2940 PART 12 Endocrinology and Metabolism

and evaluation of extraocular muscle function (e.g., Hess chart),

intraocular pressure and visual fields, acuity, and color vision.

Thyroid dermopathy occurs in <5% of patients with Graves’ disease

(Fig. 384-1B), almost always in the presence of moderate or severe

ophthalmopathy. Although most frequent over the anterior and lateral

aspects of the lower leg (hence the term pretibial myxedema), skin

changes can occur at other sites, particularly after trauma. The typical

lesion is a noninflamed, indurated plaque with a deep pink or purple

color and an “orange skin” appearance. Nodular involvement can

occur, and the condition can rarely extend over the whole lower leg and

foot, mimicking elephantiasis. Thyroid acropachy refers to a form of

clubbing found in <1% of patients with Graves’ disease (Fig. 384-1C).

It is so strongly associated with thyroid dermopathy that an alternative

cause of clubbing should be sought in a Graves’ patient without coincident skin and orbital involvement. Ophthalmopathy, dermopathy, and

acropachy have declined in incidence, probably due to better recognition and prompt treatment of the underlying thyroid disease.

Laboratory Evaluation Investigations used to determine the

existence and cause of thyrotoxicosis are summarized in Fig. 384-2.

In Graves’ disease, the TSH level is suppressed, and total and unbound

thyroid hormone levels are increased. In 2–5% of patients (and more

in areas of borderline iodine intake), only T3

 is increased (T3

 toxicosis).

The converse state of T4

 toxicosis, with elevated total and unbound

T4

 and normal T3

 levels, is occasionally seen when hyperthyroidism

is induced by excess iodine, providing surplus substrate for thyroid

hormone synthesis. Measurement of TPO antibodies or TRAb may be

useful if the diagnosis is unclear clinically but is not needed routinely.

Associated abnormalities that may cause diagnostic confusion in thyrotoxicosis include elevation of bilirubin, liver enzymes, and ferritin.

Microcytic anemia and thrombocytopenia may occur.

Differential Diagnosis Diagnosis of Graves’ disease is straightforward in a patient with biochemically confirmed thyrotoxicosis, diffuse

goiter on palpation, ophthalmopathy, and often a personal or family

history of autoimmune disorders. For patients with thyrotoxicosis who

lack these features, the diagnosis can be established by a radionuclide

(99mTc, 123I, or 131I) scan and uptake of the thyroid, which will distinguish the diffuse, high uptake of Graves’ disease from destructive thyroiditis, ectopic thyroid tissue, and factitious thyrotoxicosis, as well as

diagnose a toxic adenoma or toxic MNG. Increasingly, because of the

rapidity of laboratory test results, TRAb measurement is used instead

of radionuclide scanning to confirm the diagnosis of Graves’ disease.

Color-flow Doppler ultrasonography may distinguish between hyperthyroidism (with increased blood flow) and destructive thyroiditis. In

secondary hyperthyroidism due to a TSH-secreting pituitary tumor,

there is also a diffuse goiter. The presence of a nonsuppressed TSH

level and the finding of a pituitary tumor on CT or magnetic resonance

imaging (MRI) scan suggest this diagnosis.

Clinical features of thyrotoxicosis can mimic certain aspects of other

disorders, including panic attacks, mania, pheochromocytoma, and

weight loss associated with malignancy. The diagnosis of thyrotoxicosis can be easily excluded if the TSH and unbound T4

 and T3

 levels

are normal. A normal TSH also excludes Graves’ disease as a cause of

diffuse goiter.

Clinical Course Clinical features generally worsen without treatment; mortality was 10–30% before the introduction of satisfactory therapy. Some patients with mild Graves’ disease experience

spontaneous relapses and remissions. Rarely, there may be fluctuation between hypo- and hyperthyroidism due to changes in the

functional activity of TSH-R antibodies. About 15% of patients

who enter remission after treatment develop hypothyroidism

10–15 years later as a result of the destructive autoimmune process.

The clinical course of ophthalmopathy does not follow that

of the thyroid disease, although thyroid dysfunction can worsen

eye signs. Ophthalmopathy typically worsens over the initial

3–6 months, followed by a plateau phase over the next 12–18 months,

Primary

 thyrotoxicosis

Features of

 Graves’ diseasea?

T3 toxicosis Subclinical

 hyperthyroidism

TSH low, unbound

 T4 high

Measure TSH, unbound T4

Yes No

Normal

Measure

 unbound T3

TSH normal or increased,

 high unbound T4

TSH-secreting

 pituitary adenoma

 or thyroid hormone

 resistance syndrome

Follow up in

 6-12 weeks

High

Graves’ disease Multinodular goiter or toxic adenomab?

