thyroid disease in the emergency department: a clinical and laboratory review

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The Journal of Emergency Medicine, Vol. 28, No. 2, pp. 201–209, 2005Copyright © 2005 Elsevier Inc.

Printed in the USA. All rights reserved0736-4679/05 $–see front matter

doi:10.1016/j.jemermed.2004.08.020

Clinical Laboratoryin Emergency Medicine

THYROID DISEASE IN THE EMERGENCY DEPARTMENT:A CLINICAL AND LABORATORY REVIEW

Laura Pimentel, MD and Karen N. Hansen, MD

Division of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MarylandReprint Address: Laura Pimentel, MD, Department of Emergency Medicine, Mercy Medical Center,

301 St. Paul Place, Baltimore, MD 21202-5863

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Abstract—Emergency physicians regularly treat patientsith thyroid disorders. Until the 1950s, clinical evaluation was thenly available diagnostic tool. Since then, increasingly sophisti-ated laboratory assays have been developed to confirm thyroidathology. Thyroid physiology, fundamental to interpreting thy-oid function tests, is based on a classic negative feedback mech-nism involving the hypothalamic-pituitary-thyroid axis. Pri-ary hypothyroidism in developed countries is most commonly

aused by Hashimoto’s disease. Secondary and tertiary etiologiesre uncommon and the result of hypothalamic and pituitaryathology. Clinical presentations range from subclinical diseaseo myxedema coma. Thyrotoxicosis has many etiologies. A hy-eradrenergic state precipitates characteristic signs and symp-oms. Thyroid storm and thyrotoxic periodic paralysis are emer-ent complications. Third generation assays have made thyroidunction testing practical for emergency physicians. An ultrasen-itive thyroid stimulating hormone level is the most useful. A freehyroxine level is the preferred study for confirming a thyroidisorder. Confounding factors may affect thyroid function

nterpretation. © 2005 Elsevier Inc.

Keywords—thyroid stimulating hormone assay; free thyrox-ne assay; hypothyroidism; thyrotoxicosis; hyperthyroidism

INTRODUCTION

hyroid disease, responsible for a spectrum of pathologyrom subclinical hormonal abnormalities to life-threaten-ng disease, is easily and effectively treated. Between

Clinical Laboratory in Emergency Medicine is cBoston, Massachusetts

ECEIVED: 21 April 2004; FINAL SUBMISSION RECEIVED: 23
CCEPTED: 11 August 2004
201

.9% and 11.7% of the population has abnormal valuesn thyroid screening (1,2). Hypothyroidism is 5 to 10imes as prevalent as thyrotoxicosis; symptomatic dis-ase is found in 5% to 10% of patients with abnormalaboratory values. Thyrotoxic patients more commonlyanifest clinical symptoms. Current thyroid function

ssays allow rapid and sensitive measurement of basichyroid function (3). This review will focus on thyroidhysiology, clinical manifestations of thyroid disease,nd currently available thyroid function assays. A ratio-al strategy for ordering thyroid function tests in themergency department (ED) will be presented.

THYROID PHYSIOLOGY

hyroid-stimulating hormone (TSH), secreted by the an-erior pituitary gland, controls the synthesis and secretionf the thyroid hormones, thyroxine (T4) and triiodothy-onine (T3). Regulation of TSH levels is controlled bywo mechanisms. The first is classic negative feedback toerum thyroid hormone concentration. Large inversehanges in TSH levels are precipitated by small changesn free thyroid hormone concentrations. Secondly, TSHoncentration is regulated by the hypothalamic hormonehyrotropin-releasing hormone (TRH). The systems arenterrelated in that the negative feedback of thyroid hor-one probably affects TRH release from the hypothala-

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202 L. Pimentel and K. N. Hansen

us in addition to TSH release from the pituitary. Thy-oid-releasing hormone secretion is also affected bynput from higher cortical centers (4). This system ofhyroid hormone production is referred to as the hypo-halamic-pituitary-thyroid axis (5).

