Summary

Carbimazole is commonly used in the treatment of hyperthyroidism. We report a possible adverse reaction from carbimazole treatment which resulted in a Chinese patient developing muscle cramps and reversible increase in creatine kinase levels after carbimazole treatment for thyrotoxicosis. We also discuss the different types of muscle disorders in thyroid disease and illustrate the clinical clues in differentiating between these clinical entities.

摘要

甲元平常用於治療甲狀腺功能亢進。本文報告一種可能由它引起的不良反應：一名患有甲狀腺毒症的華裔病人，在服用甲元平後出現肌肉痙攣和可逆的血清肌酸激水平升高。我們亦討論甲腺疾病中的各類肌肉障礙，及闡明臨床上用於區分不同問題的線索。

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Introduction

Hyperthyroidism is a common condition. A good knowledge base in the pharmacological action, mechanisms and untoward effects of the anti-thyroid medications is essential in achieving a safe and successful treatment outcome. Reported side effects of carbimazole include nausea, gastrointestinal disturbances, rash, pruritus, arthralgia and rarely alopecia, hepatitis, SLE-like syndrome and agranulocytosis. We report a local Chinese subject who developed intermittent muscle cramps associated with increased serum concentration of creatine kinase following treatment with carbimazole. The clinical presentation was suggestive of the rare complication of carbimazole-related myositis.

A case report

A 46-year old housewife with good past health presented in April 2004 with neck swelling, hand tremor, palpitation and heat intolerance for 2-3 months. There was no significant change in her body weight. She did not complain of any muscle pain or weakness, or any problem with her vision. There was no family history of thyroid disorder or autoimmune disease. There was no relevant drug history. Clinical examination revealed a medium-built lady with good general condition, and a small non-tender non-obstructive goiter. There was no thyroid bruit. Her blood pressure was 124/80 mmHg, with a regular pulse of 112/min. Bilateral hand tremor and sweaty palms were prominent. Eye movements were normal. There was no lid retraction or exophthalmos. Pemburton"s sign (venous distention over the neck and difficult breathing caused by large retrosternal goiter, especially when the arms are raised) was negative. She did not have any pretibial swelling. Examination of cardiovascular, respiratory, abdominal, and neurological systems did not show abnormal findings. Muscle power was full and the tendon reflexes were normal. Blood investigations showed elevated free thyroxine (fT₄) 32.7 pmol/L (normal range 9.0-19.1) and suppressed sensitive thyroid stimulating hormone (sTSH) <0.01 mIU/L (normal range 0.35-4.94). The titre of antimicrosomal antibodies was 400 (normal <100). Other autoimmune markers including antithyroglobulin antibodies, rheumatoid factor, and antinuclear antibody were negative.

She was commenced on carbimazole 40 mg daily. The clinical response was satisfactory, and the treatment was well tolerated. Her thyrotoxic symptoms subsided readily. Dosage of treatment was titrated downwards in accordance with stabilization of the thyroid function. At about one month after starting treatment, (i.e., on 3^rd of June 2004), her thyroid function further improved with reduced level of fT₄ to 26.6 pmol/L. However, she began to complain of intermittent muscle cramps predominantly affecting the proximal muscles around both sides of the shoulder and thigh regions. The cramping pain became progressive and did not respond to topical analgesics. It was not associated with weakness or sensory disturbances. Skin and joint complaints were absent, and she was not taking any medications or herbs other than the prescribed carbimazole at a dosage of 20mg/day. There was no headache, visual disturbances or other constitutional symptoms. Musculoskeletal and neurological examinations revealed normal findings and in particular, there was no muscle wasting. On 7^th of September 2004, her muscle cramps persisted. At this point, she was taking carbimazole 10mg/day and blood tests revealed normal fT₄ of 12.7 pmol/L, normal complete blood picture, normal kidney function and levels of serum electrolytes including levels of sodium, potassium, calcium and phosphate. On 24^th of September 2004, the circulating level of creatine kinase was found to be elevated at 1027 U/L (normal <165). In view of this, carbimazole was stopped and substituted with propylthiouracil at equivalent dosage. Within one week after the changing of drug, her muscle cramps subsided completely. The level of creatine kinase also gradually returned to the normal value of 120 U/L by 25^th of January 2005. Afterwards the patient remained well and free of muscle symptoms throughout and after the whole course of anti-thyroid therapy. Table 1 below shows the temporal relationship between muscle cramp, thyroid function and the dosage of anti-thyroid drugs for the patient.

