Acute Pancreatitis Induced by Methimazole in a Patient with Graves' Disease

Abstract

Background:

Antithyroid drugs such as methimazole (MMI), the mainstay of pharmacologic therapy for Graves' disease, can provoke a variety of adverse effects. MMI-induced acute pancreatitis is very rare, being described in only a few patients and never after more than two exposures as reported here. Here, we report an 18-year-old girl with Graves' disease who developed acute pancreatitis each time she received MMI.

Summary:

The patient was an 18-year-old girl with Graves' disease who took MMI on four occasions. Each time she promptly developed similar features consisting of high fever and left upper quadrant abdominal pain. On three occasions, serum lipase and amylase values were measured. Serum lipase was elevated on all three occasions and serum amylase was elevated once. Features resolved after MMI was stopped. We considered these episodes to be most consistent with pancreatitis, and to be induced by MMI administration.

Conclusion:

MMI-induced acute pancreatitis is rare and easily misdiagnosed. Based on very limited experience, it should resolve after MMI is stopped. The pathogenesis of MMI-induced pancreatitis is not known. Clinicians should be aware of this entity so that MMI is promptly stopped if the features described here develop after MMI is started, and measures are taken to avoid future MMI treatment.

Introduction

M ethimazole (MMI) is currently accepted as the first choice among antithyroid drugs and is the mainstay of pharmacologic therapy for Graves' disease (1). MMI belongs to the imidazole class of antithyroid medications and generally is a reliable method of achieving the euthyroid state in patients with Graves' disease. Unfortunately a wide variety of adverse reactions have been reported during treatment with antithyroid drugs, including MMI. The most frequently reported reactions include pruritus, rubefaction, and fever (2). Uncommon reactions include granulocytopenia, lymphadenitis, arthritis, cholestatic jaundice, MMI-mediated lupus erythematosus, and insulin autoimmune syndrome (3). There have been only a few reports of MMI-induced acute pancreatitis. Taguchi et al. in Japan (4) and Su and Zou in China (5) each reported one case. Here, we describe a patient who developed acute pancreatitis in association with MMI treatment. In her, the unfortunate administration of this drug on four occasions provided perhaps the best documentation that MMI can induce pancreatitis.

Patient

The patient was an 18-year-old female student. Four years previously, in 2007, she developed excessive sweating, palpitations, irritability, and increased stool frequency, and was found to have a goiter by palpation. Her serum free triiodothyronine (fT3) and free thyroxine (fT4) levels were elevated and her serum level thyroid-stimulating hormone (TSH) was low. She was diagnosed as having “hyperthyroid, Graves' disease” and was treated with propylthiouracil (PTU) for almost 3 years. However, she gradually developed exophthalmos, photophobia, and tearing, and her thyroid function did not normalize on PTU treatment.

In 2009, a physician gave her treatment with MMI (20 mg/day). After 4 days of orally taking MMI, she developed a high fever of 39°C with nausea, vomiting, and dull pain in the left upper quadrant abdomen, which was considered as “thyroid crisis” in the local hospital. After withdrawing MMI and giving symptomatic treatment, the patient's condition improved. She started taking PTU after discharge, and there was no similar attack.

She was admitted to our hospital for further evaluation of her thyroid status on February 21, 2011. The levels of serum fT4, fT3, TSH, thyroglobulin antibody, and thyroid peroxidase antibody were 1.61 ng/dL (normal: 0.80–1.70), 5.95 pg/mL (normal: 2.20–4.20), <0.13 mIU/L (normal: 0.35–3.50), 20.3 IU/mL (normal: 0–115), and 94.8 IU/mL (normal: <34 IU/mL), respectively. She had no history of allergic or autoimmune diseases and denied the history of cholelithiasis and hyperlipidemia. On admission, her height was 148 cm and weight was 47 kg. Several hours after she took a 10 mg dose of MMI given by a clinician, she developed a high fever of 39°C with nausea, vomiting, and pain in the left upper quadrant abdomen. Tests revealed elevation of serum lipase with value of 484 U/L (normal: 0–300); serum amylase and urine amylase were normal (see Table 1 for details). There was no abnormity examined by abdominal ultrasonography. The patient's condition improved with fasting, fluid infusion, and antibiotic treatment.

Table 1.