At the molecular level, T4 is actually a prohormonend T3 is the biologically active chemical. All T4 isynthesized within the thyroid gland, whereas only 15%o 20% of T3 is synthesized directly. T4 is converted to3 in peripheral organs, including the kidneys and liver

5,6). Thyroglobulin is a thyroid-hormone–containingrotein stored in the colloid within thyroid follicles. T4ynthesis occurs within these follicles. Dietary iodide israpped, oxidized, and combined with tyrosine residues.oupling of these iodotyrosines produces T4 (5,7). Theajor metabolic pathway of T4 is monodeiodination. The

uter ring is removed, producing T3. Inactive RT3 isormed when the inner ring is removed. In healthy patients,bout 41% of T4 is metabolized to T3 and 38% converts toT3. Other pathways account for the remainder (4).

The daily requirement for thyroid hormone is less than% of the amount stored within the gland, allowing main-enance of normal function when a person is deprived ofodine. The excess capacity, however, creates a vulnerabil-ty to thyrotoxicosis when the thyroid gland becomes in-amed and excess thyroid hormone is released (7).

Over 99.5% of T4 and T3 are protein bound in theerum. Thyronine-binding globulin (TBG) binds approx-mately 80% of circulating hormone. Transthyretin andlbumin are minor serum binders (4). Bound hormone isetabolically inactive; thus, only the tiny percentages of

ree thyroid hormone are metabolically active and clin-cally relevant. Measurements of thyroid hormone can beisleading if only total thyroid hormone levels are ob-

ained. Free T3 (FT3) and free T4 (FT4) serum levelsrovide more valuable clinical information. Variableshat affect TBG levels such as disease, nutritional status,nd medications will affect free thyroid hormone levels;owever, the hypothalamic-pituitary-thyroid axis gradu-lly reestablishes homeostasis (3).

Thyroid-stimulating hormone secretion rhythmicallyaries between day and night. More than half is secreted inulsatile fashion between 10:00 p.m. and 4:00 a.m. Sleepeprivation increases pulses, whereas sleep diminishes theulses. The TSH molecules secreted at night demonstrateess hormonal activity than do daytime molecules. There-ore, there is no nocturnal surge in thyroid hormone levelsn response to the increased secretion of TSH (6).

HYPOTHYROIDISM

he term hypothyroidism encompasses a broad spectrum
f disease. Hypothyroidism can be congenital or ac- h
uired, primary or secondary, overt or subclinical, andoiterous or nongoiterous. Primary hypothyroidism,aused by thyroid gland failure, is responsible for morehan 95% of cases of hypothyroidism. Low TSH or TRHevels from pituitary or hypothalamic failure cause cen-ral hypothyroidism, a relatively rare condition.

In areas of the world where iodine deficiency is un-sual, most cases of primary hypothyroidism are associ-ted with Hashimoto’s thyroiditis. Also known ashronic autoimmune thyroiditis, this disease is charac-erized by lymphocytic infiltration of the thyroid glandnd the presence of antibodies directed against the TSHeceptor, thyroperoxidase (TPO), and thyroglobulin. TheSH-receptor antibodies target a different area of the

eceptor than those found in patients with Grave’s dis-ase; these antibodies block the action of TSH ratherhan stimulate the gland (8). Seven of 10 patients withashimoto’s thyroiditis are women, and the incidence

ncreases with age. The disease assumes goiterous andtrophic forms; patients with goiter are usually asymp-omatic but sometimes have thyroid tenderness not re-ponsive to steroids (9).

