Abstract
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.
Keywords: thionamides, carbimazole, methimazole, propylthiouracil, pancreatitis, hyperthyroidism
Introduction
Thionamides have been used to treat patients with hyperthyroidism for many years. On January 4, 2019, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency published a recommendation regarding the safety signals of carbimazole and methimazole (1). The committee recommended that carbimazole or methimazole should be discontinued immediately if patients develop acute pancreatitis during treatment, and that for patients with a history of acute pancreatitis, clinicians should avoid re-exposing patients to carbimazole or methimazole after a previous administration of one of these drugs. The Medicines and Health care Products Regulatory Agency of the United Kingdom followed these recommendations and published the same safety signal on February 18, 2019 (2). However, the associated risk remains clinically unclear.
The aim of this retrospective case–control study was to evaluate the associations of thionamides in general and carbimazole, methimazole, and propylthiouracil in particular with acute pancreatitis using Taiwan's Longitudinal Health Insurance Database 2000 (LHID2000). This study was approved by the Research Ethics Committee of China Medical University and Hospital (CMUH-104-REC2-115-R3).
Methods
Study population
The LHID2000 contains all claims data for 1 million insured subjects from 1996 to 2013, who were randomly selected from Taiwan's National Health Insurance Research Database. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes are used to define disease diagnoses from outpatient and inpatient data in the LHID2000. The ICD-9-CM codes used in this study are presented in Supplementary Table S1.
We identified patients with new diagnoses of acute pancreatitis—defined as ≥2 outpatient visit diagnoses or ≥1 diagnosis during hospitalization or an emergency visit—as the case group. The exclusion criteria included the following: index date not within the study period (2000–2013), age younger than 20 years, age older than 100 years, and missing sex or age data. The diagnosis date was defined as the index date. We used the same exclusion criteria to identify patients without a history of acute pancreatitis as the control group; these controls were matched for age, sex, comorbidities (including alcoholic liver disease, gallbladder stone, hyperlipidemia, and type 2 diabetes mellitus), and cancer with the case group through propensity score matching at a ratio of 1:4. A total of 52 patients without matched controls were excluded. Sensitivity analyses including the 52 excluded patients were performed at a matching ratio of 1:2 to clarify the effect of excluding the 52 unmatched patients on the association. The status of antithyroid drug use was categorized as never use and ever use.
Statistical analyses
Chi-square tests were used to compare categorical variables. Odds ratios (ORs) along with 95% confidence intervals (CIs) for the association were estimated using multivariate logistic regression. The ORs were adjusted for age, sex, alcoholic liver disease, gallbladder stone, and cancer. All statistical analyses were performed using STATA/SE version 14.0 (STATA Corp., College Station, TX). Results with a two-sided p-value of <0.05 were considered significant.
Results
As shown in Figure 1, from the total of 1 million patients in the LHID2000, 10,963 patients with newly diagnosed acute pancreatitis were included in the case group. We excluded 1536 patients for whom the date of diagnosis was not within the study period; 171 patients without sex or age data, aged <20 years, or aged >100 years; and 52 patients without matched controls (including 3 patients who had been prescribed thionamides). Finally, a total of 9204 patients were included in the case group. For the control group, we identified 989,037 patients without a history of acute pancreatitis. From these patients, 234,744 were excluded using the same exclusion criteria as the case group. Finally, the control group comprised 36,816 patients who were matched with the case group for age, sex, index year, and comorbidities at a ratio of 1:4.
FIG. 1.
Flowchart of included patients. LHID, Longitudinal Health Insurance Database.
As presented in Table 1, the proportions of patients who had ever used thionamides (1.59% vs. 1.58%), carbimazole (0.39% vs. 0.44%), methimazole (1.10% vs. 1.07%), and propylthiouracil (0.61% vs. 0.61%) were similar in the case and control groups. Patients with acute pancreatitis were younger than those without acute pancreatitis. The proportion of patients with alcoholic liver disease was higher in the case group than in the control group; however, the proportions of patients with gallbladder stone and cancer were lower in the case group than in the control group.
Table 1.
