RESUMEN
Background: Agranulocytosis is a rare antithyroid drug treatment (ATD) side effect seen in children suffering from Graves' disease (GD). Neutropenia is a recognized adverse event associated with ATD but has also been reported as pre-treatment neutropenia in GD. Methods: We performed a retrospective cohort study to analyze the longitudinal clinical and biochemical data of 161 pediatric patients with GD who received either methimazole (MMI) or carbimazole (CBZ) as ATD. The inclusion criteria were elevated free thyroxine (fT4 >25 pmol/L), suppressed thyrotropin (TSH <0.05 mlU/mL), and elevated thyrotropin receptor antibodies (TSHRAbs >2.5 IU/L). Absolute neutrophil count (ANC) was used to define neutropenia (ANC <1800/µL) and agranulocytosis (ANC <500/µL). Results: Nine of the 161 patients had neutropenia at diagnosis (ANC: 1348/µL ± 250) without further deterioration under ATD. In this subgroup, we found higher levels of free triiodothyronine (fT3: 31.45 pmol/L ± 3.99) at diagnosis in comparison with those who developed neutropenia (26.29 pmol/L ± 12.96; p = 0.07) and those without neutropenia before and during therapy (23.12 pmol/L ± 13.7; p = 0.003). Thirty-eight patients (23.6%) became neutropenic (ANC: 1479/µL ± 262) while receiving ATD. Neutropenia occurred after a mean of 551.8 (range: 10-1376) days, mostly without further deterioration. Two of these 38 patients developed agranulocytosis and underwent emergency thyroidectomy. The patients with neutropenia were significantly younger (p = 0.031). Neutropenia occurred significantly more often in patients receiving CBZ (50%; n = 20/40) than in those receiving MMI (16.5%; n = 18/110; p = 0.001). The minimum ANC was significantly lower in the CBZ (1971/µL ± 1008) than in the MMI group (2546 ± 959); p = 0.004. Conclusions: Neutropenia occurred significantly more often under CBZ than MMI. As this is potentially due to higher immunogenicity, we suggest that children with GD should be treated with MMI. Frequent measurements of ANC may be needed to detect severe agranulocytosis, although low pre-treatment ANC may not necessarily be a contraindication to ATD treatment. Young age may be potentially associated with an increased risk of reduced ANC. Further investigation is necessary to fully understand risk factors for neutropenia in children with GD.
Asunto(s)
Antitiroideos , Carbimazol , Enfermedad de Graves , Metimazol , Neutropenia , Humanos , Metimazol/efectos adversos , Metimazol/uso terapéutico , Niño , Neutropenia/inducido químicamente , Neutropenia/sangre , Antitiroideos/efectos adversos , Antitiroideos/uso terapéutico , Femenino , Masculino , Estudios Retrospectivos , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/sangre , Adolescente , Carbimazol/uso terapéutico , Carbimazol/efectos adversos , Preescolar , Agranulocitosis/inducido químicamente , Tiroxina/uso terapéutico , Tiroxina/sangre , Tirotropina/sangre , Triyodotironina/sangreRESUMEN
A 20-year-old female presented with complaints of thyroid swelling and showed signs and symptoms of thyrotoxicosis and fine-needle aspiration cytology (FNAC) was requested by the surgeon. On examination of FNAC smear, it showed thyroid follicular cells with atypical features like bizarre giant cells, pseudo nuclear inclusions, and mitotic figure. Correlation between clinical history and cytomorphologic features was done and it was reported as atypical changes in thyroid probably due to carbimazole-induced changes. It helped the patient, as radical surgery and its untoward complications were avoided.