Less common causes of hypothyroidism are listed inable 1 (5). The initial thyrotoxicosis seen in thyroiditis

s often followed by a period of transient hypothyroid-sm. Iodine deficiency is the most common cause of

able 1. Differential Diagnosis of Hypothyroidism

Mechanisms TSH FT4, FT3

rimaryhypothyroidism

Hashimoto’sdisease

Autoimmunedisease

High Low

Surgicalthyroidectomy

Iatrogenic High Low

External radiation Iatrogenic High LowAmyloidosis Infiltrative High LowLymphoma Infiltrative High LowScleroderma Infiltrative High LowIodine deficiency or

excessNutritional High Low

Drug-induced Iatrogenic High Lowecondary

hypothyroidismSheehan’s

SyndromePituitary infarction Low Low

Pituitary neoplasm Infiltrative/malignant Low LowPituitary radiation/

surgeryIatrogenic Low Low

Tertiaryhypothyroidism

Sarcoidosis Hypothalamicinfiltration

Low Low

Hypothalmicneoplasm

Malignancy Low Low

erived from reference (5).

ypothyroidism and goiter worldwide; it is rare in the

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Thyroid Function Tests 203

nited States due to the iodination of table salt. Para-oxically, iodine excess can also cause hypothyroidism:t inhibits the organification of iodine and the synthesisf T3 and T4 (the Wolff-Chaikoff effect) (10).

Methimazole and propylthiouracil decrease thyroidormone secretion and are used therapeutically to treatyperthyroid conditions. Drugs used for nonthyroid con-itions that can cause clinical hypothyroidism includemiodorone, lithium, alfa-interferon, and interluekin-2.ithium interferes with thyroid hormone synthesis andecretion: more than 50% of patients receiving long-termithium therapy develop a goiter, and 12% develop clin-cal hypothyroidism (11). Amiodorone has caused bothyperthyroidism and hypothyroidism; the rate of bothisorders is approximately 6 times higher in patientsaking amiodorone than in those on other antidysrhyth-ics (12).Clinical manifestations of hypothyroidism are the

onsequence of two basic physiologic effects of the lackf thyroid hormone: generalized slowing of metabolicrocesses and tissue deposition of glycosaminoglycans.linical manifestations of hypothyroidism with relative

requencies are listed in Table 2 (13). Because signs andymptoms of hypothyroidism are often nonspecific, de-elop insidiously, and can be mistaken for normal aging,linical detection can be difficult. Accordingly, labora-ory testing has assumed an increasingly important rolen the detection of hypothyroidism.

Myxedema coma is a rare and potentially lethal com-lication of hypothyroidism. It is usually the result ofcute decompensation in a patient with chronic hypothy-oidism, often precipitated by stress such as infection,

able 2. Sensitivity and Specificity of the 14 Symptoms andNegative Predictive Values

Symptoms/Signs Sensitivity (%)

nkle reflex 77ry skin 76old intolerancea 64oarse skin 60uffiness 60ulse rate � 75/mina 58iminished sweating 54eight increase 54araesthesia 52old skin 50onstipation 48low movements 36oarseness 34earing impairment 22

Positive predictive value.* Negative predictive value.wo signs (cold intolerance and decreased pulse rate) showedelayed relaxation of ankle reflex.erived from reference (13).

old exposure, trauma, surgery, or stroke or the use of s

edications such as amiodorone and lithium (14,15).he condition is seen almost exclusively in women over0 years of age and usually occurs during winter months16). Contrary to the name, patients do not necessarilyresent with coma or edema; clinical findings can in-lude altered mental status, hypothermia, hypoventila-ion, hypotension, bradycardia, constipation, periorbitaldema, nonpitting peripheral edema, and delayed relax-tion of deep tendon reflexes. Associated abnormal lab-ratory findings can include anemia, hyponatremia, hy-oglycemia, and elevated total creatinine kinase (CPK)evels. Myxedema coma can result in cardiovascularollapse; prompt recognition and treatment can be lifeaving. Patients presenting with possible myxedemaoma should be treated with levothyroxine, 100 �g to00 �g intravenously (17). An intravenous glucocorti-oid (hydrocortisone) is also recommended until adrenalnsufficiency and secondary hypothyroidism have beenxcluded (17). Passive rewarming, active respiratory andardiovascular resuscitation, and admission to a moni-ored setting are appropriate.