Yes No

Toxic nodular hyperthyroidism Low radionuclide uptake?

Yes No

Destructive thyroiditis, iodine excess

 or excess thyroid hormone

Rule out other causes including stimulation

 by chorionic gonadotropin

TSH low, unbound

 T4 normal

TSH and unbound

 T4 normal

No further tests

FIGURE 384-2 Evaluation of thyrotoxicosis. a

Diffuse goiter, positive thyroid peroxidase (TPO) antibodies or thyroid-stimulating hormone (TSH) receptor antibody (TRAb),

ophthalmopathy, dermopathy. b

Can be confirmed by radionuclide scan.

2941Hyperthyroidism and Other Causes of Thyrotoxicosis CHAPTER 384

and then some spontaneous improvement, particularly in the soft

tissue changes. However, the course is more fulminant in up to 5%

of patients, requiring intervention in the acute phase if there is optic

nerve compression or corneal ulceration. Diplopia may appear late

in the disease due to fibrosis of the extraocular muscles. Radioiodine

treatment for hyperthyroidism worsens the eye disease in a small

proportion of patients (especially smokers). Antithyroid drugs and

surgery have no adverse effects on the clinical course of ophthalmopathy. Thyroid dermopathy, when it occurs, usually appears 1–2 years

after the development of Graves’ hyperthyroidism; it may improve

spontaneously.

TREATMENT

Graves’ Disease

The hyperthyroidism of Graves’ disease is treated by reducing thyroid hormone synthesis, using an antithyroid drug, or reducing

the amount of thyroid tissue with radioiodine (131I) treatment or

by thyroidectomy. Antithyroid drugs are the predominant therapy

in many centers in Europe, Latin America, and Japan, whereas

radioiodine is more often the first line of treatment in North

America. These differences reflect the fact that no single approach

is optimal and that patients may require multiple treatments to

achieve remission.

The main antithyroid drugs are thionamides: propylthiouracil,

carbimazole (not available in the United States), and the active

metabolite of the latter, methimazole. All inhibit the function of

TPO, reducing oxidation and organification of iodide. These drugs

also reduce thyroid antibody levels by mechanisms that remain

unclear, and they appear to enhance spontaneous rates of remission.

Propylthiouracil inhibits deiodination of T4 → T3

. However, this

effect is of minor benefit, except in the most severe thyrotoxicosis,

and is offset by the much shorter half-life of this drug (90 min)

compared to methimazole (6 h). Due to the hepatotoxicity of propylthiouracil, the U.S. Food and Drug Administration (FDA) has

limited indications for its use to the first trimester of pregnancy,

the treatment of thyroid storm, and patients with minor adverse

reactions to methimazole. If propylthiouracil is used, monitoring of

liver function tests is recommended.

There are many variations of antithyroid drug regimens. The

initial dose of carbimazole or methimazole is usually 10–20 mg

every 8 or 12 h, but once-daily dosing is possible after euthyroidism

is restored. Propylthiouracil is given at a dose of 100–200 mg every

6–8 h, and divided doses are usually given throughout the course.

Lower doses of each drug may suffice in areas of low iodine intake.

The starting dose of an antithyroid drug can be gradually reduced

(titration regimen) as thyrotoxicosis improves. Less commonly,

high doses may be given combined with levothyroxine (LT4) supplementation (block-replace regimen) to avoid drug-induced hypothyroidism. The titration regimen is preferred to minimize the dose

of antithyroid drug and provide an index of treatment response.

Thyroid function tests and clinical manifestations are reviewed

4–6 weeks after starting treatment, and the dose is titrated based

on unbound T4

 levels. Most patients do not achieve euthyroidism

until 6–8 weeks after treatment is initiated. TSH levels often remain

suppressed for several months and therefore do not provide a sensitive index of treatment response. The usual daily maintenance

doses of antithyroid drugs in the titration regimen are 2.5–10 mg

of carbimazole or methimazole and 50–100 mg of propylthiouracil.

In the block-replace regimen, the initial dose of antithyroid drug is

held constant, and the dose of LT4 is adjusted to maintain normal

unbound T4

 levels. When TSH suppression is alleviated, TSH levels

can also be used to monitor therapy.

Maximum remission rates (up to 30–60% in some populations)

are achieved by 12–18 months for the titration regimen compared

to 6 months for the block-replace regimen and are higher in

patients in whom TRAb levels are no longer detected than in those

with TRAb persistence. For unclear reasons, remission rates appear

to vary in different geographic regions. Younger patients, males,

smokers, and patients with a history of allergy, severe hyperthyroidism, or large goiters are most likely to relapse when treatment

stops, but outcomes are difficult to predict. All patients should be

followed closely for relapse during the first year after treatment and

at least annually thereafter.

