thyrotoxicosis - lee metchick, vilma carlone e cols

8/13/2019 thyrotoxicosis - lee metchick, vilma carlone e cols

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he term thyrotoxicosisrefers to all causes of ele-vated thyroid hormones circulating in thebody, whereas the term hyperthyroidismde-scribes a disease process caused by the thyroid

gland overproducing and secreting excessive amountsof thyroid hormone. A recently published survey sug-

gests a prevalence of thyrotoxicosis in the United Statesof approximately 0.5%.1 Thyrotoxicosis causes a widerange of symptoms, including nervousness, palpita-tions, heat intolerance, diaphoresis, tremor, fatigue,and weight loss.

The most common cause of thyrotoxicosis is Gravesdisease, which accounts for approximately 60% to 80%of cases of hyperthyroidism in the United States and inother countries where the population has adequateiodine intake.2 Iodine-deficient populations have amuch lower incidence of Graves disease (< 50%).3

Graves disease is approximately 5 to 10 times more

common in women than in men; the incidence is simi-lar among Caucasian and Asian populations but loweramong African Americans.2 Patients younger than age40 years are at the highest risk for the development ofGraves disease.4

Other causes of thyrotoxicosis include toxic multi-nodular goiter, solitary toxic nodules, and thyroiditis.Treatment for thyrotoxicosis depends on the underly-ing disorder and may include -blockers, antithyroidmedications, radioactive iodine ablation, and surgery.This article reviews the clinical features of thyrotoxico-sis, including behavioral, musculoskeletal, dermatolog-ic, ophthalmologic, cardiovascular, gastrointestinal,and reproductive features. Laboratory findings arebriefly discussed, and studies used to establish the etiol-ogy of thyrotoxicosis are reviewed. The treatments arepresented in context of the specific etiology of thyro-toxicosis.

CLINICAL FEATURES

The clinical features of thyrotoxicosis are diverseand can affect most organ systems. More than 50% ofpatients with thyrotoxicosis develop symptoms of ner-

vousness, rapid heartbeat or palpitations, heat intoler-

ance, fatigue, and weight loss.5 Patients with Gravesdisease usually present with a diffusely enlarged goiter.5

The goiter is normally nontender but may be slightlytender to palpation, and, if significantly enlarged, cancause pressure symptoms. Auscultation over the lobesof the thyroid may reveal a characteristic soft bruit,

which is virtually diagnostic for Gravesdisease.

Behavioral Features

Patients with thyrotoxicosis may complain of emo-tional lability, anxiety, and difficulty concentrating. Dif-ficulty with sleep patterns in these patients can con-tribute to symptoms of moderate to profound fatiguethroughout the day. Patients with thyrotoxicosis may berestless during the history and physical portions of themedical examination.

Neurologic Features

A fine tremor is commonly seen in thyrotoxicosis.The physician may elicit the tremor by asking the pa-tient to hold the hands outstretched (simultaneouslyclosing the eyes may enhance the tremor) or by stick-ing out the tongue. Patients may also develop proximalmuscle weakness and have difficulty performing ordi-nary activities, such as climbing a flight of stairs, reach-ing the arms over the head, or standing from a sittingposition without the assistance of ones hands.

Dermatologic Features

Patients with thyrotoxicosis may have unusuallysmooth skin, especially over the elbow, because of adecrease in the keratin layer.6 The skin also can be warmand even diaphoretic because thyrotoxicosis can causean increase in blood flow. This increased warmth is usu-ally associated with heat intolerance, which is a common

T

Drs. Metchick and Carl one are fellows, Divi sion of Endocrinology,

Diabetes, and Metabolism, Baystate Medical Center, Springfield, MA.

Dr. Haag is medical director, Division of Endocrinology, Diabetes, and

Metabolism, Baystate Medical Center, and associate clinical professor of

medicine, Tufts University School of Medicine, Boston, MA.

