ACEP News
February 2006

By Joel Kravitz, MD

Hyperthyroidism can present in several forms, ranging from the subtle tremor or palpitations of mild hyperthyroidism to the agitation and homeostatic dysfunction seen in thyroid storm. Given its prevalence of 1% in the general population, the average emergency physician can expect to see many cases of hyperthyroidism over his or her career. Not only is the prevalence of hyperthyroidism higher in women (rising to almost 5%), but thyrotoxicosis and thyroid storm become more common with advancing age. The emergency physician must be able to both recognize the subtler presentations and stabilize the more life-threatening manifestations.

If you're anything like me, you spent the better part of medical school saying, "OK, I know the thyroid gland is the regulator for the whole body, but what does it actually do?" The thyroid's main actions can be divided into two large groups. The genomic actions of the thyroid involve the stimulation of various genes encoding for things such as growth hormone and myelin proteins. The nongenomic actions are somewhat more powerful than the genomic actions. These are membrane- and mitochondrial-based functions that deal primarily with alterations in signal transduction to change vascular tone, ion homeostasis, and cellular respiration, to name a few. The effects of these changes can be seen within a few minutes and are predominantly responsible for the acute symptoms of thyrotoxicosis and thyroid storm that are seen in the emergency department.

Hyperthyroidism, thyrotoxicosis, and thyroid storm don't necessarily have hard diagnostic break points, but are best thought of on a spectrum. As a patient progresses from hyperthyroidism to thyrotoxicosis, the often-seen signs and symptoms are intensified. Complaints of palpitations, anxiety, heat intolerance, and weight loss become more noticeable. Depending on the etiology of the hyperthyroid state, a goiter is not always seen. Thyrotoxic patients are often nervous or anxious, as well as tachycardic, and have warm, moist skin. Although lid lag can occur with any cause of hyperthyroidism, exophthalmos and impaired extraocular motility are more specific for Graves' disease (the most common cause of hyperthyroidism).

Apathetic thyrotoxicosis (also known as "masked hyperthyroidism") is a term coined by Lahey in 1931 for the atypical presentation of thyrotoxicosis in the elderly. These patients are generally older than 70 and tend to present with lethargy, depression, and weakness as opposed to the agitation and anxiety usually seen in hyperthyroid patients. The usual adrenergic symptom complex is absent. The hyperthyroid symptoms in these patients are usually confined to one organ system, most commonly the cardiovascular system--and often consist of atrial fibrillation, congestive heart failure, or both. To further confound the diagnosis, these patients often have neither ophthalmopathy nor a goiter.

Thyroid storm is an uncommon but life-threatening complication of hyperthyroidism. Graves' disease is still by far the most common cause, although it can be seen occasionally with toxic adenoma or multinodular goiter. Physiologic stress is a less common cause because patients are now made euthyroid before a surgical procedure. Medical conditions such as pneumonia and stroke have been known to precipitate thyroid storm in hyperthyroid patients. Finally, medications, such as amiodarone, can precipitate either thyrotoxicosis or thyroid storm.

Thyroid storm can be differentiated from thyrotoxicosis by several factors. Thyroid storm tends to be more abrupt in onset, and the adrenergic symptoms seen in hyperthyroidism are exaggerated. Fever is far more common with thyroid storm, and the tachycardia seen in these patients is usually disproportionate to the degree of fever. Alteration in mental status is the most glaring clinical difference. While thyrotoxic patients are often nervous or anxious, patients in thyroid storm can present with agitation, psychosis, and, occasionally, coma. Diarrhea, which can be seen in thyrotoxicosis, is often a harbinger of "the coming storm." Hepatomegaly and mild jaundice also portend a worse prognosis.

The diagnosis of thyroid storm often can be made on clinical grounds, although in the absence of an obvious goiter or a known history of thyroid disease, this may be difficult.

Laboratory testing should not delay the initiation of treatment when clinical suspicion is sufficiently high. Most sources contend that the thyroid stimulating hormone (TSH) level is the single best screening test of thyroid function. Small changes in thyroid function cause large changes in TSH levels because of the sensitive position TSH holds in the negative feedback loop (it is usually immeasurably low in thyrotoxicosis and thyroid storm). In the less common situations of hypothalamic-pituitary axis diseases, additional testing is necessary, as it would be if the patient were undergoing treatment for hyperthyroidism.