The common minor side effects of antithyroid drugs are rash,

urticaria, fever, and arthralgia (1–5% of patients). These may

resolve spontaneously or after substituting an alternative antithyroid drug; rashes may respond to an antihistamine. Rare but major

side effects include hepatitis (especially with propylthiouracil; avoid

use in children) and cholestasis (methimazole and carbimazole);

vasculitis; and, most important, agranulocytosis (<1%). It is essential that antithyroid drugs are stopped and not restarted if a patient

develops major side effects. Written instructions should be provided regarding the symptoms of possible agranulocytosis (e.g., sore

throat, fever, mouth ulcers) and the need to stop treatment pending

an urgent complete blood count to confirm that agranulocytosis

is not present. Management of agranulocytosis is described in

Chap. 102. It is not useful to monitor blood counts prospectively,

because the onset of agranulocytosis is idiosyncratic and abrupt.

Propranolol (20–40 mg every 6 h) or longer-acting selective β1

receptor blockers such as atenolol may be helpful to control adrenergic symptoms, especially in the early stages before antithyroid

drugs take effect. Beta blockers are also useful in patients with

thyrotoxic periodic paralysis, pending correction of thyrotoxicosis.

In consultation with a cardiologist, anticoagulation should be considered in all patients with atrial fibrillation; there is often spontaneous reversion to sinus rhythm with control of hyperthyroidism,

and long-term anticoagulation is not usually needed. Decreased

warfarin doses are required when patients are thyrotoxic. If digoxin

is used, increased doses are often needed in the thyrotoxic state.

Radioiodine causes progressive destruction of thyroid cells and

can be used as initial treatment or for relapses after a trial of

antithyroid drugs. There is a small risk of thyrotoxic crisis (see

below) after radioiodine, which can be minimized by pretreatment with antithyroid drugs for at least a month before treatment.

Antecedent treatment with an antithyroid drug and a beta blocker

should be considered for all elderly patients or for those with

cardiac problems. Carbimazole or methimazole must be stopped

2–3 days before radioiodine administration to achieve optimum

iodine uptake and can be restarted 3–7 days after radioiodine in

those at risk of complications from worsening thyrotoxicosis. Propylthiouracil appears to have a prolonged radioprotective effect and

should be stopped for a longer period before radioiodine is given,

or a larger dose of radioiodine will be necessary.

Efforts to calculate an optimal dose of radioiodine that achieves

euthyroidism without a high incidence of relapse or progression to

hypothyroidism have not been successful. Some patients inevitably

relapse after a single dose because the biologic effects of radiation

vary between individuals, and hypothyroidism cannot be uniformly

avoided even using accurate dosimetry. A practical strategy is to

give a fixed dose based on clinical features, such as the severity of

thyrotoxicosis, the size of the goiter (increases the dose needed),

and the level of radioiodine uptake (decreases the dose needed).

131I dosage generally ranges between 370 MBq (10 mCi) and

555 MBq (15 mCi). Most authorities favor an approach aimed

at thyroid ablation (as opposed to euthyroidism), given that LT4

replacement is straightforward and most patients ultimately progress to hypothyroidism over 5–10 years, frequently with some delay

in the diagnosis of hypothyroidism.

Certain radiation safety precautions are necessary in the first

few days after radioiodine treatment, but the exact guidelines vary

depending on local protocols. In general, patients need to avoid

close, prolonged contact with children and pregnant women for

5–7 days because of possible transmission of residual isotope and

exposure to radiation emanating from the gland. Rarely, there may

be mild pain due to radiation thyroiditis 1–2 weeks after treatment.

Hyperthyroidism can persist for 2–3 months before radioiodine

2942 PART 12 Endocrinology and Metabolism

takes full effect. For this reason, β-adrenergic blockers or antithyroid drugs can be used to control symptoms during this interval.

Persistent hyperthyroidism can be treated with a second dose of

radioiodine, usually 6 months after the first dose. The risk of hypothyroidism after radioiodine depends on the dosage but is at least

10–20% in the first year and 5% per year thereafter. Patients should

be informed of this possibility before treatment and require close

follow-up during the first year followed by annual thyroid function

testing.