46 Hospital Physician March 2005 www.turner-white.com

C l i n i c a l R e v i e w A r t i c l e

Thyrotoxicosis

Lee N. Metchick, MD

Vilma Carlone, MD

Burritt L. Haag, MD


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feature of thyrotoxicosis. The fingernails of patients withthyrotoxicosis may be soft and loosened from the nailbed, developing a characteristic onycholysis or Plum-mers nails.More rapid hair shedding occurs in thyro-

toxicosis, causing diffuse hair loss and thinning.In a small subset of patients with Gravesdisease,dermopathy may be present, characterized by lymphocyt-ic infiltration of the dermis layer of skin, accumulation ofglycosaminoglycans, and edema.7Although uncommon,this infiltrative dermopathy or localized myxedema tendsto occur in older patients with severe ophthalmopathy.8

The most frequent area of occurrence is over the antero-lateral aspects of the shin (pretibial myxedema) butdermopathy can also occur at other sites, especially aftermild trauma. The dermopathy is usually nonpitting,thickened, indurated, and although usually asymptomat-

ic, may be pruritic or painful.

Ophthalmologic Features

Thyrotoxicosis can result in contraction of the eye-lid muscles (levator palpebrae) because of increasedsympathetic tone that causes both the characteristicstare and lid lag.9 Approximately 25% of patients

with Gravesdisease develop clinically evident ophthal-mopathy.10 These clinical features can even precedethe diagnosis of Gravesdisease.2 Ophthalmopathy inGravesdisease is more common in Caucasians than

Asians, and older men are at highest risk of severe oph-

thalmopathy.11 In addition, ophthalmopathy in Gravesdisease appears to be more common and severe in pa-tients who smoke cigarettes.12Almost all patients whodevelop bilateral ophthalmopathy are diagnosed withGravesdisease.

Most of the clinical manifestations of ophthalmopa-thy associated with Gravesdisease are caused by anincrease in the volume of retrobulbar tissue.13 This in-crease results in the characteristic exophthalmos(proptosis). Ophthalmopathy in Gravesdisease ischaracterized by edema and inflammation of theextraocular muscles and increased orbital connectivetissue and fat. The edema is thought to be caused bythe hydrophilic action of fibroblast-secreted glycos-aminoglycans, whereas the inflammation results fromlymphocytic infiltration of the extraocular muscles andorbital connective tissue.14 Involvement of the extraoc-ular muscles can result in impairment of eye musclefunction, leading to diplopia. Exophthalmos occurs inapproximately 25% to 30% of patients with ophthal-mopathy in Gravesdisease; approximately 5% to 10%of these patients develop diplopia.15 Severe ophthal-mopathy may lead to a dry or grittysensation in theeyes and even to the development of corneal ulcera-

tions because of the inability to fully close the eyelidsduring sleep. Other complications include periorbitaledema, conjunctival edema, conjunctival hyperemia,and photophobia.

The clinical course of Gravesophthalmopathy isindependent of thyroid status but is usually more severein patients with poorly controlled hyperthyroidism. Theclinical features typically worsen over the initial 12 to18 months and subsequently stabilize; however, sudden

worsening of ophthalmopathy may occur spontaneous-ly and independent of therapy. Spontaneous improve-ment of mild ophthalmopathy occurs in approximately60% of patients.16

Cardiovascular Features

The hypermetabolic state of thyrotoxicosis leads to

an increase in cardiac output manifested by increasedheart rate, widened pulse pressure, and decreasedperipheral vascular resistance.17A flow murmur may bedetected during cardiac examination of a patient withthyrotoxicosis. High-output congestive heart failurecan occur in patients with severe thyrotoxicosis. A com-mon feature of thyrotoxicosis is the development ofcardiac arrhythmia. Atrial fibrillation occurs in up to20% of patients with thyrotoxicosis and is more com-mon in patients age 60 years or older; other arrhyth-mias, such as atrial ectopy, also can occur.18 In morethan 50% of patients with thyrotoxicosis-induced atrial

fibrillation, the rhythm can spontaneously convert tosinus rhythm when the thyrotoxicosis is treated.19 Thehypermetabolic state increases oxygen consumption,causing some patients to develop symptoms of angina,dyspnea, and chest discomfort.20

Gastrointestinal Features

Patients with thyrotoxicosis often become hyper-phagic to compensate for their higher metabolic rate.This increase in appetite usually occurs in conjunction

with weight loss. Gut motility is increased, causing hy-perdefecation (but not necessarily diarrhea), whichcan lead to malabsorption of nutrients. Additionally,symptoms of obstructive dysphagia can occur when alarge goiter is present.