THYROTOXICOSIS AND HYPERTHYROIDISM

hyrotoxicosis refers to the increased metabolic and sym-athetic nervous state that develops when serum concentra-ions of free thyroid hormone are elevated. One effect isncreased sensitization to catecholamines. The terms thyro-oxicosis and hyperthyroidism are not synonymous. Hyper-hyroidism, defined as thyroid gland hyperfunction, causeshyrotoxicosis due to increased thyroid hormone biosynthe-

of Hypothyroidism and Analysis of Their Positive and

ecificity (%) PPV* (%) NPV** (%)

93.5 92.2 80.363.8 67.7 72.765 64.6 64.481.2 76.1 6796.3 94.2 70.742.5 50.2 50.386.2 79.6 65.277.5 70.6 62.882.5 74.8 63.280 71.4 61.585 76.2 6298.7 96.5 60.787.5 73.1 5797.5 89.8 52.6

e and negative predictive values below 70%. “Ankle reflex” is

Signs

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ccur, however, when thyroid gland function is normal.xamples include excess release of stored hormone from

hyroid gland inflammation, excess exogenous thyroid hor-one ingestion, and production of thyroid hormone from

ctopic foci (7). Careful clinical evaluation complementedy appropriate laboratory investigation can clarify the spe-ific etiology of thyrotoxicosis.

Graves’ disease is the most common cause of hyper-hyroidism in middle-aged patients and is the etiology for0% to 80% of all hyperthyroid patients. It is autoim-une in origin. Anti-TSH antibodies cause hyperstimu-

ation of thyroid hormone and thyroid follicle hyperpla-ia (18). On physical examination, goiter, exophthalmos,nd pretibial myxedema constitute the classic triad ofraves’ disease. Other causes of hyperthyroidism are

isted in Table 3 (7,19,20).Patients with thyrotoxicosis without hyperthyroidism

ay present initially to the ED. Subacute or de Quer-ain’s thyroiditis classically presents with a tender thy-oid gland, tachycardia, and flu-like symptoms. Multipleiruses have been linked to the disease. Physical exam-nation reveals a tender and enlarged thyroid gland. Thellness is self-limited and may be treated symptomati-ally with aspirin. More severe symptoms respond torednisone. Beta blockers may be used to treat peripheralanifestations of thyrotoxicosis (5).Subacute painless thyroiditis occurs in 2% to 6% of

ostpartum women in the United States. The usual timeourse is 3 to 6 months after delivery. It is likely the

able 3. Differential Diagnosis of Thyrotoxicosis

Mechanis

yperthyroid etiologiesGraves’ disease TSH receptor antibodiesToxic multinodular goiter Multiple foci of autonomoToxic adenoma Benign thyroid tumor with

functionMolar pregnancy Greatly increased HCG le

receptorsPituitary tumor TSH hypersecretionPituitary resistance to

thyroid hormoneFailure of normal feedbac

onhyperthyroid etiologiesDeQuervain’s thyroiditis Release of stored hormonPostpartum thyroiditis Release of stored hormonLingual goiter Ectopic thyroid hormoneStruma ovarii Ectopic thyroid hormoneThyroid carcinoma Ectopic thyroid hormoneJod-Basedow phenomenon Iodine exposure seconda

studiesChronic amiodarone use Iodine exposure from amThyrotoxicosis facititia Intentional thyroid hormoIatrogenic thyrotoxicosis Excessive dose of thyroid

supplement

erived from references (7,19,20).

esult of rebound immune activity. Fifty percent of pa- s

ients manifest a firm painless goiter on physical exam-nation. Thyrotoxic symptoms persist from 1 to 3onths. Beta blockade is effective symptomatic therapy

5). Clinical manifestations are precipitated by excessiveelease of thyroid hormone. Thyroiditis, a non-hyperthyroidondition, is differentiated from thyroid gland hyperfunc-ion by measurement of radioactive iodine (RAI) uptake.atients with hyperthyroidism will have high RAI uptakeue to the increased glandular activity. Those with thyroid-tis or exogenous thyroid ingestion will have low RAIptake in the face of thyrotoxicosis (19).

