long-term propylthiouracil exposure with its serious side effects.

scholarly journals Parameters affecting the period for being euthyroid in newly-diagnosed Graves’ disease treated with antithyroid agent

2020 ◽  
Vol 8 (9) ◽  
pp. 3165
Author(s):  
Iskender Ekinci ◽  
Hande Peynirci
Keyword(s):  
Thyroid Function ◽  
Smoking Status ◽  
Antithyroid Drug ◽  
Thyroid Stimulating Hormone ◽  
Graves Disease ◽  
Thyroid Function Tests ◽  
Newly Diagnosed ◽  
Function Tests ◽  
Significant Difference ◽  
Stimulating Hormone

Background: There are limited data about the factors affecting the response time to medical treatment in Graves’ disease (GD) although many studies examined the predictors of the relapse after drug withdrawal. The aim of the current study was to evaluate the time for becoming euthyroid under antithyroid drug (ATD) therapy and the parameters influencing this period in patients diagnosed as GD.Methods: Patients with newly-diagnosed GD and decided to treat with ATD initially between March 2017 and September 2018 were retrieved retrospectively. Sociodemographic features as well as laboratory parameters like thyroid function tests and thyroid-stimulating hormone-receptor antibody (TRab) at the time of diagnosis were recorded.Results: Out of 41 patients, 63.4% (n=26) were female. The mean age was 36.1±11.7 years and 43.9% (n=18) of them were smoking. The time between the initiation of treatment and the duration of becoming euthyroid was 2.4±1.8 months. No significant difference was noted between age, gender, and smoking status and the time to become euthyroid under ATD treatment. This period was significantly positively correlated with levels of free triiodothyronine, free thyroxine, and negatively correlated with thyroid-stimulating hormone. Response to ATD therapy was higher in patients with pre-treatment TRab levels <10 IU/l than TRab ≥10 IU/l (p=0.011).Conclusions: Pretreatment thyroid function tests and TRab levels may be taken into consideration before deciding treatment in patients with newly diagnosed GD. It would be useful to design more comprehensive studies so that this proposal can find a response in clinical practice.

scholarly journals Long-Term Antithyroid Drug Treatment of Graves’ Disease in Children and Adolescents: A 20-Year Single-Center Experience

2021 ◽  
Vol 12 ◽  
Author(s):  
Ari Song ◽  
Su Jin Kim ◽  
Min-Sun Kim ◽  
Jiyeon Kim ◽  
Insung Kim ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Remission Rate ◽  
Antithyroid Drug ◽  
Thyroid Stimulating Hormone ◽  
Graves Disease ◽  
Tertiary Institution ◽  
Single Center Experience ◽  
Predicting Factors ◽  
The Mean

Background/purposeGraves’ disease (GD) is the most common cause of thyrotoxicosis in children and adolescents. There is some debate regarding the optimal treatment and predicting factors of remission or relapse in children and adolescents with GD. In this study, we report a retrospective study of 195 children and adolescents with GD treated at a single tertiary institution in Korea.MethodsThis study included children and adolescents with GD diagnosed before 19 years of age from January of 2000 to October of 2020. The diagnosis of GD was based on clinical features, high thyroxine (FT4), suppressed thyroid-stimulating hormone, and a positive titer of thyrotropin receptor antibodies. Remission was defined as maintenance of euthyroid status for more than six months after discontinuing antithyroid drug (ATD).ResultsA total of 195 patients with GD were included in this study. The mean age at diagnosis was 12.9 ± 3.2 years, and 162 patients (83.1%) were female. Among all 195 patients, five underwent thyroidectomy and three underwent radioactive iodine therapy. The mean duration of follow-up and ATD treatment were 5.9 ± 3.8 years and 4.7 ± 3.4 years, respectively. The cumulative remission rates were 3.3%, 19.6%, 34.1%, 43.5%, and 50.6% within 1, 3, 5, 7, and 10 years of starting ATD, respectively. FT4 level at diagnosis (P = 0.001) was predicting factors for remission [HR, 0.717 (95% CI, 0.591 – 0.870), P = 0.001]. Methimazole (MMI)-related adverse events (AEs) occurred in 11.3% of patients, the most common of which were rash and hematologic abnormalities. Of a total of 26 AEs, 19 (73.1%) occurred within the first month of taking MMI.ConclusionsIn this study, the cumulative remission rate increased according to the ATD treatment duration. Long-term MMI treatment is a useful treatment option before definite treatment in children and adolescents with GD.

scholarly journals Serum TSH level as predictor of Graves’ disease recurrence following antithyroid drug withdrawal: A systematic review

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245978
Author(s):  
Imam Subekti ◽  
Gracia Jovita Kartiko ◽  
Zahra Farhanni Suhardi ◽  
Muhadi ◽  
Wismandari Wisnu
Keyword(s):  
Recurrence Rate ◽  
Antithyroid Drug ◽  
Disease Recurrence ◽  
Thyroid Stimulating Hormone ◽  
Treatment Withdrawal ◽  
High Recurrence Rate ◽  
Graves Disease ◽  
Adequate Treatment ◽  
Risk Of Disease

Graves’ disease (GD) has a high recurrence rate despite various and adequate treatment. Numerous studies have been performed to identify the predictor of disease recurrence. This report aims to investigate the role of thyroid stimulating hormone (TSH) level as a thyrotropin in predicting the recurrence of Graves’ disease within 1 to 2 years following antithyroid drug (ATD) withdrawal. Literature searching was conducted on PubMed, Scopus, Cochrane, Proquest, EBSCO in August 2019 and Google Scholar in October 2020. The study criteria include the study that evaluates TSH level 4 weeks following ATD withdrawal, with subjects ≥18 years old who are retrospectively or prospectively followed up after 1 to 2 years following ATD withdrawal. Four eligible studies were selected based on inclusion/exclusion criteria, all of which measured TSH level at 4 weeks following ATD withdrawal. All studies had 1 to 2 years follow up. One study was an RCT, two studies were done in prospective cohort and another in retrospective cohort. All studies had comparable validity and applicability. Three out of four studies suggested that low TSH level measured 4 weeks following treatment withdrawal was associated with higher risk of disease recurrence. In conclusion, low TSH level obtained 4 weeks after ATD withdrawal was associated with higher rate of recurrence rate in GD.

scholarly journals A Case of Antithyroid Drug-Induced Agranulocytosis Pre-Covid 19 Era

2020 ◽  
pp. 1-4
Author(s):  
MosabNouraldein Mohammed Hamad
Keyword(s):  
Side Effects ◽  
Neutrophil Count ◽  
Antithyroid Drug ◽  
Drug Effects ◽  
Medical Advice ◽  
Antithyroid Drugs ◽  
Graves Disease ◽  
Drug Induced ◽  
Immunological Mechanisms ◽  
Noticeable Reduction

Agranulocytosis is an infrequent and serious side effect of antithyroid drugs characterized by a noticeable reduction in granulocyte and neutrophil count, it usually occurs within the first 2-3 months of treatment. There is a variety of mechanisms by which ATD can induce agranulocytosis, direct drug effects, and immunological mechanisms. We present 33 years old female attended Atbara teaching hospital who has developed agranulocytosis 2 weeks after starting ATD to treat relapsed Graves' disease. What was unusual about this patient is that symptoms have occurred in a period less than 15 days of starting treatment and with a dose of 45 mg /day. The physician must educate the patient about the possibility of early onset of serious side effects of ATD and to seek medical advice as soon as possible.

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