Reproductive System Features

Menstrual irregularities can be the presenting symp-tom in women with thyrotoxicosis. Oligomenorrhea,the most common menstrual disorder in thyrotoxicosis,is characterized by elevated luteinizing hormone (LH)and follicle-stimulating hormone levels, loss of mid-cycle LH peak, and consequent anovulation. Excessthyroid hormone increases sex hormonebinding

M e t c h i c k e t a l : T h y r o t o x i c o s i s : p p . 4 6 5 6

www.turner-white.com Hospital Physician March 2005 47


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globulin (SHBG) production, thereby increasing serumestrogen and testosterone levels.21Whereas the circulat-ing total sex hormone concentrations are increased,the free hormone concentrations are normal or evenslightly reduced. Estrogen is metabolized more rapidlybecause of the hypermetabolic state. This combinationof factors reduces the mid-cycle surge of LH secretion,causing oligomenorrhea and, in cases of severe thyro-toxicosis, amenorrhea.22

In men, gynecomastia and sexual dysfunction as fea-tures of thyrotoxicosis have been well established. Thefrequency of gynecomastia in men with thyrotoxicosishas been reported to be up to 40%.23 Gynecomastia asthe initial presentation is uncommon but has beenreported.24,25 As previously described, SHBG produc-tion is increased in thyrotoxicosis. SHBG binds bothandrogens and estrogens but has a higher affinity forandrogens; therefore, the level of free androgen rela-tive to estrogen is lower, leading to increased estrogenbioactivity.26Also, enhanced aromatization of testos-

terone in the periphery occurs, which also contributesto increased estrogen levels.24,27

Bone Health

A high level of thyroid hormone stimulates boneresorption, thereby causing a loss of both cortical andtrabecular bone (a higher degree of cortical bone lossthan trabecular bone loss occurs).28 The higher rate ofbone resorption may lead to hypercalcemia. Overall,untreated thyrotoxicosis is a significant risk factor forthe development of osteoporosis and fractures.29

LABORATORY FINDINGS

The diagnosis of thyrotoxicosis may be evident basedon clinical findings and subsequently confirmed bio-chemically. Thyroid-stimulating hormone (TSH) con-centrations are suppressed because of the high levels ofcirculating thyroid hormone. The most cost-effectiveinitial test to diagnose thyrotoxicosis is a serum TSHconcentration alone (Figure). The clinician should be



Suspected thyrotoxicosis; check TSH

Toxic solitary

nodule or multi-

nodular goiter

TSH 0.44.0 U/mL TSH > 4.0 U/mLTSH < 0.4 U/mL

? Hyperthyroidism

Verify and check FT4 and FT3 levels

Hyperthyroidism; check 123I uptake

FT4 normal; FT3 normal FT4 low; FT3 low or normal

Repeat TSH, FT4

, and

FT3 in 2 months

Subclinical hyperthyroidism

YesNo

? Central hypothyroidism

Normal or high

Silent thyroiditis;

postpartum

thyroiditis

Subacute

thyroiditis

Diffuse goiter Nodular goiter

Hypothyroidism

Figure. Algorithm for the diagnosis of hyperthyroidism. FT3 = free triiodothyronine; FT4 = free thyroxine; TSH = thyroid-stimulating

hormone.

Euthyroid

Gravesdisease

FT4 elevated; FT3 normal

or elevated

FT4 normal; FT3 elevated

Painful thyroid gland?