The clinical presentation of thyrotoxicosis resembleshyperadrenergic state. Younger patients are more likely

o present classically. Symptoms and physical findingsre presented in Table 4 (7,18–20). Variables affectinghe severity of the clinical presentation include durationf illness, hormone concentrations, and patient age (20).

Apathetic hyperthyroidism describes the blunted andtypical presentation of thyrotoxicosis in older adults. Co-orbidities may further confuse the picture (21). Nordyke

t al. found that weight loss was an increasingly commonnding in thyrotoxic patients with advancing age, reported

n 79% of those in the 8th decade (22). Thyromegaly washe most common physical finding, noted in 81% of patientslder than 60 years. Atrial fibrillation occurred in 13% ofhose over the age of 60 compared with 2% of hyperthyroidatients under that age.

Thyroid storm is an emergent multisystem disorderhat manifests when organs respond violently to exces-

RAI Uptake TSH FT4, FT3

High Low Highroid function High Low Highomous High Low High

imulate TSH High Low High

High High Highhanism High High High

Low Low HighLow Low High

on Low Low Highon Low Low Highon Low Low Highdiologic Low Low High

e Low Low Highstion Low Low High

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s precipitated by infections, trauma, surgery, diabeticetoacidosis, pseudoephedrine, salicylates, excessive in-estion of iodine, and incorrect discontinuation of anti-hyroid drugs (20,23–26). Clinical manifestations in-lude fever, confusion, seizure, coma, tachycardia out ofroportion to fever, diaphoresis, nausea, vomiting, diar-hea, and cardiac dysfunction (26,27). Thyroid storm canccur in patients of any age, from children to the elderly26,28,29). The diagnosis must be suspected on clinicalrounds and confirmed with thyroid function tests. Theattern of abnormality in thyroid storm is identical to thatn thyrotoxicosis, with a very depressed TSH concentra-ion and elevations of FT4 and FT3. No specific levelistinguishes the two. Other laboratory abnormalitiesncountered in thyroid storm include hyperglycemia, hy-ercalcemia, and hepatic function abnormalities (29).his disorder is frequently fatal, with a mortality rate ofpproximately 30% in the treated patient. High-dose betalockers can be life saving in conjunction with propyl-hiouracil, stable iodide, glucocorticoid administration,nd supportive care. Iodide administration should beelayed 1 h after initiation of propylthiouracil (30).

Thyrotoxic periodic paralysis (TPP) is most com-only seen in Asian men in the third decade of life.hough there is a strong female predominance amongatients with hyperthyroidism, TPP is an overwhelm-ngly male disorder (31),. Kelley et al. found an inci-ence of TPP of 0.1% to 0.2% among North American

able 4. Clinical Manifestations of Thyrotoxicosis

Organ System Symptoms

ardiovascular PalpitationsDyspnea

ermatologic Hair loss

astrointestinal Increased appetiteWeight lossHyperdefecationDiarrhea

ynecologic OligomenorrheaAmenorrheaSymptoms following

europsychiatric AnxietyFatigueInsomniaIrritabilityHeat intolerance

phthalmologic Feeling of grittinessRetrobulbar pressureDiplopia

hyroid gland Neck fullnessDysphagia

erived from references (7,18–20)

yperthyroid patients (32). Clinically, patients present s

ith proximal symmetric muscle weakness. Progressiono paralysis may occur. Lower extremity weakness is moreommon than upper (32). High carbohydrate loads, strenu-us physical activity followed by rest, trauma, surgery, coldxposure, infection, insulin, catecholamines, and glucocor-icoid and mineralocorticoid administration have been iden-ified as precipitating or predisposing factors (33,34). Therimary laboratory finding is hypokalemia (32). TheSH level should be low or undetectable Acute treatmentonsists of potassium replacement. Beta-blocker therapyay be instituted for hyperadrenergic symptoms and in

