Affiliations: Department of Emergency Medicine, University of Nevada School of Medicine, University Medical Center of Southern Nevada, Las Vegas, Nevada.
A 33 year old female presented to the emergency department (ED) complaining of a “racing heart.” She arrived anxious, febrile, and tachycardic to our ED having recently arrived from Florida on vacation. Her other complaints included mild diffuse abdominal pain, a few episodes of emesis and diarrhea, and bilateral lower extremity swelling. Her only past medical history was asthma which she intermittently took albuterol. Thyroid storm was suspected early in this patients ED course, and before her thyroid functions returned for confirmation, she was administered propranolol and methimazole. Although the diagnosis and supportive management of a patient with thyroid storm is well-known to emergency physicians, the choice regarding which thyroid-directed treatment is best may not be as evident. The primary objective of this case-report is to review the relevant literature and level of evidence which supports the use of methimazole in most cases of thyroid storm.
Thyroid storm is an uncommon ED diagnosis and the management has been debated over the cornerstone of treatment – the antithyroids PTU and MMI (1). These drugs inhibit the synthesis of thyroid hormone in 1-2 hours but have no effect on decreasing the release of preformed thyroid hormones (2). PTU has been favored in the past with having the added benefit of decreasing peripheral conversion of T4 to T3. However, recent literature favors MMI over PTU secondary to a decreased side effect profile and no increased efficacy (3). Although the diagnosis and supportive management of a patient with thyroid storm is well-known to emergency physicians, the choice regarding which thyroid-directed treatment is best may not be as evident. The primary objective of this case-report is to review the literature and level of evidence which support the use of methimazole in most cases of thyroid storm.
Case report:
A 33-year-old woman presented to our ED by private vehicle with her husband complaining of three days of “racing heart.” She also described generalized fatigue, non-radiating sub-sternal chest pressure, gradually increasing shortness of breath, subjective chills, bilateral lower extremity swelling, and mild diffuse abdominal pain with several episodes of non-bloody, non-bilious emesis and non-bloody, non-melanotic diarrhea. She recently traveled from Florida four days prior. She denied any history of cancer, recent surgery, or history of venous thromboembolism. She denied cough or hemoptysis and there was no travel out of the country. Her review of systems (ROS) was otherwise unremarkable. Her past medical history was significant only for asthma, which she intermittently took albuterol. She also denied known history of thyroid disease, alcohol, tobacco, and recreational drug use.
Her vital signs on arrival were most pertinent for a pulse of 150 and a bladder temperature of 105.1 F. Her blood pressure was 130/72 mmHg, pulse oximetry 98% on room air, and respirations ranging from 18-30. She was in moderate distress and anxious, however her airway was patent, she was phonating without difficulty, speaking in full sentences, and alert and oriented times four. Her physical exam was most pertinent for mild thyromegaly without goiter, tachycardia without murmurs, rubs, or gallops, tachypnea with crackles at the bilateral bases without accessory muscle use, mild distention and edema of the abdomen without tenderness, and 2+ pitting edema of the bilateral lower extremities without calf tenderness.
She was placed on continuous cardiac and oxygenation monitoring and had two large bore peripheral IVs established. An ECG was obtained and showed a sinus tachycardia in the 150s with nonspecific T wave inversions, however no ST elevation or depression. A portable chest radiograph showed opacification of the right lower lung field however no other cardiopulmonary abnormalities. The patient was given a two liter normal saline bolus, started on broad spectrum antibiotics and laboratory tests were ordered.
While her blood work was pending, the patient was empirically treated for thyroid storm. She received propranolol, hydrocortisone, and MMI in the ED with rapid relief of her symptoms. Her history of asthma was mild, however we closely monitored her respiratory status and there were no adverse effects from administration of propranolol. A repeat ECG done just 2 hours after antibiotics, fluids, and treatment for thyroid storm showed a sinus rhythm at approximately 75 without other changes . The patients temperature decreased with the interventions for thyroid storm as well as fluids and antibiotics, and she was feeling much improved.