Low


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measurements can be helpful in differentiating Gravesdisease from toxic multinodular goiter in older pa-tients who have none of the usual signs of Gravesdis-ease. Thyroid peroxidase antibodies are present in

many patients with Gravesdisease and can also be use-ful in differentiating Gravesdisease from toxic multi-nodular goiter. For cases in which radioiodine uptakeand thyroid scintigraphy are contraindicated (eg, preg-nant patients), laboratory measurement of serum T3 toT4 ratio may sometimes be helpful. A serum T3 to T4ratio greater than 20 would favor Gravesdisease.32

Graves Disease

Gravesdisease is an autoimmune disease caused byproduction of antibodies to the TSH receptor. Gravesdisease shares many immunologic features with Hashi-

motos thyroiditis (chronic lymphocytic thyroiditis),which is the most common cause of hypothyroidism.These shared features of disease include high serumconcentrations of antibodies against thyroglobulin andthyroid peroxidase.33 Thyroid-stimulating immuno-globulins cause enlargement of the thyroid follicles,

which results in the characteristic diffuse goiter andoverproduction of thyroid hormone.34 Althoughthyroid-stimulating immunoglobulins are the cause ofGravesdisease, the titers can be very low or even unde-tectable in this disease.35

Treatment should be directed at the amelioration ofthe symptoms of hyperthyroidism via the use of-blockers, antithyroid medications, radioactive iodineablation, or surgery (Table 2).36Whichever option isselected, monitoring the patient clinically and bio-chemically is important to determine the point at

which the patient becomes euthyroid or hypothyroidor if the patient remains hyperthyroid.

-Blockers. Thyrotoxicosis is associated with in-creased sympathetic activity, causing various symptomsincluding palpitations, anxiety, tremors, and heat intol-erance. Therefore, the earliest relief patients can re-ceive during initial treatment of their symptoms is from

-blockers. -Blockers offer a beneficial adjunctivetherapy to antithyroid medications. Treatment shouldbe initiated early during the diagnostic evaluation ofthyrotoxicosis because it does not interfere with fur-

ther diagnostic testing. It is important to rememberthat, although -blockers alleviate symptoms, thesedrugs do not work to reduce thyroid hormone produc-tion. (Of note, propranolol has some ability to de-crease the conversion of T4 to T3 in peripheral tissue).Most -blockers are equally as effective, but the pre-ferred medications are those with a longer duration ofaction. Several preparations of -blockers are long act-ing, either because of a long half-life (atenolol) or asustained-release preparation (metoprolol and propra-nolol). Initially, higher doses may be required until aeuthyroid state is achieved; appropriate titration

should then be performed. Patients with congestiveheart failure or asthma should be followed closely

when -blockers are added to their regimen.Antithyroid medications. Medical therapy with anti-

thyroid drugs, thionamides (propylthiouracil [PTU] ormethimazole), is a valid option for Gravesdisease.Both PTU and methimazole (when converted to itsactive metabolite carbimazole) act to inhibit thyroidperoxidase, thereby inhibiting thyroid hormone syn-thesis.36 PTU has a secondary action of blocking theextrathyroidal deiodination of T4 to T3. This additionalaction may more quickly improve symptoms by rapidlyreducing serum T3 concentrations. Most physiciansprefer methimazole to PTU because methimazole hasa longer duration of action that allows for dosing 1 to2 doses/d versus 2 to 4 doses/d with PTU. In the preg-nant patient, PTU is preferred for treatment of thyro-toxicosis because the risk of aplasia cutis is slightlyincreased with methimazole.

When initiating therapy with thionamides, the start-ing dose should be the lowest dose necessary to obtain aeuthyroid state; that dose varies according to the severityof the hyperthyroidism. The dose is lower in patients

with smaller thyroid glands and lower initial radioiodine



Table 2. Comparison of Treatment Options for GravesDisease

Treatment Definitive Permanent Side

Modality Treatment Hypothyroidism Pregnancy Effects

Medical therapy Lower probability Unlikely

(thionamides)

Radioactive Yes Likely

iodine

Surgery Yes Definite

Risk of fetal goiter or hypothy-

roidism (if dose is too high)

