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Home , Hyperthyroidism, Myxedema, Myxedema coma, Thyroid storm

The Art and Science of Infusion Nursing Angela M. Leung , MD, MSc

Thyroid Emergencies

cal manifestations, diagnostic methods, and treatments of ABSTRACT and , both in the and storm are thyroid nonacute and life-threatening forms of these diseases. emergencies associated with increased mortality. Prompt recognition of these states—which repre- sent the severe, life-threatening conditions of THYROID HORMONE PRODUCTION AND METABOLISM extremely reduced or elevated circulating thyroid hormone concentrations, respectively—is neces- sary to initiate treatment. Management of myxe- The normal physiology of the hypothalamic-pituitary- dema coma and requires both med- thyroid axis involves the production of T4 and T3 by the thyroid gland, a process that is regulated by thyroid- ical and supportive therapies and should be treated stimulating hormone (TSH) secreted by the pituitary, in an setting. which is, in turn, regulated by thyrotropin-releasing hor- Key words: hypothyroidism , hyperthyroidism , mone (TRH) secreted by the hypothalamus. Both serum ICU , , thyroid emergencies , T4 and T3 concentrations act as negative feedback regu- thyroid storm lators of TSH and TRH secretion, but can be altered by environmental conditions—including food availability he thyroid is a 15- to 20-gram gland located and temperature—and disease states, such as .1 in the anterior neck. It is responsible for the Thyroid hormone synthesis is achieved first through production of the T4 (thy- active transport of circulating iodide, which is taken in roxine) and T3 (). Various from the diet, by the sodium/iodide symporter located at factors can thyroid hormone synthesis, the basolateral membrane of the . 2 Tincluding acute illness, coexisting morbidities, and certain Iodide then becomes oxidized by . Both the states of low thyroid hormone con- (TPO) and hydrogen peroxide at the apical membrane, centrations (hypothyroidism) and thyroid hormone excess which then attaches to the tyrosyl residues on thyroglob- (thyrotoxicosis) can be transient or permanent. The ulin (Tg) to produce monoiodotyrosine (MIT) and diio- decompensated, severe forms of hypothyroidism and dotyrosine (DIT). MIT and DIT are the precursors to the hyperthyroidism, termed myxedema coma and thyroid thyroid hormones, which are produced by the linkage of storm , are associated with increased morbidity and mor- 2 DIT molecules to form T4 and the linkage of MIT and tality. Prompt recognition of both conditions is necessary DIT to produce T3. Release of T4 and T3 into the circu- to initiate treatment and supportive measures. This lation results from the digestion of Tg in MIT and DIT review will summarize the essential principles of the clini- by endosomal and lysosomal proteases. The metabolic effects of thyroid hormone action result Author Affiliations: Division of , David Geffen from the binding of the thyroid hormone to thyroid hor- School of Medicine at UCLA, and the VA Greater Los Angeles mone transporters located in specific target tissues, which Healthcare System, Los Angeles, California. Angela M. Leung, MD, MSc, is an assistant clinical professor of is mediated by the thyroid hormone nuclear receptor (TR) 3 medicine in the Division of Endocrinology at the David Geffen that is encoded by the genes TRα and TRβ . While the School of Medicine at the University of California, Los Angeles, sole source of T4 is the thyroid gland, the majority and the VA Greater Los Angeles Healthcare System, both in Los Angeles, California. (approximately 80%) of T3 is produced from the The author received funding from the National Institutes of Health, extrathyroidal conversion of T4 to T3 by the action of the NIH 7K23HD068552. The author has no other potential conflicts of 5´-deiodinase enzymes—D1 or D2—located in the liver, interest to disclose. brain, brown adipose tissue, and muscles.4 T4 can also be Corresponding Author: Angela M. Leung, MD, MSc, VA Greater converted to the inactive thyroid hormones, reverse T3 or Los Angeles Healthcare Sysem, Divison of Endocrinology (111D), 11301 Wilshire Blvd, Los Angeles, CA 90073 ( AMLeung@mednet. T2, by the 5´-deiodinase D3. The activity and expression ucla.edu ). of the deiodinases are specific to different tissues and envi- DOI: 10.1097/NAN.0000000000000186 ronmental conditions.