Asunto(s)
Neoplasias de la Tiroides , Nódulo Tiroideo , Femenino , Humanos , Adulto Joven , Adulto , Neoplasias de la Tiroides/patología , Carbimazol/efectos adversos , Biopsia con Aguja Fina , Nódulo Tiroideo/patologíaRESUMEN
BACKGROUND Hyperthyroidism is an overproduction of thyroid hormones. Carbimazole is an anti-thyroid medication used to treat hyperthyroidism in adults and children. It is a thionamide associated with rare adverse effects such as neutropenia, leukopenia, agranulocytosis, and hepatotoxicity. Severe neutropenia is a life-threatening event characterized by a sharp drop in absolute neutrophil count. Severe neutropenia can be treated by discontinuation of the precipitating medication. Administration of granulocyte colony-stimulating factor provides longer protection against neutropenia. Elevated liver enzymes indicate hepatotoxicity, which usually normalize after discontinuation of the offending medication. CASE REPORT A 17-year-old girl was treated with carbimazole since the age of 15 for hyperthyroidism secondary to Graves' disease. She initially received 10 mg of carbimazole orally twice daily. After 3 months, the patient's thyroid function reflected residual hyperthyroidism and was then up-titrated to 15 mg orally in the morning and 10 mg orally in the evening. She presented to the emergency department reporting fever, body aches, headache, nausea, and abdominal pain for 3 days. She was diagnosed with severe neutropenia and hepatotoxicity induced by carbimazole after 18 months of dose modification. CONCLUSIONS In hyperthyroidism, it is important to maintain patients in a euthyroid state for a long period to minimize the autoimmunity and hyperthyroid relapse, which often requires long-term use of carbimazole. However, severe neutropenia and hepatotoxicity are rare and serious adverse effects of carbimazole. Clinicians should be aware of the importance to discontinuation of carbimazole, administration of granulocyte colony-stimulating factors, and supportive treatment to reverse the consequences.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Enfermedad de Graves , Hipertiroidismo , Neutropenia , Adulto , Femenino , Humanos , Niño , Adolescente , Carbimazol/efectos adversos , Recurrencia Local de Neoplasia , Neutropenia/inducido químicamente , Hipertiroidismo/tratamiento farmacológico , Enfermedad de Graves/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiologíaRESUMEN
The World Health Organization (WHO) has listed 525 different drugs, that can lead to acute pancreatitis cases, as a medication side-effect. Among them, methimazole (MMI also known as thiamazole, the active form of carbimazole [CBZ]) was included. We reported case reports of patients with overall features compatible with acute pancreatitis episodes following and presumably triggered by the exposure to MMI and its prodrug CBZ. A systematic search was performed on MEDLINE (PubMed). We included case reports of patients with overall features compatible with acute pancreatitis episodes following and presumably triggered by the exposure to MMI and its prodrug CBZ Data extraction and analysis were undertaken in duplicate. We identified 7 case reports. Most patients were female, and one patient was male. Mean age at baseline ranged from 18 to 80 years old. The average time, that elapses between the initiation of the therapy with MMI/CBZ and the onset of typical clinical signs and symptoms pathognomonic of acute pancreatitis, was 2-3 weeks. Based on the data derived from these case reports, it could be considered the possibility of a potential association between MMI/CBZ exposure. Evidence is, however, limited and requires more studies of high quality to confirm this association.
Asunto(s)
Pancreatitis , Profármacos , Humanos , Masculino , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Metimazol/efectos adversos , Carbimazol/efectos adversos , Enfermedad Aguda , Pancreatitis/inducido químicamente , Pancreatitis/diagnóstico , Pancreatitis/tratamiento farmacológicoRESUMEN
OBJECTIVES: The risk of congenital anomalies following in utero exposure to thionamide antithyroid drugs (ATDs) is unresolved. Observational studies are contradictory and existing meta-analyses predate and preclude more recent studies. We undertook an updated meta-analysis of congenital anomaly risk in women exposed to carbimazole or methimazole (CMZ/MMI), propylthiouracil (PTU), or untreated hyperthyroidism in pregnancy. METHODS: We searched Medline, Embase, and the Cochrane database for articles published up till August 2021. We pooled separate crude and adjusted risk estimates using random effects models and subgroup analyses to address heterogeneity. RESULTS: We identified 16 cohort studies comprising 5957, 15,785, and 15,666 exposures to CMZ/MMI, PTU, and untreated hyperthyroidism, respectively. Compared to nondisease controls, adjusted risk ratio (RR) and 95% confidence intervals (95% CIs) for congenital anomalies was increased for CMZ/MMI (RR, 1.28; 95% CI, 1.06-1.54) and PTU (RR, 1.16; 95% CI, 1.08-1.25). Crude risk for CMZ/MMI was increased relative to PTU (RR, 1.20; 95% CI, 1.01-1.43). Increased risk was also seen with exposure to both CMZ/MMI and PTU, that is, women who switched ATDs in pregnancy (RR, 1.51; 95% CI, 1.14-1.99). However, the timing of ATD switch was highly variable and included prepregnancy switches in some studies. The excess number of anomalies per 1000 live births was 17.2 for patients exposed to CMZ/MMI, 9.8, for PTU exposure, and 31.4 for exposure to both CMZ/MMI and PTU. Risk in the untreated group did not differ from control or ATD groups. The untreated group was however highly heterogeneous in terms of thyroid status. Subgroup analysis showed more positive associations in studies with >500 exposures and up to 1-year follow-up. CONCLUSIONS: ATD therapy carries a small risk of congenital anomalies which is higher for CMZ/MMI than for PTU and does not appear to be reduced by switching ATDs in pregnancy. Due to key limitations in the available data, further studies will be required to clarify the risks associated with untreated hyperthyroidism and with switching ATDs in pregnancy.