Contraindicated

Possible in second or third

trimester

Rash/hives, arthralgias, anorexia, nausea,

abnormal taste

Possible radiation-induced thyroiditis or

worsened ophthalmopathy

Increased risk for hypoparathyroidism, recur-

rent laryngeal nerve damage, hemorrhage


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uptakes and, conversely, higher in patients with largegoiters and higher radioiodine uptakes. Thyroid func-tion tests should be rechecked 4 to 6 weeks after initia-tion of therapy, and doses should be adjusted as needed

to achieve and maintain a euthyroid state and to avoidhypothyroidism. Initially, focus should be on the free T3and free T4 levels when trying to achieve a euthyroidstate because patients with Gravesdisease may have lowor suppressed TSH levels for up to several months afterperipheral thyroid hormone levels have been normal-ized. The thyroid function of patients receiving therapy

with thionamides should be assessed at 4- to 6 -weekintervals until the function is stable.

Medical therapy for Gravesdisease has distinctadvantages. It offers a chance for remission while avoid-ing radioactive treatments or surgery. In addition,

medical therapy costs less than other treatment op-tions.37 Medical therapy has several disadvantages, how-ever, that must be discussed with the patient. Severalprospective randomized studies have demonstratedthat treatment with thionamides should only be usedfor 1 to 2 years because longer treatment offers noadditional benefit.3840 The chance of permanent re-mission after cessation of therapy is approximately35% to 50% versus definitive treatment with radio-active iodine or surgery.41 In approximately 15% ofpatients with Gravesdisease, autoimmune hypothy-roidism develops 10 to 15 years after medical treat-ment.42 Additionally, the side effect profile of thion-amides complicates long-term therapy. Side effectsinclude rash, hives, arthralgias, and gastrointestinalproblems. Thionamides also have a low incidence (re-ported 0.2%0.5%) of agranulocytosis.43 If the patientdevelops fever or signs of upper respiratory infection, acomplete blood count must be performed to ensurethat the patient is not neutropenic.44

Radioactive iodine. Radioactive iodine 131 (131I) isthe therapy of choice for most patients with Gravesdisease in the United States.45 Iodine 131 is rapidly con-centrated in thyroid tissue and ablates the thyroid usu-

ally within 6 months after the administration.46 Radio-active iodine can be given as an initial therapy to pa-tients with mild to moderate hyperthyroidism; howev-er, patients with severe hyperthyroid states, elderly

patients, or patients with underlying heart diseaseshould be pretreated with a thionamide and -blockersto achieve a euthyroid state prior to radioactive iodinetreatment. Radioactive iodine therapy is contraindicat-ed in pregnant women.

Although the advantage of radioactive iodine thera-py is the permanent elimination of hyperthyroidism atminimal inconvenience to the patient, there are somedisadvantages. The most significant disadvantage isthat almost all patients with Gravesdisease treated

with radioactive iodine become hypothyroid. Anotherdisadvantage occurs in patients with Gravesophthal-

mopathy. Via a mechanism that is not clearly under-stood, there is a risk of worsening the ophthalmopathyin those patients treated with radioiodine, especially inthe patients who smoke.47 Patients with significantGravesopthalmopathy should be treated with gluco-corticoids at the time of radioactive iodine ablation fora minimum of 1 month.48

Patients receiving radioactive therapy must followcertain precautions for 3 to 4 days after the administra-tion of 131I. These precautions include avoiding contact

with young children and pregnant women, avoidingclose contact with other people (ie, maintaining a dis-

tance of more than 3 ft except for short periods oftime), and ensuring proper hygiene to avoid 131I inbodily secretions from affecting other people. Rarely,symptomatic radiation thyroiditis may develop. Patientsshould be cautioned about the possible exacerbationof thyrotoxic symptoms following the dose administra-tion because thyroid hormone is released from thedamaged thyroid tissue.