Pregnancy and breast-feeding are absolute contraindications to

radioiodine treatment, but patients can conceive safely 6 months

after treatment. The presence of ophthalmopathy, especially

in smokers, requires caution. Prednisone, 0.2–0.5 mg/kg per d

(depending on ophthalmopathy severity), at the time of radioiodine

treatment, tapered over 6–12 weeks, may prevent exacerbation of

ophthalmopathy, but radioiodine should generally be avoided in

patients with active moderate to severe eye disease. Although many

physicians avoid radioiodine in children and adolescents because

of the potential risks of malignancy, others have advocated radioiodine use in older children. A recent long-term follow-up study of

adults found a modest increased lifetime risk of solid cancers after

radioiodine treatment, contrary to previous findings. It is unclear

how this will alter management in the future.

Total or near-total thyroidectomy is an option for patients who

relapse after antithyroid drugs and prefer this treatment to radioiodine. Some experts recommend surgery in young individuals,

particularly when the goiter is very large. Careful control of thyrotoxicosis with antithyroid drugs, followed by potassium iodide

(SSKI; 1–2 drops orally tid for 10 days), is needed prior to surgery

to avoid thyrotoxic crisis and to reduce the vascularity of the

gland. The major complications of surgery—bleeding, laryngeal

edema, hypoparathyroidism, and damage to the recurrent laryngeal

nerves—are unusual when the procedure is performed by highly

experienced surgeons. Recurrence rates in the best series are <2%,

but the rate of hypothyroidism is similar to that following radioiodine treatment, especially with the current trend away from subtotal

thyroidectomy.

Antithyroid drugs should be used to manage Graves’ disease

in pregnancy. Because transplacental passage of these drugs may

produce fetal hypothyroidism and goiter if the maternal dose is

excessive, maternal antithyroid dose titration should target serum

free or total T4

 levels at or just above the pregnancy reference range.

If available, propylthiouracil should be used until 14–16 weeks’

gestation because of the association of rare cases of methimazole/

carbimazole embryopathy, including aplasia cutis and other defects,

such as choanal atresia and tracheoesophageal fistulae. Because of

the potential for teratogenic effects, recent recommendations suggest discontinuation of antithyroid medication in a newly pregnant

woman with Graves’ disease who is euthyroid on a low dose of

methimazole (<5–10 mg/d) or propylthiouracil (<100–200 mg/d),

after evaluating recent thyroid function tests, disease history, goiter size, duration of therapy, and TRAb measurement. Following

cessation, careful monitoring of maternal thyroid function tests is

essential. On the other hand, for women at high risk of developing

thyrotoxicosis if antithyroid drugs are discontinued (large goiter,

requirement for higher antithyroid drug dosage), continued therapy is necessary, with propylthiouracil (if available) administration

in the first trimester. However, because of its rare association with

hepatotoxicity, propylthiouracil should be limited to the first trimester and then maternal therapy should be converted to methimazole (or carbimazole) at a ratio of 15–20 mg of propylthiouracil to

1 mg of methimazole. It is often possible to stop treatment in the

last trimester because TSIs tend to decline in pregnancy. Nonetheless, the transplacental transfer of these antibodies if present at

levels three times higher than the normative range rarely causes

fetal or neonatal thyrotoxicosis. Poor intrauterine growth, a fetal

heart rate of >160 beats/min, advanced bone age, fetal goiter, and

high levels of maternal TSI after 26 weeks’ gestation may herald this

complication. Antithyroid drugs given to the mother can be used

to treat the fetus and may be needed for 1–3 months after delivery,

until the maternal antibodies disappear from the baby’s circulation. The postpartum period is a time of major risk for relapse of

Graves’ disease. Breast-feeding is safe with low doses of antithyroid

drugs. Graves’ disease in children is usually managed initially with

methimazole or carbimazole (avoid propylthiouracil), often given

as a prolonged course of the titration regimen. Surgery or radioiodine may be indicated for severe or relapsing disease.

Thyrotoxic crisis, or thyroid storm, is rare and presents as a

life-threatening exacerbation of hyperthyroidism, accompanied by

fever, delirium, seizures, coma, vomiting, diarrhea, and jaundice.

The mortality rate due to cardiac failure, arrhythmia, or hyperthermia is as high as 30%, even with treatment. Thyrotoxic crisis is usually precipitated by acute illness (e.g., stroke, infection,

trauma, diabetic ketoacidosis), surgery (especially on the thyroid),

or radioiodine treatment of a patient with partially treated or

untreated hyperthyroidism. Management requires intensive monitoring and supportive care, identification and treatment of the

precipitating cause, and measures that reduce thyroid hormone

synthesis. Large doses of propylthiouracil (500–1000 mg loading

dose and 250 mg every 4 h) should be given orally or by nasogastric tube or per rectum; the drug’s inhibitory action on T4 → T3

conversion makes it the antithyroid drug of choice. If not available,

methimazole can be used in doses of 20 mg every 6 h. One hour

after the first dose of propylthiouracil, stable iodide (5 drops SSKI

every 6 h) is given to block thyroid hormone synthesis via the

Wolff-Chaikoff effect (the delay allows the antithyroid drug to prevent the excess iodine from being incorporated into new hormone).