Asunto(s)
Anomalías Inducidas por Medicamentos , Hipertiroidismo , Complicaciones del Embarazo , Anomalías Inducidas por Medicamentos/tratamiento farmacológico , Anomalías Inducidas por Medicamentos/epidemiología , Anomalías Inducidas por Medicamentos/etiología , Antitiroideos/efectos adversos , Carbimazol/efectos adversos , Femenino , Humanos , Hipertiroidismo/tratamiento farmacológico , Metimazol/efectos adversos , Embarazo , Complicaciones del Embarazo/inducido químicamente , Complicaciones del Embarazo/tratamiento farmacológico , Propiltiouracilo/efectos adversosRESUMEN
OBJECTIVE: To elucidate the role of bone marrow-mesenchymal stem cells (BM-MSCs) on the structure of periodontal tissues in carbimazole (antithyroid drug) treated rats at different durations. DESIGN: 28 albino rats were divided into: Group I: received distilled water. Group II: received therapeutic dose of carbimazole. Group III: received carbimazole then single injection of BM-MSCs by the end of 3rd week. Group IV: received carbimazole and single injection of BM-MSCs at the beginning of the experiment. Specimens were examined by light microscope. New collagen and ß-catenin-immunoreactivity area% were assessed histomorphometrically, and statistically using ANOVA test. RESULTS: Histological examination revealed normal periodontal tissues structure in Groups I & IV. Group II showed disorganized periodontal ligament fibers and different stainability of cementum and alveolar bone. Group III illustrated dense periodontal ligament fibers, normal stainability of cementum and most of alveolar bone. Masson's trichrome results of Groups I & IV illustrated large areas of new collagen in periodontal ligament, old collagen in cementum and intermingled old and new collagen in alveolar bone. Group II showed old collagen. Group III revealed only new collagen. ß-catenin-immunoreactivity was strong in Groups I & IV, negative in Group II and moderate in Group III. Statistically, Group III showed highest mean of new collagen area% followed by Groups I, IV and II respectively. Highest mean of ß-catenin-immunoreactivity area% was for Group I followed by Groups IV, III and II respectively. CONCLUSIONS: Carbimazole has damaging effects and BM-MSCs are capable to mend these destructive outcomes in time dependent manner.
Asunto(s)
Carbimazol/efectos adversos , Células Madre Mesenquimatosas/citología , Periodoncio/citología , Animales , Células de la Médula Ósea , Trasplante de Células Madre Mesenquimatosas , Ligamento Periodontal , RatasRESUMEN
Background: Thionamides have been extensively used to treat patients with hyperthyroidism worldwide. Recent pharmacovigilance studies have revealed a safety signal between carbimazole or methimazole and pancreatitis. The associated risk remains unclear. Methods: We identified patients with newly diagnosed acute pancreatitis from 2000 to 2013 as the case group from the Taiwan Longitudinal Health Insurance Database 2000, which contains data from 1996 to 2013. Each patient with acute pancreatitis was matched for age, sex, comorbidities, and cancer with four controls through propensity score matching. A total of 52 patients without matched controls were excluded. Sensitivity analyses including the 52 excluded patients were performed using a matching ratio of 1:2. Odds ratios (ORs) along with 95% confidence intervals (CIs) for the association were estimated using multivariate logistic regression. Results: We included 9204 and 36,816 patients in the case and control groups, respectively. The proportions of patients who had used thionamides, carbimazole, methimazole, and propylthiouracil were similar in these two groups. In addition, the adjusted OR (CI) for the association of acute pancreatitis with thionamides was 1.03 (0.86-1.24), with carbimazole it was 0.90 (0.63-1.30), with methimazole it was 1.05 (0.84-1.31), and with propylthiouracil it was 1.00 (0.74-1.34). The sensitivity analysis results were unchanged. Conclusions: We were unable to demonstrate an association between acute pancreatitis and usage of thionamides.
