Transient thyrotoxicosis from thyroiditis induced by sibutramine overdose

Abstract

Sibutramine is an antiobesity drug that inhibits the reuptake of serotonin and noradrenalin in the hypothalamus. A 37-year-old Korean man presented to the emergency room for the oral intake of 280 mg of sibutramine. The patient was in thyrotoxic state. The ^99mTechnetium-pertechnetate thyroid scan showed irregular uptake of radioisotope and thyroid-stimulating hormone receptor antibody and thyroperoxidase antibody were negative. Thyroid function normalized after that. The patient had transient thyrotoxicosis with thyroiditis. We report a case of thyrotoxicosis accompanied by thyroiditis resulting from the intentional overdose of sibutramine.

Introduction

Sibutramine is an antiobesity drug that inhibits the reuptake of serotonin and noradrenalin in the hypothalamus, leading to loss of appetite, early satiety and eventual weight loss. Sibutramine was widely used after approval by the US Food and Drug Administration (FDA) in 1997. However, Sibutramine Cardiovascular Outcomes Trial (SCOUT) revealed that the drug increased cardiovascular risk. ¹ The FDA’s postmarketing surveillance identified some adverse effects of sibutramine in the endocrine system such as goiter, hyperthyroidism and hypothyroidism. ² However, a prospective clinical trial to demonstrate that sibutramine use increases the incidence of thyroid diseases has not been conducted. Sibutramine use was withdrawn in the market in the United States and many other countries in 2010. However, some herbal weight-loss products, which can be purchased over the Internet, contain undeclared concentration of sibutramine. Several cases of sibutramine intoxication from herbal medications are reported. ³ Thus, possible adverse drug reaction of sibutramine deserves more attention.

In this report, we describe a case of thyrotoxicosis with thyroiditis caused by intake of high-dose sibutramine in a 37-year-old male with no history of thyroid disease.

Case report

A 37-year-old Korean man presented to the emergency room with drooling of saliva and perspiration after intentional overdose of sibutramine. Upon arrival, his vital signs were as follows: blood pressure, 170/90 mmHg; heart rate, 120 beats per minute; respiratory rate, 24 times per minute; body temperature, 36.4°C; and his level of consciousness was delirious. Neither exophthalmos nor goiter was noted on head and neck examination. There was no tenderness on the thyroid. The results of blood test were as follows: white blood cell count, 23,260 mm⁻³; hemoglobin, 15.0 g dL⁻¹; hematocrit, 45.0%; platelet count, 372,000 mm⁻³. The results of biochemical test were as follows: glucose, 186 mg dL⁻¹; blood urea nitrogen, 11.7 mg dL⁻¹; creatinine, 1.64 mg dL⁻¹; sodium, 117.5 mmol L⁻¹; potassium, 3.3 mmol L⁻¹; chloride, 74.4 mmol L⁻¹; aspartate transaminase, 72 IU L⁻¹; alanine transaminase, 12 IU L⁻¹; total protein, 7.6 g dL⁻¹, albumin, 4.7 g dL⁻¹; total bilirubin, 1.39 mg dL⁻¹. The patient had generalized tonic clonic seizure with drooling of saliva for 30 s following arrival to the emergency room, which was controlled with intravenous administration of diazepam 10 mg. The seizure did not recur thereafter. Electrocardiogram showed sinus tachycardia and corrected QT interval of 0.388s, which is within normal limits.

The thyroid function test (TFT) showed thyroid-stimulating hormone (TSH) of 0.21 mIU L⁻¹ (0.27–4.20), free T4 of 7.15 ng dL⁻¹ (0.93–1.70) and total T3 of 651 ng dL⁻¹ (80–200). The patient was in the state of thyrotoxicosis. TSH-receptor antibody and antithyroid peroxidase (anti-TPO) antibody were with in normal limits of 0.3 IU L⁻¹ (0–1.5) and 9.3 IU mL⁻¹ (0–34), respectively. ^99mTechnetium-pertechnetate thyroid scan on the 10th day of hospitalization displayed 3.8% (1.7–4.0) uptake of radioisotope and slightly enlarged bilateral lobes of the thyroid with heterogeneous uptake of radioisotope, which were consistent with thyroiditis (Figure 1). No abnormality was noted on the ultrasonography of the thyroid, either. Thyrotoxicosis caused by destructive thyroiditis following the ingestion of overdose sibutramine was presumed. He had no history of thyroid disease. His TFT results at the health examination center 2 years before this event were within normal limits. There was no medication that he took on a regular basis.

Figure 1.