Discussion

Muscle disorder in thyroid diseases can present as thyrotoxic proximal myopathy, hypokalaemic periodic paralysis, myopathy associated with hypothyroidism, or polymyositis associated with Graves" disease. In addition, a few cases of myopathy and/or myositis related to antithyroid drugs have been reported previously.^1-3 The clinical presentation of our index patient was rather different from that of the first four clinical entities. In thyrotoxic proximal myopathy, the patient develops painless proximal muscle weakness and wasting, and the condition resolves after normalization of the thyroid function. The concentration of creatine kinase is normal or on the low side. Hypokalaemic periodic paralysis has a predilection for thyrotoxic Asian males. It is associated with a low potassium concentration and a normal creatine kinase level. Myopathy in hypothyroidism is painful with increased muscle mass and raised creatine kinase. Graves" disease-related polymyositis is an uncommon condition. Diagnostic cues include a positive family history of autoimmune disease, and the presence of antinuclear antibodies and inflammatory changes on muscle biopsy.

For our patient, she developed intermittent muscle cramps after receiving 4 weeks of carbimazole treatment at a dosage of 30-40mg/day. The symptom was not associated with muscle wasting or weakness, and it continued even after persistent normalization of the thyroid function. Serum electrolytes, in particular the potassium level, were also normal. Antinuclear antibody, rheumatoid factor and anti-thyroglobulin antibody were absent and there was no history of autoimmune diseases in her family. At this point of analysis, it was possible that carbimazole treatment itself was the culprit of the whole clinical presentation. Most important of all, both the clinical and biochemical abnormalities resolved readily after carbimazole was withdrawn and changed to propylthiouracil, and since then the patient had remained free of symptoms throughout and after the whole course of anti-thyroid treatments. This temporal relationship supported the diagnosis of possible adverse drug reaction related to the use of carbimazole, causing drug-related myositis. In this context, it is pertinent to note that creatinine kinase level is normal in the "antithyroid arthritis syndrome",⁴ which comprises myalgia, arthralgia, pruritus, rash and fever.

As with most anecdotal reports of myositis associated with antithyroid drugs in Japanese or Caucasian subjects,^1-3 our case of carbimazole-induced myositis was proposed mainly on clinical grounds and lacked concrete support from histological or electromyographic evidence. In those previous reports, this complication was also diagnosed on clinical grounds, except in one patient in whom muscle biopsy was performed and revealed muscle microvasculitis. Comparing our patient with those in other case series, their clinical features were similar. All the affected patients were females in the 20 to 40 age group. The painful muscle cramps occurred within several weeks of starting carbimazole treatment at a dosage of 30mg daily, and proximal muscles were primarily affected. The concentration of creatine kinase was raised in all cases, to levels from a few hundred to up to 1000 U/L. All the patients responded to a replacement of carbimazole with propylthiouracil, with resolution of symptoms within days to weeks and normalization of creatine kinase level after 2 to 3 months.

We are not clear about the underlying mechanism for this possible phenomenon of carbimazole-induced myositis. In fact, both carbimazole and propylthiouracil are thionamides which act through similar pathway to inhibit the function of thyroid peroxidases and reduce thyroid antibody levels to enhance rates of remission. The reason why more often carbimazole but not propylthiouracil was associated with this complication in previous reports is unknown. It is possible that this distinct clinical entity has been overlooked over the years. As a matter of fact, there was once a single case report suggesting the development of polymyositis after propylthiouracil treatment for hyperthyroidism.⁵ But it was uncertain whether this represented a cause-effect association or a chance occurrence. Nonetheless, physicians should be vigilant to this rare adverse drug reaction when managing thyrotoxic patients with muscle symptoms. In the case of an anti-thyroid drug causing the muscle symptom, the patient usually responded readily to the timely removal of the culprit agent.

Conclusion

Our patient may have illustrated the rare occurrence of carbimazole-related myopathy/myositis. It is important to be alert to this complication, since it responds readily to discontinuation of carbimazole.

Key messages

1. Carbimazole-related myositis is a rare clinical condition occurring in both Caucasians and Asians.
2. The muscle symptoms usually occur within a few weeks of starting carbimazole. They are not dose-related and may persist unless the culprit agent has been removed from body.
3. Physicians should be vigilant to this rare adverse drug reaction when managing thyrotoxic patients with muscle symptoms.

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References