Characteristics of Patients
| Acute pancreatitis |
p | ||
|---|---|---|---|
| Yes (case) (n = 9204), n (%) | No (control) (n = 36,816), n (%) | ||
| Thionamides | 0.970 | ||
| Never | 9058 (98.41) | 36,234 (98.42) | |
| Ever | 146 (1.59) | 582 (1.58) | |
| Carbimazole | 0.539 | ||
| Never | 9168 (99.61) | 36,655 (99.56) | |
| Ever | 36 (0.39) | 161 (0.44) | |
| Methimazole | 0.822 | ||
| Never | 9103 (98.90) | 36,422 (98.93) | |
| Ever | 101 (1.10) | 394 (1.07) | |
| Propylthiouracil | 0.976 | ||
| Never | 9148 (99.39) | 36,591 (99.39) | |
| Ever | 56 (0.61) | 225 (0.61) | |
| Sex | 0.744 | ||
| Women | 3516 (38.20) | 14,132 (38.39) | |
| Men | 5688 (61.80) | 22,684 (61.61) | |
| Age | <0.001 | ||
| <40 | 2382 (25.88) | 7639 (20.75) | |
| 40–65 | 4066 (44.18) | 16,999 (46.17) | |
| ≥65 | 2756 (29.94) | 12,178 (33.08) | |
| Comorbidity | |||
| Alcoholic liver disease | <0.001 | ||
| Without | 8198 (89.07) | 33,612 (91.30) | |
| With | 1006 (10.93) | 3204 (8.70) | |
| Gallbladder stone | <0.001 | ||
| Without | 6768 (73.53) | 26,252 (71.31) | |
| With | 2436 (26.47) | 10,564 (28.69) | |
| Hyperlipidemia | 0.904 | ||
| Without | 6288 (68.32) | 25,128 (68.25) | |
| With | 2916 (31.68) | 11,688 (31.75) | |
| Type 2 diabetes mellitus | 0.256 | ||
| Without | 6878 (74.73) | 27,723 (75.30) | |
| With | 2326 (25.27) | 9093 (24.70) | |
| Cancer | <0.001 | ||
| Without | 8671 (94.21) | 34,310 (93.19) | |
| With | 533 (5.79) | 2506 (6.81) | |
As indicated in Table 2, the adjusted OR (CI) for acute pancreatitis was 1.03 (0.86–1.24) for thionamides, 0.90 (0.63–1.30) for carbimazole, 1.05 (0.84–1.31) for methimazole, and 1.00 (0.74–1.34) for propylthiouracil. Sensitivity analyses conducted using a matching ratio of 1:2 (9256 patients vs. 18,512 patients; Supplementary Table S2) revealed that the risks of acute pancreatitis remained unchanged in users of all thionamides (1.10 [CI: 0.90–1.35]), carbimazole users (1.00 [CI: 0.67–1.49]), methimazole users (1.08 [CI: 0.85–1.37]), and propylthiouracil users (1.16 [CI: 0.83–1.61]; Supplementary Table S3).
Table 2.
Association Between Antithyroid Drugs and Acute Pancreatitis
| Thionamides |
Carbimazole |
Methimazole |
Propylthiouracil |
|||||
|---|---|---|---|---|---|---|---|---|
| Adjusted OR (CI) | p | Adjusted OR (CI) | p | Adjusted OR (CI) | p | Adjusted OR (CI) | p | |
| Drug | ||||||||
| Never | Ref. | Ref. | Ref. | Ref. | ||||
| Ever | 1.03 (0.86–1.24) | 0.751 | 0.90 (0.63–1.30) | 0.581 | 1.05 (0.84–1.31) | 0.655 | 1.00 (0.74–1.34) | 0.994 |
| Sex | ||||||||
| Women | Ref. | Ref. | Ref. | Ref. | ||||
| Men | 0.96 (0.91–1.01) | 0.098 | 0.96 (0.91–1.01) | 0.089 | 0.96 (0.91–1.01) | 0.097 | 0.96 (0.91–1.01) | 0.094 |
| Age (years) | ||||||||
| <40 | Ref. | Ref. | Ref. | Ref. | ||||
| 40–65 | 0.76 (0.72–0.81) | <0.001 | 0.76 (0.72–0.81) | <0.001 | 0.76 (0.72–0.81) | <0.001 | 0.76 (0.72–0.81) | <0.001 |
| ≥65 | 0.75 (0.70–0.80) | <0.001 | 0.75 (0.70–0.80) | <0.001 | 0.75 (0.70–0.80) | <0.001 | 0.75 (0.70–0.80) | <0.001 |
| Comorbidity | ||||||||
| Alcoholic liver disease | ||||||||
| Without | Ref. | Ref. | Ref. | Ref. | ||||
| With | 1.31 (1.21–1.41) | <0.001 | 1.31 (1.21–1.41) | <0.001 | 1.31 (1.21–1.41) | <0.001 | 1.31 (1.21–1.41) | <0.001 |
| Gallbladder stone | ||||||||
| Without | Ref. | Ref. | Ref. | Ref. | ||||
| With | 0.96 (0.91–1.02) | 0.195 | 0.97 (0.91–1.02) | 0.198 | 0.96 (0.91–1.02) | 0.195 | 0.96 (0.91–1.02) | 0.197 |
| Cancer | ||||||||
| Without | Ref. | Ref. | Ref. | Ref. | ||||
| With | 0.89 (0.81–0.99) | 0.026 | 0.89 (0.81–0.99) | 0.026 | 0.89 (0.81–0.99) | 0.026 | 0.89 (0.81–0.99) | 0.026 |
Adjusted for age, sex, alcoholic liver disease, gallbladder stone, and cancer.
CI, 95% confidence interval; OR, odds ratio.