Propranolol should also be given to reduce tachycardia and other

adrenergic manifestations (60–80 mg PO every 4 h, or 2 mg IV

every 4 h). Although other β-adrenergic blockers can be used, high

doses of propranolol decrease T4 → T3

 conversion, and the doses

can be easily adjusted. Caution is needed to avoid acute negative

inotropic effects, but controlling the heart rate is important, as some

patients develop a form of high-output heart failure. Short-acting

IV esmolol can be used to decrease heart rate while monitoring for signs of heart failure. Additional therapeutic measures

include glucocorticoids (e.g., hydrocortisone 300 mg IV bolus, then

100 mg every 8 h), antibiotics if infection is present, cholestyramine

to sequester thyroid hormones, cooling, oxygen, and IV fluids.

Ophthalmopathy requires no active treatment when it is mild

or moderate, because there is usually spontaneous improvement.

General measures include meticulous control of thyroid hormone

levels, cessation of smoking, and an explanation of the natural

history of ophthalmopathy. Discomfort can be relieved with artificial tears (e.g., hypromellose 0.3% or carbomer 0.2% ophthalmic

gel), paraffin-based eye ointment, and the use of dark glasses with

side frames. Periorbital edema may respond to a more upright

sleeping position or a diuretic. Corneal exposure during sleep

can be avoided by using patches or taping the eyelids shut. Minor

degrees of diplopia improve with prisms fitted to spectacles. Some

authorities also advocate selenium 100 μg bid. Severe ophthalmopathy, with optic nerve involvement or chemosis resulting in

corneal damage, is an emergency requiring joint management with

an ophthalmologist. Pulse therapy with IV methylprednisolone

(e.g., 500 mg of methylprednisolone once weekly for 6 weeks, then

250 mg once weekly for 6 weeks) is preferable to oral glucocorticoids, which are used for moderately active disease. When glucocorticoids are ineffective, orbital decompression can be achieved

by removing bone from any wall of the orbit, thereby allowing displacement of fat and swollen extraocular muscles. The transantral

route is used most often because it requires no external incision.

Proptosis recedes an average of 5 mm, but there may be residual

or even worsened diplopia. Once the eye disease has stabilized,

surgery may be indicated for relief of diplopia and correction of the

appearance. External beam radiotherapy of the orbits has been used

for many years, but the efficacy of this therapy remains unclear,

and it is best reserved for those with moderately active disease

who have failed or are not candidates for glucocorticoid therapy.

2943Hyperthyroidism and Other Causes of Thyrotoxicosis CHAPTER 384

Teprotumumab, a human monoclonal antibody, received breakthrough designation and was approved by the FDA in 2020. Randomized clinical trials of patients with active thyroid eye disease

demonstrated rapid effects on proptosis, diplopia, clinical activity

score, and quality of life. Responses appear comparable to surgery.

Teprotumumab is administered at an initial dose of 10 mg/kg IV

and thereafter at 20 mg/kg IV every 3 weeks for 21 weeks.

Thyroid dermopathy does not usually require treatment, but

it can cause cosmetic problems or interfere with the fit of shoes.

Surgical removal is not indicated. If necessary, treatment consists of

topical, high-potency glucocorticoid ointment under an occlusive

dressing. Octreotide may be beneficial in some cases.

■ OTHER CAUSES OF THYROTOXICOSIS

Destructive thyroiditis (subacute or silent thyroiditis) typically presents

with a short thyrotoxic phase due to the release of preformed thyroid

hormones and catabolism of Tg (see “Subacute Thyroiditis,” below).

True hyperthyroidism is absent, as demonstrated by a low radionuclide

uptake. Circulating Tg levels are typically increased. Other causes of

thyrotoxicosis with low or absent thyroid radionuclide uptake include

thyrotoxicosis factitia, iodine excess, and, rarely, ectopic thyroid tissue,

particularly teratomas of the ovary (struma ovarii) and functional

metastatic follicular carcinoma. Whole-body radionuclide studies can

demonstrate ectopic thyroid tissue, and thyrotoxicosis factitia can be

distinguished from destructive thyroiditis by the clinical features and

low levels of Tg. Amiodarone treatment is associated with thyrotoxicosis in up to 10% of patients, particularly in areas of low iodine intake

(see below).

TSH-secreting pituitary adenoma is a rare cause of thyrotoxicosis.

