Carbimazole-induced atypia - A mimicker of malignancy in fine-needle aspiration cytology.

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.

Severe Neutropenia and Hepatotoxicity After Carbimazole Drug Therapy for Hyperthyroidism in a Pediatric Patient: A Case Report.

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.

Acute pancreatitis caused by methimazole/carbimazole assumption: a case-series.

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.

Antithyroid drug therapy in pregnancy and risk of congenital anomalies: Systematic review and meta-analysis.

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.

Histological, Histochemical and Immunohistochemical Evaluation of the Role of Bone Marrow-Derived Mesenchymal Stem Cells on the Structure of Periodontal Tissues in Carbimazole-Treated Albino Rats.

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.

Association Between Thionamides and Acute Pancreatitis: A Case-Control Study.

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.

Safety of antithyroid drugs in pregnancy: update and therapy implications.

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.

Thyrotropin receptor antibodies and a genetic hint in antithyroid drug-induced adverse drug reactions.

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.

Carbimazole-induced eosinophilic pleural effusion.

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.

Long-term outcome of thyrotoxicosis in childhood and adolescence in the west of Scotland: the case for long-term antithyroid treatment and the importance of initial counselling.

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.

Graves' disease in a 3 year-old patient with agranulocytosis due to anti-thyroid drugs: Radioiodine ablation therapy as an effective alternative. / Enfermedad de Graves en un paciente de 3 años con agranulocitosis asociada a fármacos antitiroideos: terapia ablativa con radioyodo como una alternativa eficaz.

The case is presented of a 3 year-old girl with mitochondrial disease (subacute necrotizing encephalomyelopathy of Leigh syndrome), v-stage chronic kidney disease of a diffuse mesangial sclerosis, as well as developmental disorders, and diagnosed with hyperthyroidism Graves-Basedow disease. Six weeks after starting the treatment with neo-carbimazole, the patient reported a serious case of agranulocytosis. This led to stopping the anti-thyroid drugs, and was treated successfully with 131I ablation therapy. The relevance of the article is that Graves' disease is uncommon in the paediatric age range (especially in children younger than 6 years old), and developing complications due to a possible late diagnosis. Agranulocytosis as a potentially serious adverse effect following the use of anti-thyroid drugs, and the few reported cases of ablation therapy with 131I at this age, makes this case unique.