Her laboratory work returned with an undetectable thyroid stimulating hormone (TSH) (<.10) and significant elevations in free triiodothyronine (FT3) at 5.7 and free thyroxine (FT4) at 2.97. Her other lab work included an elevated troponin at 1.3, normal lactate, unremarkable complete blood count (CBC), metabolic acidosis on arterial blood gas (ABG), negative urine, normal coagulation studies, negative pregnancy, normal liver functions, and normal lipase. A computed tomography angiogram (CTA) of the chest was ordered after a discussion over the risks and benefits of contrast administration in the setting of thyroid storm was held. While it has been studied that administration of iodinated contrast can put subclinical hyperthyroidism into thyroid storm (4), we could find no evidence of the risks of IV contrast administration while being treated for thyroid storm. Because of the concern for pulmonary embolism and other pathology causing this patient’s clinical state, we felt it best to obtain the CTA which showed no PE but a small to moderate right pleural effusion. A computed tomography (CT) of the abdomen/pelvis was unremarkable for acute findings. The patient was admitted to the intensive care unit (ICU) in serious but stable and improved condition.
The patient remained in the hospital for a total of twelve days and her final discharge diagnoses included thyroid storm, Klebsiella bacteremia, right pleural effusion, mild pulmonary hypertension, insomnia, and multifocal atrial tachycardia. Endocrinology was consulted and her thyroid storm was attributed to sepsis secondary to Klesiella bacteremiea. She was discharged home on ciprofloxacin, nexium, propanolol, methimazole, lasix, mv, and thiamine. To date she has not returned to our ED.
Discussion:
Thyroid storm is an uncommon ED diagnosis, however is important to recognize and begin treatment promptly as the mortality is high. It is most common in patients with underlying Grave’s disease, however it is also seen in conjunction with toxic multinodular goiter, sepsis (as in our patient), diabetic ketoacidosis, trauma, myocardial infarction, and several others (5). Patients most commonly have multiple complaints to include fever, irritability, agitation, emotional lability, poor weight gain, excessive sweating, heat intolerance, profuse sweating, respiratory distress, fatigue, nausea and vomiting, diarrhea, abdominal pain, anxiety, altered behavior, seizures, and in severe cases coma. The patient’s fever and tachycardia that seem out of proportion are frequently the first things recognized in these patients on top of their overall anxious appearance (6). The differential is large and immediately a large differential diagnosis is considered to include: congestive heart failure, pulmonary edema, delirium tremens, diabetic ketoacidosis, heat illness, neuroleptic malignant syndrome, panic disorder, sepsis, anticholinergic, serotonin syndrome, sympathomimetic, and withdrawal to name a few (2,7). The multitude of complaints and the overall ill appearance of the patient leads one to consider thyroid storm and a TSH quickly rules in or out the diagnosis (8). The TSH has the highest sensitivity and specificity for thyroid storm and a normal TSH essentially excludes the possibility of hyperthyroidism. Free T4 and free T3 are added to this to make the definitive diagnosis (8).
Once the diagnosis of thyroids storm is entertained, treatment is started before confirmatory testing returns as the mortality is high (5). There are three goals in the treatment of thyroid storm, frequently referred to as the three B’s. The first goal is to block the production and release of thyroid hormones. Production of thyroid hormones is blocked by the use of the antithyoids, either PTU or MMI, and will be the cornerstone of our discussion. The release is blocked by the iodides and needs to be administered 1-2 hours after the administration of the antithyroid medication. The second goal is to block the sympathetic outflow, achieved most commonly with propranolol. The third goal is to block the peripheral conversion of T4 to T3 with the use of both propranolol and corticosteroids (6, 3). Our discussion over the treatment of thyroid storm will again focus on the first goal and a review of the literature regarding PTU and MMI.