Experimental Parameters During the Course of Four Episodes of Methimazole-Induced Acute Pancreatitis

Index	Unit	Reference range	Second episode of pancreatitis (February 21, 2011)	Third episode of pancreatitis (March 2, 2011)	Fourth episode of pancreatitis (May 17, 2011)
Serum amylase	U/L	0–140	48	193	117
Serum lipase	U/L	0–300	484	1449	450
Urine amylase	U/L	62–640	278	489	897
Total bilirubin	μM	3.4–20.5	12.2	24	54
Direct bilirubin	μM	0–6.8	4.2	5.5	0.3
Alanine aminotransferase	U/L	13–69	8	13	43
Aspartate aminotransferase	U/L	15–46	13	10	30
White blood cells	×10⁹ cells/L	3.7–9.2	6.99	12.52	17.12
Percentage of neutrophils	%	60–80	56.4	85.7	85.7

After treatment, above abnormal test results returned to normal.

On March 2, 2011, the patient self-medicated herself with a 10 mg dose of MMI. Unfortunately, she once again developed a fever of 37.7°C with nausea as well as left epigastric pain with intensified paroxysms, radiating to the back. Upon physical examination, there was tenderness in the left upper quadrant abdomen without rebound pain or muscular tension, and Murphy's sign was negative. Experimental tests revealed elevation of serum amylase and serum lipase, with values of 193 U/L (normal: 0–140) and 1449 U/L (normal: 0–300), respectively (see Table 1 for details). Ultrasonographic examination and computed tomography scanning revealed no abnormalities in the pancreas. The professors considered that this was a rare case of acute pancreatitis induced by MMI. Therefore, she was placed on a regimen of no intake by mouth and given gastrointestinal decompression, antispasmodic atropine, as well as inhibitory stomach acid treatment. After this, symptoms disappeared and the levels of serum enzyme returned to normal. Further studies revealed a high thyroid radioiodine uptake of 99.4% at 24 hours. Ultrasonic examination revealed that the thyroid gland was moderately enlarged and she was considered to have a diffuse toxic goiter. Therefore, she was treated with 8 mCi ¹³¹I radiotherapy. Her exophthalmos and goiter were relieved. After discharge, her thyroid function was not completely normal, so she took PTU again.

On May 17, 2011, a nonendocrine outpatient clinician gave her a prescription of MMI 10 mg, two times daily, during follow-up. After taking MMI for the second time, a high fever of 39.2°C with nausea, vomiting, diarrhea, and pain in the left upper quadrant abdomen developed. Biochemically, the levels of serum lipase and urine amylase were 450 U/L (normal: 0–300) and 897 U/L (normal: 62–640), respectively (see Table 1 for details). After stopping MMI and giving symptomatic treatment, the amylase isozyme returned to normal.

Discussion

MMI usually induces hypersensitivity reactions. In contrast, MMI-induced acute pancreatitis is very rare. In 1999 Taguchi et al. (4) reported a patient with Graves' disease who developed acute pancreatitis and parotitis 3 weeks after the start of MMI treatment and in whom the symptoms resolved after MMI was stopped. Because there was no report of MMI-induced acute pancreatitis/parotitis in the literature at that time, they restarted MMI and the symptoms recurred. Therefore the patient was considered to have MMI-induced acute pancreatitis. Su and Zou from China (5) also reported a patient with hyperthyroidism who was treated with MMI. They thought that MMI induced the type V hyperlipidemia and this led to acute pancreatitis. They tried to exclude other causes of pancreatitis, including cholelithiasis.

Based on her history and clinical features we diagnosed our patient as having thyrotoxicosis and multiple episodes of MMI-induced acute pancreatitis. After taking MMI, she consistently developed high fever and abdominal pain along with elevations of amylase and/or lipase. With symptomatic treatment, including withdrawing MMI, the condition improved but it reoccurred when she again took MMI. These features were consistent with diagnostic criteria for drug-induced acute pancreatitis (6).

The mechanism of MMI-induced acute pancreatitis is unclear. Direct toxic effects, hypersensitivity reactions, and an autoimmune reaction have all been considered (4,7,8) but definitive conclusions cannot be made at this time.

Conclusion

Acute pancreatitis is a rare and severe adverse reaction induced by MMI, apparently in individuals who are susceptible for no clear reasons. It occurs abruptly shortly after MMI is started and progresses rapidly. As our patient and at least one other report in the literature (4) illustrates, there needs to be better recognition of this entity so that MMI is promptly stopped in susceptible patients who develop this reaction and measures are taken to avoid future exposure to MMI. These measures should include appropriate alerts in the medical record and thorough counseling of the patient, including providing the patient with the trade and generic names of MMI and closely related drugs such as carbimazole.

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist.

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