^99mTechnetium-pertechnetate thyroid scan of the patient on 10th day after sibutramine intoxication. The thyroid is diffusely enlarged in mild degree with heterogeneous uptake pattern. The uptake ratio is 3.8% (normal range: 1.7–4.0%).

Three weeks after the intoxication of sibutramine, the state of thyrotoxicosis was improved, in which TSH was 0.32 mIU L⁻¹, free T4 was 1.12 ng dL⁻¹ and total T3 was 120 ng dL⁻¹.

Discussion and conclusion

The recommended daily dose of sibutramine is 10 or 15 mg. The patient ingested 280 mg at a single time, equivalent to the cumulative dosage of a month, which probably caused thyroiditis. Drug-induced thyroiditis by sibutramine has never been reported before. However, the total dosage of the drug taken at a single time was 20–30 times higher than the recommended daily dose, it is assumed that unknown adverse effects of the drug were developed.

In thyrotoxic state without thyroidal tenderness, Graves’ disease and thyrotoxic state by painless thyroiditis should be differentiated. We are able to exclude Graves’ disease in that exophthalmos or goiter was not detected on physical examinations, thyroid autoantibodies were all negative and thyroid function spontaneously normalized without any antithyroid medications. Moreover, Graves’ disease shows enlargement of both lobes and considerably increased uptake of radioisotope with high free T4 level. We could exclude Graves’ disease by thyroid scan, which was consistent with thyroiditis.

The possibility that sibutramine was ingested coincidentally during the period of painless thyroiditis-induced thyrotoxicosis is considerably low because the prevalence of painless thyroiditis is low in young males and anti-TPO antibody was negative in the patient. ⁴ The patient is estimated to have developed temporary thyrotoxicosis caused by drug-induced thyroiditis based on the facts that he developed thyrotoxicosis 12 h after sibutramine intoxication, showing temporal causality, and his TFT was normal 2 years before the event with no medical history of thyroid disease.

Saleh and Bisher ⁵ administered sibutramine 7 mg kg⁻¹ for 6 weeks to Wistar mice and assessed thyroid function. Total T3 was increased from 1.21 ± 0.08 ng mL⁻¹ to 1.78 ± 0.025 ng mL⁻¹ (p ≤ 0.05) and total T4 was decreased from 5.20 ± 1.44 μg dL⁻¹ to 1.98 ± 0.062 μg dL⁻¹ (p ≤ 0.01) after treatment of sibutramine. Sibutramine produced contrary results on the thyroid, increasing total T3 and decreasing total T4, which implies its potential effects on thyroid function. Sibutramine is degraded into six active demethylation metabolites by cytochrome P450 2B6. ^6,7 It is presumed that rapid increase in sibutramine concentration in blood results in rapid accumulation of sibutramine or its metabolites, which causes secretion of thyroid hormones into the circulation eventually causing thyrotoxicosis. However, it has not proved that these substances have direct toxicity on the thyroid yet.

Sibutramine increases the levels of serotonin and noradrenaline, and we should be careful for its side effects such as palpitation, constipation, headache, dizziness, insomnia, neurosis and anxiety. The increase in sibutramine concentration especially triggers serotonin syndrome that can induce altered mentality, autonomic nerve hyperactivity and disorder in neuromuscular system. The drooling of saliva, perspiration, elevated blood pressure, mydriasis and epileptic seizure shown in the patient were probably caused by serotonin syndrome. ^8,9 A case of sibutramine overdose that caused the serotonin syndrome was reported. ¹⁰ A 4-year-old girl who ingested 27 tablets of 15 mg at a time (23 mg kg⁻¹) developed perspiration, tachycardia, hypertension, anxiety, sleep disorder, action disorder, hypertonia and hallucination recovered from them. TFT of the girl was not conducted, and it was not evident whether the girl developed thyroiditis or not.

The SCOUT study to assess the stability of sibutramine in the cardiovascular system of obese patients revealed increased incidence of myocardial infarction and cerebrovascular event. ¹ However, the potential effects on the thyroid function were not evaluated due to lack of TFT in the SCOUT study.

The authors experienced a case in which a 37-year-old Korean man developed thyrotoxicosis after overdose-ingestion of sibutramine. The patient was diagnosed with thyrotoxicosis by thyroiditis. Then he recovered from the disease without any specific treatment after 3 weeks. This is the first case of thyrotoxicosis with the thyroiditis induced by sibutramine intoxication. With withdrawal of sibutramine from many countries, the legal use of sibutramine may be impossible. However, there are many cases of uncommon adverse events related to herbal medications. Thus, further studies will be necessary to evaluate the mechanisms of sibutramine induced thyroid dysfunction.