xtreme cases may be life saving (33).The single best screening tool for thyrotoxicosis is an

ltrasensitive TSH screen (35). Patients with the labora-ory combination of undetectable TSH and normal FT3nd FT4 serum levels may have subclinical hyperthy-oidism secondary to Graves’ disease. Although overtymptoms of disease are absent in patients with subclin-cal hyperthyroidism, subtle manifestations of thyrotox-cosis may be present (22). Sawin et al., using theramingham data, found the relative risk of atrial fibril-

ation to be 3.1 in elderly patients with subclinical hy-erthyroidism, relative to euthyroid patients (36).

TSH ASSAYS

n patients with an intact hypothalamic-pituitary axis,

Physical Findings

Sinus tachycardiaAtrial fibrillationCongestive heart failureHair lossWarm, moist, smooth skinPalmar erythemaPretibial myxedema Onycholysis

ncyFine tremorHyperreflexiaMuscle wasting and weaknessPeriodic paralysis

ExophthalmosConjunctival injectionOphthalmoplegiaThyroid enlargement

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arge inverse changes in the TSH level. Therefore, a lowerum TSH concentration indicates elevated thyroid hor-one activity, whereas a high TSH concentration sug-

ests hypothyroidism. Due to the remarkable sensitivityf the hormonal feedback mechanism, the TSH is a morerecise indicator of thyroid status than the actual thyroidormone level; abnormal TSH values indicate mild thy-oid dysfunction (subclinical hyperthyroidism or hypo-hyroidism) even when FT4 is within the normal range.n the absence of hypothalamic or pituitary disease, aormal TSH value effectively excludes significant thy-oid disease.

The first generation of TSH assays was developed in the960s using radioimmunoassay (RIA) technology and hadfunctional sensitivity of approximately 1 mU/L. These

ests were useful only in detecting high TSH values indi-ating hypothyroidism. Thyrotoxic states could not be de-ected because the tests lacked sufficient sensitivity to dis-inguish between low and normal TSH values.

In the past 20 years, second- and third-generationSH tests with improved sensitivity have been devel-ped. These immunometric assays use a sandwich tech-ique, whereby serum is first incubated with monoclonalnti-TSH antibodies attached to beads or another form ofolid support. After washing, a second labeled anti-TSHntibody is introduced, which binds to the fixed TSHolecules. The amount of labeled antibody bound to the

olid support is then measured, giving an estimate of theuantity of TSH in the specimen. The original second-eneration immunometric TSH assays developed in the980s used radioisotopic labels (I125). These assays wereound to be 10-fold more sensitive than the first-eneration RIA assays, with a functional sensitivity ofpproximately 0.1 mU/L. New third-generation assayseveloped in the 1990s, utilizing fluorescence, chemilu-inescence, and other non-isotopic methods, have even

igher functional sensitivity, 10-fold greater, to 0.01U/L. Commercial TSH assays are marketed as having

pecific functional sensitivities, but the manufacturer’stated sensitivity is not always duplicated in clinicalractice (37). Accordingly, independent verification ofn assay’s functional sensitivity is recommended. Cur-ent guidelines recommend the use of an assay that caneliably detect a TSH level of 0.02 mIU/L or less (35).ormal TSH values fall between 0.5 and 5.0 mIU/L.The cost of a TSH level is reflected in the Medicare

eimbursement rate. In 2004, the national limit for reim-ursement for a TSH assay (CPT Code 84443) was23.47 (Medicare Clinical Diagnostic Laboratory Feechedule, publicly available at www.cms.hhs.gov).hen offered as a stat test, hospital laboratories offer 2-h

ompletion times. Technology for point-of-care testingurrently exists but not for the ultrasensitive third-
eneration quantitative test. The detection threshold for a r
5-min test is .2 mIU/L (38). This degree of sensitivity isseful only for the diagnosis of hypothyroidism.