VOLUME 39 | NUMBER 5 | SEPTEMBER/OCTOBER 2016 Copyright © 2016 Infusion Nurses Society 281 Copyright © 2016 Infusion Nurses Society. Unauthorized reproduction of this article is prohibited. SERUM THYROID FUNCTION AND TABLE 1 Serum TSH is the most sensitive test to suggest thyroid dysfunction, because of the logarithmic-linear relation- of Hypothyroidism ship between serum TSH and thyroid hormone levels. General Overt thyroid dysfunction, whether referring to hypo- thyroidism or hyperthyroidism, is defined by the sole Fatigue abnormality of an elevated serum TSH concentration, Lethargy while subclinical thyroid dysfunction refers to both elevated serum TSH and decreased T3 and/or T4 con- Sleepiness centrations. The range of subclinical to overt thyroid dysfunction can be regarded as a continuum of increas- Cold intolerance ingly severe biochemical , which inciden- and hair tally may or may not correlate to the severity of any Dry, thick skin corresponding symptoms, if present. Coarse hair Eyebrow thinning HYPOTHYROIDISM Brittle nails Decreased Hypothyroidism refers to the state of low circulating Cardiovascular system thyroid hormones. In 2 large US population-based stud- ies of data collected in the 1980s to the 1990s, the preva- lence of overt hypothyroidism ranged from 0.3% to Elevation of blood pressure 0.4%, while that of subclinical hypothyroidism ranged Hyperlipidemia from 4.3% to 8.5%, among the general population.5 , 6 Respiratory system The most common etiology of hypothyroidism in the United States is Hashimoto’s , an autoimmune Hoarse voice disease that is more prevalent among older women; nutritional deficiency is the most common etiology Sleep apnea worldwide. Additional etiologies of hypothyroidism Gastrointestinal system include a history of , radioactive iodine Constipation therapy, and, less commonly, decreased TSH production Decreased appetite by the pituitary. Predisposition factors for the develop- ment of hypothyroidism include thyroid autoimmunity Reproductive system (which can be assessed by the determination of serum Menstrual cycle irregularities thyroid autoantibodies, such as TPO and [Tg] Infertility titers), the use of certain medications (ie, , ami- Musculoskeletal system odarone, interferon-alpha), and excess iodine exposure (ie, from radiographic studies), in Arthralgia which individuals with a history of thyroid disease are at Neurological system higher risk of iodine-induced hypothyroidism.7 Paresthesia Thyroid hormone is important for the metabolic func- Depression tions of many major organs, including the heart, brain, Mental impairment liver, and muscle. Signs and symptoms of hypothyroidism are widely variable (Table 1 ), often subtle, and may Slow movements include fatigue, malaise, weight gain, dry and puffy skin, Hyporeflexia constipation, cold intolerance, altered cognition, and hyporeflexia. In children, there may be stunted growth, and in women, menstrual abnormalities may be present. fetus, and young children. As thyroid hormone is cru- cial for the complex processes of neurodevelopment and 8 Hypothyroidism Among Women of growth, which begins in the first trimester of pregnan- Reproductive Age and in Children cy and continues into the first few years of infancy, these groups are especially susceptible to the effects of Normal thyroid function is particularly important even mild thyroid dysfunction. Several studies have among pregnant and lactating women, the developing demonstrated that low thyroid hormone levels among