Propothyouracil and methimazole are the cornerstone of treatment in thyroid storm. They both work by inhibiting the synthesis of thyroid hormones within 1-2 hours. Both have no effect on the release of preformed thyroid hormones and PTU has may influence decreasing the peripheral conversion of T4 to T3 (10). PTU has been around since 1947 and methimazole just shortly thereafter in 1950. PTU and methimazole are both actively concentrated by the thyroid to inhibit iodine utilization by the thyroid by inhibition of “coupling” of iodotyrosines with a complete mechanism of action that remains to be completely elucidated. PTU has an added effect to block peripheral T4 to T3 conversion (10). Does this additional peripheral conversion lead to better efficacy? In Nakamura et al. JCEM 2007 in a prospective RCT for 12 weeks, the comparison of methimazole and PTU in hyperthyroidism due to Graves’ Disease was studied with three arms: methimazole 15 mg daily, methimazole 30 mg daily, and PTU 300 mg daily. In this study they recommended methimazole 15 mg/d for patients with mild and moderate graves as it can as effectively obtain euthyroidism as 30mg/day with fewer side effects. They did not recommend PTU as an initial antithyroid because of its high frequency of adverse reactions and rather poor efficacy to decrease TH levels (1). An article published in NEJM in 2005 also concluded that even with PTU having the added effect of decreased peripheral conversion of T4-T3, there was no evidence for increased efficacy of PTU over methimazole (3).
Reports of liver failure had been observed with the use of PTU and methimazole. In 2009 the FDA conducted a search of post-marketing adverse event reports for propylthiouracil and methimazole submitted to the agency from 1969 to June 2009 (11). The FDA identified 34 cases of severe liver injury associated with PTU and five were associated with methimazole. Of the 34 cases with PTU, 23 were adults and 11 were pediatric. Thirteen of the 23 adult cases resulted in deaths and five required liver transplants. Seven of the 11 pediatric cases required liver transplants and two died. The FDA only identified five cases of severe liver injury reported with methimazole and all were in adult patients. Three of these cases resulted in death. Based on these findings as well as a review of the medical literature, meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community, the FDA concluded that use of propylthiouracil is associated with a higher risk for clinically serious or fatal liver injury compared to methimazole in both adult and pediatric patients (11).
The only recommendations for the use of PTU are in pregnancy where the FDA's review found that congenital malformations were reported approximately three times more often with prenatal exposure to methimazole compared to propylthiouracil. A total of 29 cases were reported with methimazole and the majority of the congenital malformations were craniofacial defects or gastrointestinal atresias or aplasias (12). There were 9 cases associated with PTU and the FDA did not find a consistent pattern of birth defects associated with the use of propylthiouracil. The birth defects associated with the use of methimazole occurred during the 1st trimester of pregnancy and were not found when the drug was given later in pregnancy (13). There was no consistent pattern of birth defects associated with the use of propylthiouracil. Their conclusion was that there is no convincing evidence of an association between propylthiouracil use and congenital malformations, even with use during the 1st trimester (11).
Summary:
In conclusion, thyroid storm carries a high mortality and its ED recognition and emergent treatment are critical for a good outcome. Here we reviewed a case seen in our ED. While there has been much debate in the past over the use of the antithyroids PTU and methimazole, current literature suggests PTU to be considered second-line therapy except in people who are allergic, intolerant to methimazole, or pregnant. No current literature suggests better efficacy with PTU and the increased risk for adverse events make methimazole the preferred agent in hyperthyroid states.
References:
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Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease. J Clin Endocrinol Metab. 2007 Jun;92(6):2157-62. Epub 2007 Mar 27.
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9. Thyroid Storm: Treatment Strategies By Nadia Awad, PharmD, BCPS|November 11th, 2013|Endocrine-Metabolic, Expert Peer Reviewed (Clinical), Tox & Medications
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11. FDA Drug Safety Communication: New Boxed Warning on severe liver injury with propylthiouracil.http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm209023.htm#aihp Published April 21, 2010. Updated May 6, 2010. Accessed May 8, 2015.
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