The single best test to assess for thyrotoxicosis and thyroid storm is the Free T4 Index (FTI). This test, which is the biologic product of the total T4 and T3 resin uptake measurements, provides a measure of the total amount of active thyroid hormone in the bloodstream. While the FTI is a more accurate measure, it is not routinely available on an emergency basis. Other tests, like thyroid-binding globulin levels (which may be altered in pregnancy or estrogen therapy) and T3 levels, can be ordered, but they provide little assistance to the emergency physician and are not available emergently. A free T4 level is often available on an emergency basis and, in combination with a TSH, has very good sensitivity for thyrotoxicosis and thyroid storm.

Correcting the hyperthyroid state requires a series of steps that, if done in the wrong order, actually can cause the patient to deteriorate. To treat thyrotoxicosis and thyroid storm effectively, the emergency physician must correct the hyperthyroid state and stabilize any homeostatic decompensation, but must also be mindful to treat the precipitant of the condition.

The first step to correct the hyperthyroid state is the administration of a thionamide: propylthiouracil (PTU) or methimazole (MMI). Thionamides block the incorporation of iodine into thyroglobulin within 1 hour. PTU is more often used because it has the additional therapeutic advantage of decreasing the peripheral conversion of T4 to T3. Both drugs are available only in oral form (although there are reports of rectal administration in comatose patients), and both should be withheld if the patient has a history of hepatotoxicity or agranulocytosis. The dose for PTU is a 900- to 1,200-mg load, followed by 200-250 mg orally every 4 hours. The dose of MMI is one-tenth that of PTU.

While prior practice discouraged the use of PTU in pregnancy, current studies suggest that there is likely no significant difference in the placental crossing of PTU and MMI. Both PTU and MMI can cross the placental barrier and inhibit fetal thyroid hormone production. Some experts have suggested that thyrotoxic pregnant women should be treated with iodides rather than thionamides. However, as explained in the next paragraph, this practice can be dangerous. The Quebec Neonatal Screening Program revealed that 4 out of 400,000 children screened have transient hypothyroidism caused by PTU administration, and that the incidence of transient hypothyroidism in neonates exposed to PTU is approximately 1%-5%. To balance the low incidence of neonatal hypothyroidism against the maxim that "treatment of the mother equals treatment of the fetus," many experts recommend using lower doses of thionamides in thyrotoxic pregnant women.

The next step in treating thyrotoxicosis or storm is to block the synthesis of thyroid hormone, which is achieved via the administration of inorganic iodine. Perhaps the most important principle of management is to ensure that iodine treatment is begun at least 1 hour after the administration of thionamides. Otherwise, providing iodine substrate to an overactive thyroid that has not been blocked is akin to throwing oil on a fire. Typical dosing is 5 drops of 1% potassium iodide (KI) given every 6 hours, or 8 drops of Lugol's iodide every 6 hours. If your radiology department uses ipodate (Orografin), this iodine-based compound has the added advantage of inhibiting the conversion of T4 to T3 (unfortunately, not all contrast dyes have this effect).

While the author contends that iodine should not be given without thionamide pretreatment, very large doses of iodine can also inhibit hormone synthesis by blocking organification of the thyroglobulin molecule, a principle called the Wolff-Chaikoff effect. Lithium can also be used to block thyroid hormone synthesis, but its use has been largely replaced by iodines.

Once the thyroid gland has been suppressed, the last step in correcting the hyperthyroidism is to reduce the peripheral conversion of T4 (tetraiodo-thyronine) to T3 (triiodothyronine). T3 is approximately 10 times more biologically active than T4. PTU, propranolol, and steroids (dexamethasone, in stress doses equivalent to 200-300 mg of cortisol) all reduce the conversion of thyroid hormone to its more active form. Fortuitously, these drugs all have indications for use in the hyperthyroid patient that make them effective for multiple reasons.

Resuscitation and homeostatic stabilization should occur concomitantly with the reversal of the hyperthyroid state (never ignore the ABCs). These patients often have massive fluid losses, and glucose should be added, given the catabolic nature of thyrotoxicosis and thyroid storm.

The cornerstone of control of the hypersympathetic drive is propranolol given in doses of 1 mg IV every few minutes as needed to control symptoms (to a maximum of 10 mg). The dose that achieved an improvement in symptoms can then be given every 3-4 hours IV as needed. IV propranolol works within 10 minutes; the oral equivalent of 20-120 mg every 4-6 hours works within 1 hour. While any ?-blocker will achieve control of symptoms caused by sympathetic overdrive, propranolol has remained the preferred agent because of its ability to reduce the conversion from T4 to the more active T3.