282 Copyright © 2016 Infusion Nurses Society Journal of Infusion Nursing Copyright © 2016 Infusion Nurses Society. Unauthorized reproduction of this article is prohibited. pregnant women are associated with increased risks of impaired state of the patient. Suggested regimens for the preterm delivery, spontaneous miscarriage, fetal death, initial and maintenance doses of thyroid hormone in a and cognitive deficits, 9 including a decrement in intelli- patient with myxedema coma are provided in Table 2 . gence quotient and memory scores of the offspring, In general, a loading dose of 200 to 400 μ g IV levothy- compared with euthyroid women. 10-13 Neuroimaging roxine (T4) is to be followed by a maintenance dose of studies also show abnormalities of hippocampal and 1.6 μ g/kg/d when given orally or 75% of this when corpus callosum size, and of gray matter, among chil- given intravenously; consideration can also be made for dren with a form of low thyroid hormone levels at birth the coadministration of (T3), since T4 to termed congenital hypothyroidism . 14 , 15 T3 conversion may be impaired in patients with myxe- dema coma. 20 It is important to note that IV thyroid hormone replacement should be administered only as a Myxedema Coma push through a syringe, rather than through infusion tubing, in which up to 40% of the starting concentra- Myxedema coma refers to the state of severe, life- tion may be lost from adherence to polypropylene tub- threatening, and decompensated hypothyroidism in ing. 21 Improvements in serum T3 and T4 concentra- which thyroid hormone levels are dangerously low. The tions may be seen before the normalization of serum diagnosis appears to be more common in elderly women TSH concentrations, and measurement of serum thy- with long-standing preexisting hypothyroidism. Triggers roid function tests every 1 to 2 days during treatment is may include cold temperature (thus, it is more common reasonable. 20 Improvements in clinical cardiovascular, during winter months); precipitating comorbidities, renal, pulmonary, and metabolic parameters may take such as infection, , and ; or the use of as much as a week to be observed. 20 , analgesic, antidepressant, hypnotic, antipsy- chotic, or anesthetic medications. 16 Patients with preex- isting hypothyroidism may also present with myxedema THYROTOXICOSIS coma following a period of prolonged noncompliance with thyroid hormone replacement. Thyrotoxicosis refers to the state of thyroid hormone Signs and symptoms usually are exacerbations of the excess arising from either overproduction from the thyroid usual manifestations of hypothyroidism and may include gland (termed hyperthyroidism) or extrathyroidal, extreme lethargy, which can progress to stupor or coma, including exogenous, sources. Of the etiologies attributable , respiratory depression, bradycardia, to hyperthyroidism, the most common cause worldwide , and renal impairment. The diagnosis of is Graves’ disease, resulting from the autoimmune myxedema coma is made with the confirmation of a biochemical thyroid profile consistent with hypothyroid- ism and corresponding clinical manifestations. A diag- TABLE 2 nostic scoring system has been proposed to guide the clinician toward a diagnosis of myxedema coma based Management of on body temperature, central nervous system signs, gas- trointestinal symptoms, precipitating events, cardiovas- Myxedema Coma cular dysfunction, and metabolic disturbances.17 Thyroid hormone replacement Treatment of myxedema coma should be considered as quickly as possible, given the increased mortality of (T4) the disease (25%-60% despite treatment),18 and can be Loading dose of 200-400 μ g IV once started even before confirmation of laboratory results Maintenance dose of 1.6 μ g/kg/d IV/PO demonstrating abnormal serum TSH and T4 concentra- tions. The management of myxedema coma should be Liothyronine (T3) in an intensive care unit (ICU) setting. The central ten- Loading dose of 5-20 μ g IV/NG once ets of treatment are thyroid hormone replacement, Maintenance dose of 2.5-10 every 8 hours IV/PO stress-dose corticosteroids if concomitant adrenal insuf- Supportive measures ficiency is suspected, supportive care, and the treatment of any underlying and coexisting conditions ( Table 2). IV fluids containing electrolytes and glucose Supportive care may include the administration of Passive rewarming with a blanket intravenous (IV) fluids, sodium replacement if hypona- Treatment of any underlying comorbidities, including infection tremia is present, and the use of warming blankets Glucocorticoids (although aggressive rewarming should be avoided, given the risks of vasodilation).19 100 mg IV every 8 hours if is suspected Thyroid hormone replacement should be adminis- tered as T4 and/or T3, often intravenously, given the Abbreviations: IV, intravenous; NG, nasogastric; PO, per oral.