Asunto(s)
Pancreatitis/sangre , Pancreatitis/tratamiento farmacológico , Tioamidas/sangre , Adulto , Anciano , Antitiroideos/efectos adversos , Carbimazol/efectos adversos , Estudios de Casos y Controles , Comorbilidad , Bases de Datos Factuales , Femenino , Humanos , Hipertiroidismo/complicaciones , Masculino , Metimazol/efectos adversos , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Farmacovigilancia , Propiltiouracilo/efectos adversos , Estudios Retrospectivos , Riesgo , Taiwán/epidemiología , Tioamidas/efectos adversosRESUMEN
Introduction: The thionamide antithyroid drugs, methimazole (MMI), its pro-drug derivative carbimazole (CMZ), and propylthiouracil (PTU) are the mainstay of treatment for hyperthyroidism in pregnancy. However, antithyroid drugs carry risks of adverse effects that can affect fetal and maternal well-being.Areas covered: This review provides an update on the safety of antithyroid drugs in pregnancy, focusing on the most serious concerns of severe liver disease and congenital anomalies.Expert opinion: PTU-induced liver disease is uncommon but can run a catastrophic course in pregnancy with a risk of liver failure and threats to maternal or fetal survival. Acute pancreatitis is a relatively rare occurrence that has been linked to thionamide use in a handful of reports in non-pregnant individuals. Observational studies on the risk of birth defects with antithyroid drug exposure in pregnancy overall show an increase in birth defect risk with exposure to CMZ/MMI, and to a lesser extent, PTU. Further studies are required to determine whether the currently recommended approach of switching between thionamide drugs in pregnancy improves outcomes. Ultimately, a preventative strategy of offering definitive therapy to hyperthyroid women of childbearing potential offers the best approach to truly reduce the risks of antithyroid drug adverse effects in pregnancy.
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Antitiroideos/efectos adversos , Hipertiroidismo/tratamiento farmacológico , Complicaciones del Embarazo/tratamiento farmacológico , Anomalías Inducidas por Medicamentos/epidemiología , Anomalías Inducidas por Medicamentos/etiología , Antitiroideos/administración & dosificación , Carbimazol/administración & dosificación , Carbimazol/efectos adversos , Femenino , Humanos , Metimazol/administración & dosificación , Metimazol/efectos adversos , Embarazo , Propiltiouracilo/administración & dosificación , Propiltiouracilo/efectos adversosAsunto(s)
Antitiroideos/efectos adversos , Carbimazol/efectos adversos , Displasia Ectodérmica/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Dermatosis del Cuero Cabelludo/inducido químicamente , Dermatosis del Cuero Cabelludo/congénito , Adulto , Femenino , Humanos , Recién Nacido , Embarazo , Complicaciones del Embarazo/tratamiento farmacológicoAsunto(s)
Antitiroideos/efectos adversos , Carbimazol/efectos adversos , Metimazol/efectos adversos , Pancreatitis/inducido químicamente , Enfermedad Aguda , Hipersensibilidad a las Drogas/complicaciones , Femenino , Enfermedad de Graves/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Carbimazol/efectos adversos , Enfermedad de Graves/complicaciones , Propiltiouracilo/efectos adversos , Vasculitis Leucocitoclástica Cutánea/inducido químicamente , Carbimazol/uso terapéutico , Femenino , Enfermedad de Graves/terapia , Humanos , Persona de Mediana Edad , Propiltiouracilo/uso terapéutico , TiroidectomíaAsunto(s)
Agranulocitosis/inducido químicamente , Amiodarona/efectos adversos , Antiarrítmicos/efectos adversos , Antitiroideos/efectos adversos , Fibrilación Atrial/tratamiento farmacológico , Carbimazol/efectos adversos , Infecciones por Escherichia coli/etiología , Choque Séptico/etiología , Tirotoxicosis/inducido químicamente , Tirotoxicosis/tratamiento farmacológico , Resultado Fatal , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéuticoRESUMEN
BACKGROUND: Antithyroid drugs (ATDs) are known to cause various adverse drug reactions (ADRs) that can lead to treatment complexity and unpredictable risks. With the aim of ensuring safer drug use, we assessed whether thyrotropin receptor antibody (TRAb) titers are associated with ATD-induced cutaneous reactions and/or hepatotoxicity, and examined potential genetic predisposition factors. METHODS: We compared TRAb titers of 37 Graves' disease (GD) patients who had experienced carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity with those of 40 normal individuals, or 78 GD patients without the aforementioned ATD-induced ADRs. We performed a genome-wide association study and/or human leukocyte antigen genotyping on GD patients [first stage (chart reviews): 24 cases with ADRs and 423 controls; second stage (actively recruited): 45 cases with ADRs and 137 controls]. RESULTS: For patients with Graves' hyperthyroidism, individuals with higher TRAb titers showed a predisposition to carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity, with an estimated odds ratio of 5.19 (cut-off value: 64%). Potential associations with the rs144542704 and rs61893841 on chromosomes 17 and 11, respectively, warrant further genetic association analysis. CONCLUSION: Our findings support the use of carbimazole/methimazole in patients with low TRAb titers to ensure safer drug use. The identified genetic associations warrant further research.