It is characterized by the presence of an inappropriately normal or

increased TSH level in a patient with hyperthyroidism, diffuse goiter,

and elevated T4

 and T3

 levels (Chap. 380). Elevated levels of the α

subunit of TSH, released by the TSH-secreting adenoma, support this

diagnosis, which can be confirmed by demonstrating the pituitary

tumor on MRI or CT scan. A combination of transsphenoidal surgery,

sella irradiation, and octreotide may be required to normalize TSH,

because many of these tumors are large and locally invasive at the time

of diagnosis. Radioiodine or antithyroid drugs can be used to control

thyrotoxicosis.

Thyrotoxicosis caused by toxic MNG and hyperfunctioning solitary

nodules is discussed below.

THYROIDITIS

There are several classification systems to describe the clinical syndromes of thyroiditis. One is based on the onset and duration of disease

(Table 384-3); others are based on the absence or presence of pain.

■ ACUTE THYROIDITIS

Acute thyroiditis is rare and due to suppurative infection of the thyroid.

In children and young adults, the most common cause is the presence

of a piriform sinus, a remnant of the fourth branchial pouch that

connects the oropharynx with the thyroid. Such sinuses are predominantly left-sided. A long-standing goiter and degeneration in a thyroid

malignancy are risk factors in the elderly. The patient presents with

thyroid pain, often referred to the throat or ears, and a small, tender

goiter that may be asymmetric. Fever, dysphagia, and erythema over

the thyroid are common, as are systemic symptoms of a febrile illness

and lymphadenopathy.

The differential diagnosis of thyroid pain includes subacute or,

rarely, chronic thyroiditis; hemorrhage into a cyst; malignancy including lymphoma; and, rarely, amiodarone-induced thyroiditis or amyloidosis. However, the abrupt presentation and clinical features of acute

thyroiditis rarely cause confusion. The erythrocyte sedimentation rate

(ESR) and white cell count are usually increased, but thyroid function

is normal. Fine-needle aspiration (FNA) biopsy shows infiltration by

polymorphonuclear leukocytes; culture of the sample can identify

the organism. Caution is needed in immunocompromised patients as

fungal, mycobacterial, or Pneumocystis thyroiditis can occur in this

setting. Antibiotic treatment is guided initially by Gram stain and,

subsequently, by cultures of the FNA biopsy. Surgery may be needed

to drain an abscess, which can be localized by CT scan or ultrasound.

Tracheal obstruction, septicemia, retropharyngeal abscess, mediastinitis, and jugular venous thrombosis may complicate acute thyroiditis

but are uncommon with prompt use of antibiotics.

■ SUBACUTE THYROIDITIS

This is also termed de Quervain’s thyroiditis, granulomatous thyroiditis, or viral thyroiditis. Many viruses have been implicated, including

mumps, coxsackie, influenza, adenoviruses, and echoviruses, but

attempts to identify the virus in an individual patient are often unsuccessful and do not influence management. Recently, subacute thyroiditis associated with the SARS-CoV-2 was described. The diagnosis of

subacute thyroiditis is often overlooked because the symptoms can

mimic pharyngitis. The peak incidence occurs at 30–50 years, and

women are affected three times more frequently than men.

Pathophysiology The thyroid shows a characteristic patchy

inflammatory infiltrate with disruption of the thyroid follicles and

multinucleated giant cells within some follicles. The follicular changes

progress to granulomas accompanied by fibrosis. Finally, the thyroid

returns to normal, usually several months after onset. During the initial phase of follicular destruction, there is release of Tg and thyroid

hormones, leading to increased circulating T4

 and T3

 and suppression

of TSH (Fig. 384-3). During this destructive phase, radioactive iodine

uptake is low or undetectable. After several weeks, the thyroid is

depleted of stored thyroid hormone and a phase of hypothyroidism

typically occurs, with low unbound T4

 (and sometimes T3

) and moderately increased TSH levels. Radioactive iodine uptake returns to normal or is even increased as a result of the rise in TSH. Finally, thyroid

hormone and TSH levels return to normal as the disease subsides.

Clinical Manifestations The patient usually presents with a

painful and enlarged thyroid, sometimes accompanied by fever. There

may be features of thyrotoxicosis or hypothyroidism, depending on

the phase of the illness. Malaise and symptoms of an upper respiratory

tract infection may precede the thyroid-related features by several

weeks. In other patients, the onset is acute, severe, and without obvious

antecedent. The patient typically complains of a sore throat, and examination reveals a small goiter that is exquisitely tender. Pain is often

referred to the jaw or ear. Complete resolution is the usual outcome,

but late-onset permanent hypothyroidism occurs in 15% of cases, particularly in those with coincidental thyroid autoimmunity. A prolonged

course over many months, with one or more relapses, occurs in a small

percentage of patients.