Surgery. Surgery is infrequently performed today asa treatment for Gravesdisease, given the enormoussuccess and safety of radioactive iodine. Surgical inter-

vention may be offered to pregnant women withGravesdisease who have experienced a severe adversereaction to antithyroid medication. Surgery is also indi-cated for patients who have experienced a severeadverse effect to antithyroid medication and refuseradioactive iodine therapy; as well as those who havehad a 1- to 2-year trial of antithyroid medication, havenot gone into remission, and refuse radioactive iodinetherapy. Surgical intervention may also be offered topatients with Gravesdiseases who have a suspiciousnodule within the gland or to those who have verylarge goiters and in whom medical therapy is unsuc-cessful because in such cases, radioactive iodine may be



Adverse Laboratory

Reactions Monitoring Cost

Agranulocytosis or lupus-like

syndrome

Requires radiation safety pre-

cautions after treatment

Risks associated with general

anesthesia

Frequent

Within 2 to

3 months

Within 2 months

Lower cost

Higher cost

Higher cost


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less effective and repeated doses may have to be admin-istered for successful treatment. Surgery can offer apermanent cure of the hyperthyroid state in patients

with Graves disease.49 Complications associated with

surgical removal of the thyroid may be the induction ofhypothyroidism, increased risk for hypoparathyroid-ism, recurrent laryngeal nerve damage, or complica-tions surrounding general anesthesia.

Toxic Multinodular Goiter

The exact mechanism for an autonomous function-ing nodule or nodules is not fully understood but isbelieved to involve a mutation of the TSH receptor orof the Gs -subunit resulting in the activation of theTSH receptor.50 Similar to Graves disease, patients

with a toxic multinodular goiter usually present with

features of thyrotoxicosis; however, examination of thethyroid usually discloses multiple palpable nodules ver-sus the smooth gland found in Gravesdisease. Whenradioactive iodine uptake and scintigraphy are per-formed in cases of toxic multinodular goiter, a hetero-geneous pattern is seen with many regions of hyperac-tivity (hotareas) noted on the scan relating to theregions of autonomous overproduction of thyroid hor-mone interspersed with hypoactive regions. Given themixed pattern of activity, the overall uptake of the thy-roid gland may be lower than that in Gravesdisease, in

which the entire gland is overactive. Toxic multinodu-

lar goiters occur more commonly in the elderly and inpopulations who have low iodine intake.51

The treatment of a toxic multinodular goiter in theUnited States is usually with radioactive iodine abla-tion. Given that the overall uptake of the gland may belower, higher doses of radioactive iodine are necessary;however, the cure rates are similar to those described

with Gravesdisease.52Antithyroid medications can beused in toxic multinodular goiter but are not appropri-ate for long-term use because, unlike Gravesdisease,there is no possibility of remission. Thyroidectomy canbe offered to patients with a toxic multinodular goiterthat produces compressive symptoms because thedecrease in the size of the gland after radioactive io-dine is often minimal.

Toxic Solitary Nodules

Solitary adenomas occur sporadically and similarlyto toxic multinodular goiters: autonomous productionof thyroid hormone occurs and is likely a result of acti-

vating mutations in the TSH receptor or Gs alpha sub-unit.50 However, the single adenoma causes suppres-sion of the remaining thyroid gland. The adenomatends to be a large nodule ( 3 cm) and usually can be

palpated on physical examination.53 Treatment can besurgery, particularly in young patients, or radioactiveiodine ablation, especially in older patients. The pa-tients who choose to undergo radioactive iodine abla-

tion usually have a lower incidence of post-ablationhypothyroidism because the radioactive iodine is usual-ly concentrated within the solitary hyperfunctioningadenoma rather than affecting the entire gland as inGravesdisease.

Iodine-Induced Thyrotoxicosis

Iodine-induced thyrotoxicosis is a relatively uncom-mon disorder that has increased in incidence over thepast several decades. Iodine-induced thyrotoxicosis hasbeen shown to develop after a patient has receivediodine for a radiologic procedure (eg, computed tomog-

raphy or angiography) or when a patient has receivedamiodarone, which has a high iodine content, resultingin amiodarone-induced thyrotoxicosis type 1 (as notedlater in this discussion).54,55 The course of iodine-induced thyrotoxicosis is usually self-limited after thesource of iodine is removed. However, in the case ofamiodarone use, the effect can be prolonged becauseamiodarone is stored in fat and has a half-life of months.