Asunto(s)
Antitiroideos/efectos adversos , Carbimazol/efectos adversos , Enfermedad de Graves/tratamiento farmacológico , Metimazol/efectos adversos , Adolescente , Adulto , Anciano , Anticuerpos/inmunología , Antitiroideos/administración & dosificación , Carbimazol/administración & dosificación , Estudios de Casos y Controles , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Erupciones por Medicamentos/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Metimazol/administración & dosificación , Persona de Mediana Edad , Receptores de Tirotropina/inmunología , Adulto JovenRESUMEN
We report the case of a 41-year-old woman who presented with a unilateral exudative effusion with prominent eosinophils on pleural cytology. Carbimazole had been started 4 weeks prior to presentation. No immediate cause was identified on imaging or laboratory testing. The effusion persisted at 2-month follow-up. Further investigation at this time, including autoimmune serology was negative. At 2-month follow-up, the effusion was loculated on ultrasound imaging and had a low fluid pH on diagnostic aspiration, in keeping with an empyema. The patient received treatment for pleural empyema, including antibiotics, intercostal drain insertion and video-assisted thoracoscopic pleural biopsy. Carbimazole was stopped, and following treatment for the empyema, the effusion did not reaccumulate.This case illustrates the diagnostic difficulties that pleural effusions may present. It demonstrates that drug reactions should be considered in the differential diagnosis following thorough investigation for other potential causes and also describes the complications that may occur.
Asunto(s)
Carbimazol/efectos adversos , Empiema Pleural/patología , Exudados y Transudados/química , Pleura/patología , Derrame Pleural/inducido químicamente , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Antitiroideos/efectos adversos , Diagnóstico Diferencial , Empiema Pleural/diagnóstico por imagen , Empiema Pleural/tratamiento farmacológico , Empiema Pleural/cirugía , Eosinófilos/citología , Eosinófilos/patología , Exudados y Transudados/citología , Exudados y Transudados/microbiología , Femenino , Humanos , Pleura/citología , Derrame Pleural/diagnóstico por imagen , Derrame Pleural/microbiología , Streptococcus oralis/aislamiento & purificación , Cirugía Torácica Asistida por Video/métodos , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Ultrasonografía/métodosRESUMEN
BACKGROUND: Thyrotoxicosis is both rarer and more severe in children than in adults, rendering management difficult and often unsatisfactory. OBJECTIVE: To ascertain outcome in a geographically defined area of Scotland between 1989 and 2014. METHOD: Retrospective case note review with follow-up questionnaire to family doctors for patients with Graves' disease and Hashimoto's thyroiditis. RESULTS: Sixty-six patients (58 females:8 males) comprising 53 with Graves' disease and 13 with Hashimoto's thyroiditis were diagnosed at median 10.4 (2.9-15.8) years and followed up for 11.8 (2.6-30.2) years. Antithyroid drug (ATD) therapy was stopped electively in 35 patients after 4.5 (1.5-8.6) years, resulting in remission in 10/13 Hashimoto's thyroiditis and 10/22 Graves' disease. Side effects occurred in 12 patients receiving carbimazole, six of whom changed to propylthiouracil; no adverse events occurred in the latter patients.Second-line therapy was given to 37 patients (34 with Graves' disease), comprising radioiodine (22) at 15.6 (9.3-24.4) years for relapse (6), poor control/adherence (14) or electively (2); and surgery (16) at 12 (6.4-21.3) years for relapse (4), poor control/adherence (5) and electively (7). Adherence problems with thyroxine replacement were reported in 10/33 patients in adulthood. CONCLUSIONS: Hashimoto's thyroiditis should be distinguished from Graves' disease at diagnosis since the prognosis for remission is better. Remission rates for Graves' disease are low (10/53 patients), time to remission variable and adherence with both ATD and thyroxine replacement often problematic. We recommend (a) the giving of long-term ATD rather than a fixed course of treatment in GD and (b) meticulous and realistic counselling of families from the time of diagnosis onwards.