VOLUME 39 | NUMBER 5 | SEPTEMBER/OCTOBER 2016 Copyright © 2016 Infusion Nurses Society 283 Copyright © 2016 Infusion Nurses Society. Unauthorized reproduction of this article is prohibited. stimulation of the thyroid by serum thyroid-stimulating TABLE 3 immunoglobulin, followed by toxic multinodular goiter and toxic adenoma. In the United States, the prevalence of hyperthyroidism from all causes is approximately Signs and Symptoms 1.2%, of which 0.5% is overt and 0.7% is subclinical. 22 of Thyrotoxicosis Other causes of thyrotoxicosis include overproduction of TSH from a , thyroiditis, exogenous General thyroid hormone ingestion, ectopic hyperthyroidism Fatigue (such as from or metastatic thyroid cancer), or human chorionic gonadotropin-mediated hyperthyroidism (such as from or a molar ). Heat intolerance The signs and symptoms of thyrotoxicosis are reflec- Eyes tive of the excess concentrations of thyroid hormone , lid lag, or periorbital/conjunctival , if present ( Table 3 ) and can include , fatigue, dia- thyrotoxicosis is due to Graves’ disease phoresis, heat intolerance, , , tachy- Skin and hair cardia, weight loss, , and warm and moist Warm, moist skin skin. In women, menstrual abnormalities may be seen. In patients in whom the thyrotoxicosis is due to Graves’ Thin, fine hair disease, specific clinical manifestations may also include Brittle nails thyroid eye disease (ie, exophthalmos, lid lag), a diffuse Diaphoresis goiter with a , localized dermopathy, thyroid Thyroid acropachy if due to Graves’ disease acropachy (ie, digital clubbing and swelling), and the Localized dermopathy, if due to Graves’ disease coexistence of other autoimmune diseases in the patient or the patient’s family. Cardiovascular system Palpitations Thyroid Storm Atrial Thyroid storm is the clinical manifestation of elevated Systolic serum thyroid hormone concentrations, resulting in the Hyperdynamic precordium extreme alteration of usual hyperthyroid symptoms. The diagnosis can occur in patients with or without Respiratory system preexisting hyperthyroidism. It is a rare diagnosis and Shortness of breath usually triggered by precipitants such as trauma, myo- Gastrointestinal system cardial infarction, (including thyroid surgery Loose stools or hyperdefecation for hyperthyroidism or other in general), or Increased appetite infection. In some cases, acute exposure to excess iodine (ie, administration of iodinated contrast radio- Reproductive system graphic scan) may result in iodine-induced hyperthy- Menstrual cycle irregularities 23 roidism to trigger thyroid storm. Patients with known Infertility severe hyperthyroidism who are noncompliant with Musculoskeletal system prescribed antithyroid medications may also develop thyroid storm. , especially of proximal muscles Prompt recognition of thyroid storm is essential to Neurological system initiate treatment, which should be performed in an Nervousness ICU setting. Clinical manifestations of thyroid storm Anxiety can be quite varied and may include , cardiac arrhythmias, , and impaired mental status. Patients with thyroid storm have increased inpatient Hyperactivity mortality rate, overall hospital and ICU length of stay, Hyperreflexia and ventilation requirements compared with those with compensated thyrotoxicosis. 24 The mortality rate of thyroid storm ranges from 10% to 20%. 25 , 26 life-threatening symptoms of hyperthyroidism. Several Diagnosis of thyroid storm is made using a combi- diagnostic scoring systems have been proposed that nation of biochemical laboratory tests confirming can be used to assess the likelihood of thyroid storm in thyrotoxicosis in a patient displaying the severe, patients. The Burch-Wartofsky scoring system is based

284 Copyright © 2016 Infusion Nurses Society Journal of Infusion Nursing Copyright © 2016 Infusion Nurses Society. Unauthorized reproduction of this article is prohibited. on factors related to temperature, central nervous sys- CONCLUSION tem effects, gastrointestinal/hepatic dysfunction, car- diovascular dysfunction, heart failure, and any pre- 27 Hypothyroidism and thyrotoxicosis are common endo- cipitant history. The Akamizu criteria are similar crine disorders, each with a variety of etiologies, and and have also been proposed as another diagnostic 28 most patients with thyroid dysfunction are easily man- scoring system in the assessment of thyroid storm. aged. However, in certain patients, severe, life-threatening Treatment usually consists of multiple measures forms of these states, representing rare thyroid emergen- and medications aimed to target the various causes cies, can develop on exposure to precipitating triggers or and effects of thyrotoxicosis, as summarized in 19,22 among patients with preexisting thyroid dysfunction or Table 4. Symptomatic improvement of tachycar- noncompliance with medical treatment. Both myxedema dia and clinical manifestations reflecting the increased coma, corresponding to extremely low serum thyroid adrenergic tone can be achieved with beta-blocker hormone concentrations, and thyroid storm, correspond- therapy. Methimazole or should be ing to extremely elevated thyroid hormone concentra- initiated to decrease production of thyroid hormone. tions, are associated with increased mortality and must Saturated solution of can be used to be recognized promptly. Treatment of myxedema coma inhibit thyroid hormone release from the thyroid and thyroid storm is multifaceted and should be man- gland. Glucocorticoids decrease the conversion of T4 aged by the interdisciplinary team of an ICU setting. to T3, which can also be accomplished by the use of 29 propylthiouracil. Supportive measures include IV REFERENCES fluids, oxygen, cooling, and treatment of any precipi- tating causes. Finally, if necessary when the above 1. Fekete C , Lechan RM . Central regulation of hypothalamic- treatments cannot be used or are unsuccessful, plas- pituitary-thyroid axis under physiological and pathophysiological mapheresis can be attempted to decrease thyroid hor- conditions . Endocr Rev. 2014 ; 35 ( 2 ): 159-194. mone excess, as well as cytokines and putative anti- 2. Zimmermann MB , Boelaert K . and thyroid disorders . Lancet Endocrinol. 2015 ; 3 ( 4 ): 286-295 . bodies, in the circulation.30 3. Brent GA . Mechanisms of thyroid hormone action. 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286 Copyright © 2016 Infusion Nurses Society Journal of Infusion Nursing Copyright © 2016 Infusion Nurses Society. Unauthorized reproduction of this article is prohibited.