Thyroid-Stimulating HormoneProducing Pituitary

Adenoma

A TSH-producing pituitary adenoma is extremely

rare. These tumors are usually large (macroadenomas)at the time of diagnosis because the progression of thedisease is so indolent. Frequently, the presenting symp-toms are caused by the mass effect of the macroadeno-ma.56 This disorder is characterized by an elevation offree T4 in conjunction with a serum TSH value that isinappropriately elevated or within the normal range.In this situation, treatment should be removal of thepituitary tumor.

Human Chorionic GonadotropinInduced

Thyrotoxicosis

Human chorionic gonadotropin (hCG) shares anidentical -subunit with TSH and can (with a low affin-ity) stimulate thyroid hormone production. In healthypregnant women, during the first trimester of pregnan-cy when the levels of -hCG are elevated, results ofthyroid function tests can be outside the standard ref-erence range used for the healthy nonpregnant pa-tient. These pregnant women may have low or sup-pressed TSH levels and normal free T4 levels andgenerally do not have clinical features of thyrotoxicosis.This condition is very similar to subclinical hyperthy-roidism.




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One common entity in which the diagnosis of thyro-toxicosis may be confusing is hyperemesis gravidarum.

Women with hyperemesis gravidarum usually presentwith nausea and vomiting caused by the unusually high

levels of -hCG, and some of these patients may haveclinical symptoms of thyrotoxicosis, termed hCG-induced thyrotoxicosis. These patients usually have a sup-pressed TSH and elevated serum free T3 and free T4measurements correlating with the elevation of serumhCG concentrations. Examination of the thyroid glandusually does not reveal a significantly large goiter.Unlike Gravesdisease, the symptoms of thyrotoxicosistend to subside once the vomiting improves, usually bythe second trimester. If the symptoms persist, a diagno-sis of Gravesdisease must be considered, and treat-ment may be necessary. Other conditions that may re-

sult in hCG-induced thyrotoxicosis include molarpregnancies and choriocarcinoma.57,58

Destructive Thyroiditis

The term thyroiditisrefers to a group of disorders inwhich an insult to the thyroid gland results in the releaseof preformed thyroid hormones. Four types of thyroiditisare reviewed in the following discussion: de Quervainsthyroiditis, postpartum thyroiditis, silent thyroiditis, andamiodarone-induced thyrotoxicosis type II.

de Quervains thyroiditis.Also termed subacute gran-ulomatous thyroiditis, de Quervains thyroiditis is associat-

ed with a painful thyroid gland, fever, myalgias, andmalaise and is usually precipitated by a viral syndrome,although no specific virus has been isolated. The labo-ratory hallmark of de Quervains thyroiditis is a mark-edly elevated erythrocyte sedimentation rate. Thecourse of disease is typically mild thyrotoxicosis fol-lowed by the possible development of hypothyroidismin the recovery phase. Ultimately most patients revertto a euthyroid state within several weeks to severalmonths; however, a small percentage of patients re-main hypothyroid.30 The disease course is usually self-limited. Antithyroid medication has no role becauseincreased synthesis of thyroid hormone does not occur.Therapy should be directed at symptomatic relief.Nonsteroidal anti-inflammatory drugs may be initiatedbut usually a course of glucocorticoids proves to benecessary and results in a prompt resolution of symp-toms. -Blockers may offer symptomatic relief for thosepatients with tremor or palpitations.

Postpartum thyroiditis. Postpartum thyroiditis oc-curs in up to 10% of women in the United States withinthe first few months after delivery.59 The hyperthyroidphase typically begins 1 to 6 months after delivery andis self-limited, usually lasting up to 2 months. The thyro-

toxic phase may be followed by a hypothyroid phase.Although permanent hypothyroidism may develop inapproximately 25% of these women, most women re-cover normal thyroid function within 1 year.60

Most women with postpartum thyroiditis have asmall, nontender, firm goiter. Laboratory assessmenttypically reveals elevated serum titers of thyroid peroxi-dase antibodies and normal erythrocyte sedimentationrates. Radioactive iodine is secreted in breast milk,therefore a radioactive iodine uptake test with 123Ishould only be performed in patients when the diagno-sis is unclear. 123I has a half-life of 13 hours; a nursingmother must be willing to pump and discard milk for atleast 2 to 3 days after the test. (131I is not used because ofits longer half-life.) Treatment during the hyperthyroidphase usually is not warranted; however, if necessary,

treatment with -blockers can be utilized. Again, anti-thyroid medications have no role.