Laboratory Evaluation As depicted in Fig. 384-3, thyroid function tests characteristically evolve through three distinct phases over

TABLE 384-3 Causes of Thyroiditis

Acute

Bacterial infection: especially Staphylococcus, Streptococcus, and Enterobacter

Fungal infection: Aspergillus, Candida, Coccidioides, Histoplasma, and

Pneumocystis

Radiation thyroiditis after 131I treatment

Amiodarone (may also be subacute or chronic)

Subacute

Viral (or granulomatous) thyroiditis

Silent thyroiditis (including postpartum thyroiditis)

Mycobacterial infection

Drug induced (interferon, amiodarone)

Chronic

Autoimmunity: focal thyroiditis, Hashimoto’s thyroiditis, atrophic thyroiditis

Riedel’s thyroiditis

Parasitic thyroiditis: echinococcosis, strongyloidiasis, cysticercosis

Traumatic: after palpation

2944 PART 12 Endocrinology and Metabolism

about 6 months: (1) thyrotoxic phase, (2) hypothyroid phase, and (3)

recovery phase. In the thyrotoxic phase, T4

 and T3

 levels are increased,

reflecting their discharge from the damaged thyroid cells, and TSH is

suppressed. The T4

/T3

 ratio is greater than in Graves’ disease or thyroid

autonomy, in which T3

 is often disproportionately increased. The diagnosis is confirmed by a high ESR and low uptake of radioiodine (<5%)

or 99mTc pertechnetate (as compared to salivary gland pertechnetate

concentration). The white blood cell count may be increased, and thyroid antibodies are negative. If the diagnosis is in doubt, FNA biopsy

may be useful, particularly to distinguish unilateral involvement from

bleeding into a cyst or neoplasm.

TREATMENT

Subacute Thyroiditis

Relatively large doses of aspirin (e.g., 600 mg every 4–6 h) or nonsteroidal anti-inflammatory drugs (NSAIDs) are sufficient to control

symptoms in many cases. If this treatment is inadequate, or if the

patient has marked local or systemic symptoms, glucocorticoids

should be given. The usual starting dose is 15–40 mg of prednisone,

depending on severity. The dose is gradually tapered over 6–8 weeks,

in response to improvement in symptoms and the ESR. If a relapse

occurs during glucocorticoid withdrawal, the dosage should be

increased and then withdrawn more gradually. Thyroid function

should be monitored every 2–4 weeks using TSH and free T4

 levels.

Symptoms of thyrotoxicosis improve spontaneously but may be

ameliorated by β-adrenergic blockers; antithyroid drugs play no

role in treatment of the thyrotoxic phase. LT4 replacement may be

needed if the hypothyroid phase is prolonged, but doses should be

low enough (50–100 μg daily) to allow TSH-mediated recovery.

■ SILENT THYROIDITIS

Painless thyroiditis, or “silent” thyroiditis, occurs in patients with underlying autoimmune thyroid disease and has a clinical course similar

to that of subacute thyroiditis. The condition occurs in up to 5% of

women 3–6 months after pregnancy and is then termed postpartum

thyroiditis. Typically, patients have a brief phase of thyrotoxicosis lasting 2–4 weeks, followed by hypothyroidism for 4–12 weeks, and then

resolution; often, however, only one phase is apparent. The condition

is associated with the presence of TPO antibodies antepartum, and it is

three times more common in women with type 1 diabetes mellitus. As

in subacute thyroiditis, the uptake of 99mTc pertechnetate or radioactive

iodine is initially suppressed. In addition to the painless goiter, silent

thyroiditis can be distinguished from subacute thyroiditis by a normal

ESR and the presence of TPO antibodies. Glucocorticoid treatment is

not indicated for silent thyroiditis. Severe thyrotoxic symptoms can be

managed with a brief course of propranolol, 20–40 mg three or four

times daily. Thyroxine replacement may be needed for the hypothyroid

phase but should be withdrawn after 6–9 months, as recovery is the

rule. Annual follow-up thereafter is recommended, because a proportion of these individuals develop permanent hypothyroidism. The

condition may recur in subsequent pregnancies.

■ DRUG-INDUCED THYROIDITIS

Patients receiving cytokines, such as IFN-α, tyrosine kinase inhibitors,

and immune checkpoint inhibitors may develop painless thyroiditis.