Discussion
This study demonstrates no significant association between usage of thionamides (methimazole, carbimazole, and propylthiouracil) and the development of acute pancreatitis. However, previous studies have reported that acute pancreatitis was associated with methimazole or carbimazole use in nine patients (3–11). Propylthiouracil is the only thionamide without a case report, suggesting an association with the development of acute pancreatitis. As presented in Table 3, the onset of acute pancreatitis symptoms after methimazole or carbimazole exposure varied from 4 to 90 days. All symptoms and laboratory abnormalities resolved after the drug were withdrawn. The recurrent rate of acute pancreatitis after thionamide withdrawal was unknown. However, acute pancreatitis recurred in five of the five patients (four methimazole users and one carbimazole user) who were rechallenged with the original thionamide (3,4,8–10). The interval between rechallenge and the recurrence of acute pancreatitis ranged from 3 hours to 5 days. However, none of the authors mentioned whether these five patients ever experienced acute pancreatitis previously, before ever being exposed to thionamides, or ultimately developed chronic pancreatitis (Supplementary Table S4). Some case reports did not exclude viral infections (8,10) or autoimmune disease (3,8,10) as a potential etiology of acute pancreatitis. Potassium iodide (one patient), propylthiouracil (two patients), and radioactive iodine (four patients) were administrated for the management of hyperthyroidism after acute pancreatitis resolved.
Table 3.
Case Reports of Methimazole- or Carbimazole-Induced Acute Pancreatitis
| Authors | Reporting year | Ethnicity | Age | Sex | Diagnosis | Time of symptom onset | Drug | Dose (mg) | Management |
|---|---|---|---|---|---|---|---|---|---|
| Taguchi et al. (3) | 1999 | Japanese | 66 | W | Graves' disease | 21 days 3 hours after 2nd dose |
MMI | 30 10a |
PTU |
| Marazuela et al. (4) | 2002 | Spanish | 33 | W | Graves' disease | 30 days 1 day |
Carbimazole | 45 10a |
RAI |
| Su et al. (5) | 2008 | Chinese | 19 | W | Graves' disease | 75 days | MMI | 10 | RAI |
| Chng et al. (6) | 2011 | Asian | 70 | W | Graves' disease | 14 days | Carbimazole | 30 | RAI |
| Abraham et al. (7) | 2012 | Caucasian | 80 | W | Unspecified | 90 days | MMI | 10 | Unspecified |
| Yang et al. (8) | 2012 | Chinese | 18 | W | Graves' disease | 4 days Within 1 day |
MMI | 20 10b 10b 10b |
PTU |
| Jung et al. (9) | 2014 | Korean | 51 | M | Graves' disease | 14 days 5 hours | MMI | 20 10a |
Unspecified |
| Agito et al. (10) | 2015 | Caucasian | 51 | W | Toxic MNG | 21 days 5 days |
MMI | 10 10a |
RAI |
| Kikuchi et al. (11) | 2018 | Japanese | 76 | W | Graves' disease | 19 days | MMI | 10 | Potassium iodide |
There is no report of recurrent rate of acute pancreatitis in patients who were not re-exposed to thionamides.
Rechallenged.
Rechallenged three times at different times by three physicians.
M, men; MMI, methimazole; MNG, multinodular goiter; PTU, propylthiouracil; RAI, radioactive iodine; W, women.
The results of the present study are consistent with those of a previous study that reported no association between methimazole and the development of acute pancreatitis (12). Moreover, an animal study revealed that methimazole reduced the severity of cerulean-induced acute pancreatitis in rats (13). An additional study reported that propylthiouracil attenuated pancreatic activity to reduce the mortality rate of hemorrhagic pancreatitis in dogs (14).
The strengths of this study include its large real-world sample, which compensates for the absence of a randomized-controlled study. Nevertheless, despite this strength, some limitations should be acknowledged. First, the exclusion of 52 unmatched patients may have compromised the results; however, sensitivity analyses reinforced the findings. Second, a causal relationship cannot be determined using insurance claims data. Third, although the case and control groups were matched for age, sex, and some comorbidities, potentially important confounders may have been unavailable for adjustment.
In conclusion, we were unable to demonstrate an association between the development of acute pancreatitis and use of thionamides.
Supplementary Material
Authors' Contributions
C.C.C., J.Y.G., and C.L.C. designed the study and analyzed and interpreted the data. C.C.C., J.Y.G., and C.L.C. drafted the article, and C.C.C. critically revised the article. C.C.C. approved the article, is the guarantor of this work, and takes responsibility for the integrity of the data and the accuracy of the analyses.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
This work was supported by grants from the Ministry of Health and Welfare, Taiwan (MOHW108-TDU-B-212-133004), China Medical University Hospital, Academia Sinica Stroke Biosignature Project (BM10701010021), MOST Clinical Trial Consortium for Stroke (MOST 107-2321-B-039-004-), Tseng-Lien Lin Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan.
Supplementary Material
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