Guanethidine and reserpine deplete catecholamine stores, and have been used to reduce the sympathetic symptoms of thyrotoxicosis, but they have fallen out of favor since the advent of ß-blockers. Both guanethidine and reserpine can cause hypotension and diarrhea symptoms, which themselves may indicate thyroid storm. While many suggest that ß-blockers should be avoided if a major contraindication exists, this should be balanced, on a case-by-case basis, against the potential benefit of ß-blockers in thyrotoxicosis and especially in thyroid storm.

Temperature control in thyrotoxic patients should be achieved with acetaminophen or ibuprofen. Peripheral cooling can be used in severe cases. Salicylates should never be used in these patients. Not only do these drugs displace thyroid hormone from thyroglobulin, but they also increase the conversion of T4 to T3, thus likely worsening the clinical condition.

References

1. American Association of Clinical Endocrinologists: Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hyperthyroidism and Hypothyroidism. Endocrine Practice 2002;8:458-69.
2. Cooper D.S. Antithyroid drugs. N. Engl. J. Med. 2005;352:905-17.
3. Cooper D.S. Treatment of Thyrotoxicosis. In: Braverman L.E., Utiger R.D. The Thyroid: A Fundamental and Clinical Text. 6th ed. Lippincott; 1991; pp. 887-916.
4. Cooper D.S., Goldminz D., Levin A.A., et al. Agranulocytosis associated with antithyroid drugs: Effects of patient's age and drug dose. Ann. Intern. Med. 1983;98:26-9.
5. Eisenstein Z., Weiss M., Katz Y., et al. Intellectual Capacity of Subjects Exposed to Methimazole or Propylthiouracil in utero. Eur. J. Ped. 1992;151:558-9.
6. Fauci M.D., et al. Harrison's Principles of Internal Medicine. New York: McGraw-Hill, 2005.
7. Letarte J., Guyda H., Dussault J.H. Clinical biochemical, and radiological features of neonatal hypothyroid infants. In: Burrow G.N., Dussault J.H. Neonatal Thyroid Screening. New York: Raven Press; 1980; pp. 225-36.
8. Mestman J.H. Hyperthyroidism in pregnancy. Endo. Met. Clin. NA. 1998;27:127-51.
9. Nicoloff J.T. Thyroid Storm. In: Thyroid Disease. Med Clin. N. Am. Sept. 1985, pp. 1005-19.
10. Singer P.A., Cooper D.S., Levy, E.G., et al. Treatment Guidelines for Patients with Hyperthyroidism and Hypothyroidism. JAMA 1995;273:808-12.
11. Wilson J., et al. Williams' Textbook of Endocrinology. Philadelphia: WB Saunders, 2002.

Contributors

Dr. Joel Kravitz is a clinical assistant professor of emergency medicine at Jefferson Medical College, and an assistant residency director at Albert Einstein Medical Center's department of emergency medicine in Philadelphia.

Dr. Robert C. Solomon is a faculty member for the emergency medicine residency at Ohio Valley Medical Center in Wheeling, W.Va., and clinical assistant professor of medicine at West Virginia School of Osteopathic Medicine.

Disclosures

In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards and ACEP policy, contributors and editors must disclose to the program audience the existence of significant financial interests in or relationships with manufacturers of commercial products that might have a direct interest in the subject matter.

Dr. Kravitz and Dr. Solomon have disclosed that they have no significant relationships with or financial interests in any commercial companies that pertain to this educational activity.

"Focus On: Treating Hyperthyroidism in the Emergency Department" has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME).

ACEP is accredited by the ACCME to provide continuing medical education for physicians.

ACEP designates this educational activity for a maximum of 1 Category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he or she actually spent in the educational activity.

"Focus On: Treating Hyperthyroidism in the Emergency Department" is approved by ACEP for 1 ACEP Category 1 credit.

Disclaimer

ACEP makes every effort to ensure that contributors to College-sponsored programs are knowledgeable authorities in their fields. Participants are, nevertheless, advised that the statements and opinions expressed in this article are provided as guidelines and should not be construed as College policy. The material contained herein is not intended to establish policy, procedure, or a standard of care. The views expressed in this article are those of the contributors and not necessarily the opinion or recommendation of ACEP. The College disclaims any liability or responsibility for the consequences of any actions taken in reliance on those statements or opinions.

Treating Hyperthyroidism in the ED CME Quiz