Silent thyroiditis. Silent thyroiditis is a rare form of thy-rotoxicosis that accounts for approximately 1% of allcases of thyrotoxicosis and has a clinical course similar topostpartum thyroiditis; however, the symptoms of silentthyroiditis are usually more mild and only 20% of pa-tients have residual chronic hypothyroidism.61 In approx-imately 50% of these patients, a small, nontender, veryfirm, diffuse goiter may be palpated and high serum thy-roid peroxidase antibody titers are present.62

Amiodarone-induced thyrotoxicosis.Amiodarone-

induced thyrotoxicosis has been shown to occur in upto 20% of patients receiving amiodarone.63 Two types ofamiodarone-induced thyrotoxicosis may occur while apatient is receiving treatment with amiodarone. Type Iamiodarone-induced thyrotoxicosis occurs in patients

with an underlying multinodular goiter and is charac-terized by the synthesis and release of excessive thyroidhormone, inducing hyperthyroidism. In type II, thedirect toxic effect of the drug creates an inflammatoryresponse within the follicular cells of the thyroid gland,causing the release of preformed thyroid hormonefrom the damaged, inflamed thyroid gland.

Distinction between the two forms of amiodarone-induced thyrotoxicosis can be difficult and some pa-tients may have both types. A new approach to distin-guish between these two forms of disease is the use ofcolor-flow Doppler ultrasonography, which shows hy-pervascularity in type I disease versus vascularity that isfrequently reduced in type II disease.64

Medical treatment is often necessary for patients withamiodarone-induced thyrotoxicosis. Antithyroid medi-cations are used for the treatment of type I disease. If thethyrotoxicosis is severe, the addition of potassium per-chlorate may be necessary in order to prevent further




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uptake of iodine by the thyroid. Lithium also has beensuggested as an alternative therapy for the type I disease.Given the inflammatory nature of type II disease, high-dose corticosteroids are the treatment of choice. Surgi-

cal intervention with thyroidectomy may be required ifcontrol of severe cases of amiodarone-induced thyrotox-icosis cannot be obtained with medical management. Inthose patients who have developed hypothyroidism

while undergoing treatment with amiodarone, treat-ment with levothyroxine is indicated if the amiodaronecannot be discontinued.

Factitious Thyrotoxicosis

Clinical exogenous thyrotoxicosis can be seen in vari-ous settings.65 For unknown reasons, patients withouthistory of a thyroid disorder may intentionally ingest

thyroid hormone. In addition, some patients who dohave a thyroid disorder self-manage their disease by tak-ing inappropriately large amounts of thyroid hormone.Cases also have been described of patients taking thy-roid hormone to aid in weight management or treatdepression. Once the cause of identified exogenousthyrotoxicosis is identified, these patients should discon-tinue the thyroid hormone.

Ectopic Thyroid Production

Ectopic thyrotoxicosis occurs rarely and may becaused by struma ovarii and metastatic thyroid cancer.

Patients with struma ovarii have functioning thyroid tis-sue within an ovarian tumor. The treatment is the re-moval of the ovarian tumor. In cases of metastatic thyroidcancer, treatment is varied and includes medical therapy,radioactive iodine ablation, and surgical therapy.

CONCLUSION

The term thyrotoxicosisrefers to excess levels of circu-lating thyroid hormone. Thyroid dysfunction affectsalmost all organ systems of the body. The most com-mon cause of thyrotoxicosis is Gravesdisease; othercauses include thyroid nodules and thyroiditis. It isimperative to properly characterize the etiology of thy-roid dysfunction because the treatment modalities dif-fer for each disorder. Treatments include -blockers,antithyroid medication, radioactive iodine, and sur-gery. Continued follow-up is critical to monitor the pa-tients thyroid function. HP

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