T4 AND T3 ASSAYS

otal T3 (TT3) and total T4 (TT4) are measured usingmmunometric assays employing isotopic (RIA) or non-sotopic labels. Because these tests measure total (free �rotein-bound) hormone concentrations, results may notccurately reflect clinical thyroid status. Although onlynbound hormone is active, 99.7% of T3 and 99.97% of4 in serum is protein bound (4). A number of factorsltering the concentration of TBG (thyroxine-bindinglobulin) or degree of hormone protein binding willffect the accuracy of TT3 or TT4 as a measure ofhyroid function. Thyroid-binding globulin concentra-ions are elevated in patients with infectious hepatitis, inregnant women, and in patients taking estrogens, in-luding tamoxifen and oral contraceptives, or opiatesuch as methadone and heroin. Thyroid-binding globulinevels are decreased in patients with chronic liver dis-ase, nephritic syndrome, or severe systemic illness andn those taking androgens or glucocorticoids. Manyrugs interfere with hormonal protein binding, includingeparin, furosemide, phenytoin, carbamazepine, diaze-am, salicylates, and non-steroidal anti-inflammatoryrugs (NSAIDs). Due to these limitations, assays mea-uring free hormone concentrations have largely re-laced total hormone levels in clinical use.

FT4 AND FT3 ASSAYS

number of methods have been developed to approxi-ate or directly measure free hormone levels. The free

ormone indexes (FT4I and FT3I) are derived fromalculations combining TT4 or TT3 with the results of aecond assay reflecting TBG concentration, such as thehyroid-hormone–binding ratio (THBR) or TBG immu-oassay.

The THBR tests, formerly called “uptake” tests, T3esin uptake (T3RU), have long been a source of confu-ion. In the first step of such an assay, a small amount ofadiolabeled T3 (or T4) is added to a serum specimen,llowing labeled hormone to bind available TBG sites.fterward, a resin or other absorbent is introduced,hich binds remaining (free) radiolabeled hormone. The

mount of tagged hormone taken up by the resin is the3RU. The T3RU is an inverse measure of the amount ofvailable TBG in the specimen; if many binding sites arevailable (increased TBG concentration), few radiola-eled hormone molecules will be left to bind the resin, so
esin “uptake” will be low; the converse is also true. The
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HBR is the ratio of resin uptake in a given specimenompared with that of a standard; normal THBR is 0.9 to.1. The free hormone index (FT4I) gives an estimate ofT4 and is the product of TT4 and THBR: TT4 � THBR

FT4I. Although more useful than total hormone levels,ree hormone indexes can still be influenced by severebnormalities of serum-binding proteins and are there-ore less accurate than assays designed to measure freeormone concentration more directly.

The most accurate direct method of measuring freehyroid hormones requires physical separation of freerom bound hormone using equilibrium dialysis. Unfor-unately, separation techniques are too time consumingnd expensive to be clinically practical and are usedainly in reference laboratories. Commercial FT4 im-unoassay kits utilize “two-step,” “analog,” or “labeled

ntibody” methods. Most clinical laboratories now useabeled-antibody–type free hormone assays, in which theree T4 present in a patient’s serum competes with T4olecules attached to a solid phase for labeled anti-T4

ntibodies. The amount of labeled antibody binding tohe solid phase varies inversely with the concentration ofree T4 in the serum, and an estimate of the FT4 con-entration is derived. Similar assays are available tostimate FT3.

Free hormone levels are less reliable measures ofhyroid function than are TSH assays because they areore susceptible to factors that can adversely affect test

ccuracy. Free T4 assays vary in diagnostic accuracy andhe effects of patient conditions such as medications,evere nonthyroidal illness, and hormone-binding proteinbnormalities vary among the different commercial as-ays (39). Notably, the administration of heparin, includ-ng low-molecular-weight heparin, can interfere with theT4 laboratory assay, resulting in an erroneously ele-ated FT4 level (40).

The 2004 national limit for Medicare reimbursementas $12.60 for FT4 (CPT code 84439) and $23.67 forT3 (CPT code 84481) (publicly available at www.cm-.hhs.gov). This national standard is reflective of the costf the tests. When offered as a stat test by hospitalaboratories, the turn-around time for FT4 is 2 h. FT3 isess commonly available as a stat offering. Neither assays currently available as a point-of-care test.

EMERGENCY DEPARTMENTTESTING STRATEGY

any hospital laboratories can process thyroid functiontudies rapidly enough to provide results during a pa-ient’s ED evaluation. Candidates for thyroid functionesting clearly include patients with presentations con-
istent with thyroid storm or myxedema coma. Other T
atients with milder signs or symptoms consistent withhyroid dysfunction may also benefit from thyroid func-ion testing; in many cases, abnormal results will helpstablish a diagnosis and facilitate appropriate referralnd follow-up. A single sensitive TSH assay is the ap-ropriate initial test to evaluate thyroid function; withare exception, a normal TSH effectively excludes thy-oid dysfunction. A FT4 test should be obtained foratients discovered to have an abnormal TSH concentra-ion (41). Free T4 should be assessed in patients exhibitingvidence of pituitary or hypothalamic disease and thoseecently treated for thyroid disorders. Routinely screeningD patients for thyroid disease is not indicated.

CONFOUNDING FACTORS

he accuracy of the TSH measurement can be affectedy a number of other factors, which include certainedications and non-thyroidal illness. The discrepancy

etween the serum half-life of TSH (approximately 1 h)nd that of T4 (1 week) can lead to discordant TSH/FT4alues when thyroid status is in flux. Abnormal TSHevels can persist for weeks or even months after initia-ion of treatment for hyperthyroid or hypothyroid disor-ers (42,43). Accordingly, caution should be used whennterpreting a single TSH result for a patient who hasecently started treatment for either condition or whosehyroid medication has been recently adjusted.

Several commonly used drugs can directly affect theesults of thyroid function studies. Dopamine inhibitsSH secretion; prolonged administration can sometimesause central hypothyroidism (44). Glucocorticoids, so-atostatin, and octreotide are also known to lower serumSH levels but do not affect thyroid function (45).

Diagnosing thyroid disease in patients with non-hyroidal illness can be challenging because the speci-city of the TSH assay is lower in this group (46). In onetudy, 17.2% of 1580 hospitalized patients had abnormalSH results; 85% of these patients were determined to beuthyroid on follow-up evaluation (47). The value ofbnormal TSH results in patients with psychiatric illnesslso has been questioned: a meta-analysis of 1479 pa-ients hospitalized for psychiatric illness found that2.2% had abnormal TSH values, 97% of whom wereater determined to be euthyroid (46).

Patients with severe non-thyroidal illness often havebnormally low FT3 and FT4 levels, inappropriately lowSH levels, and reduced conversion of T4 to T3 (48).ormerly termed the “euthyroid sick syndrome,” someuthors now prefer the term “non-thyroidal illness syn-rome.” (49). This syndrome is thought to be a form ofentral hypothyroidism, possibly due to suppression of
RH secretion (49). The thyroid function test abnormal-


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ties are transient, and thyroid hormone treatment has noteen shown to be beneficial. A third-generation TSHssay with a sensitivity of at least 0.01 mIU/L may helpistinguish patients with undetectable TSH due to realhyroid disease from those with low but detectable TSHalues due to medications or non-thyroidal illness (50).

CONCLUSION

he recent development of highly sensitive immunomet-ic TSH assays has simplified the recommended ap-roach to thyroid function testing. The rapidity and costf the test render it suitable for use in the ED. Becausehis simple and effective tool for detecting thyroid dis-ase has only recently become available for ED use,pecific indications for the test have not been confirmed.hyroid function testing in the ED patient is an areappropriate for study for development of evidence-baseduidelines.

cknowledgment—We thank Linda Kesselring, ELS for hernvaluable assistance with this project.

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thyroid disease in the emergency department: a clinical and laboratory review

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