IFN-α, which is used to treat chronic hepatitis B or C and hematologic

and skin malignancies, causes thyroid dysfunction in up to 5% of

treated patients. It has been associated with painless thyroiditis, hypothyroidism, and Graves’ disease and is most common in women with

TPO antibodies prior to treatment. For discussion of amiodarone, see

“Amiodarone Effects on Thyroid Function,” below.

■ CHRONIC THYROIDITIS

Focal thyroiditis is present in 20–40% of euthyroid autopsy cases and

is associated with serologic evidence of autoimmunity, particularly the

presence of TPO antibodies. The most common clinically apparent

cause of chronic thyroiditis is Hashimoto’s thyroiditis, an autoimmune

disorder that often presents as a firm or hard goiter of variable size

(Chap. 383). Riedel’s thyroiditis is a rare disorder that typically occurs in

middle-aged women. It presents with an insidious, painless goiter with

local symptoms due to compression of the esophagus, trachea, neck

veins, or recurrent laryngeal nerves. Dense fibrosis disrupts normal

gland architecture and can extend outside the thyroid capsule. Despite

these extensive histologic changes, thyroid dysfunction is uncommon.

The goiter is hard, nontender, often asymmetric, and fixed, leading

to suspicion of a malignancy. Diagnosis requires open biopsy as FNA

biopsy is usually inadequate. Treatment is directed to surgical relief of

compressive symptoms. Tamoxifen may also be beneficial. There is an

association between Riedel’s thyroiditis and IgG4-related disease causing idiopathic fibrosis at other sites (retroperitoneum, mediastinum,

biliary tree, lung, and orbit).

SICK EUTHYROID SYNDROME

(NONTHYROIDAL ILLNESS)

Any acute, severe illness can cause abnormalities of circulating TSH or

thyroid hormone levels in the absence of underlying thyroid disease,

making these measurements potentially misleading. The major cause

of these hormonal changes is the release of cytokines such as IL-6.

Unless a thyroid disorder is strongly suspected, the routine testing of

thyroid function should be avoided in acutely ill patients.

The most common hormone pattern in sick euthyroid syndrome

(SES), also called nonthyroidal illness (NTI), is a decrease in total and

unbound T3

 levels (low T3

 syndrome) with normal levels of T4

 and

TSH. The magnitude of the fall in T3

 correlates with the severity of the

illness. T4

 conversion to T3

 via peripheral 5′ (outer ring) deiodination is

impaired, leading to increased reverse T3

 (rT3

). Since rT3

 is metabolized

by 5′ deiodination, its clearance is also reduced. Thus, decreased clearance rather than increased production is the major basis for increased

rT3. Also, T4

 is alternately metabolized to the hormonally inactive T3

sulfate. It is generally assumed that this low T3

 state is adaptive, because

it can be induced in normal individuals by fasting. Teleologically, the

fall in T3

 may limit catabolism in starved or ill patients.

Very sick patients may exhibit a dramatic fall in total T4

 and T3

levels (low T4

 syndrome). With decreased tissue perfusion, muscle and

liver expression of the type 3 deiodinase leads to accelerated T4

 and

T3

 metabolism. This state has a poor prognosis. Another key factor

in the fall in T4

 levels is altered binding to thyroxine-binding globulin

(TBG). The commonly used free T4

 assays are subject to artifact when

Clinical Phases

0

Time (weeks)

50

ESR

TSH (mU/L)

UT4 (pmol/L)

5

0.5

0.01

6

Thyrotoxic Hypothyroid Recovery

12 18

40

30

10

0

20

ESR (mm/h)

100

0

50

UT4

TSH

FIGURE 384-3 Clinical course of subacute thyroiditis. The release of thyroid

hormones is initially associated with a thyrotoxic phase and suppressed thyroidstimulating hormone (TSH). A hypothyroid phase then ensues, with low T4

 and

TSH levels that are initially low but gradually increase. During the recovery phase,

increased TSH levels combined with resolution of thyroid follicular injury lead to

normalization of thyroid function, often several months after the beginning of the

illness. ESR, erythrocyte sedimentation rate; UT4

, free or unbound T4

.

2945Hyperthyroidism and Other Causes of Thyrotoxicosis CHAPTER 384

serum binding proteins are low and underestimate the true free T4

level. Fluctuation in TSH levels also creates challenges in the interpretation of thyroid function in sick patients. TSH levels may range from

<0.1 mIU/L in very ill patients, especially with dopamine or glucocorticoid therapy, to >20 mIU/L during the recovery phase of SES. The

exact mechanisms underlying the subnormal TSH seen in 10% of sick

patients and the increased TSH seen in 5% remain unclear but may be

mediated by cytokines including IL-12 and IL-18.

Any severe illness can induce changes in thyroid hormone levels, but

certain disorders exhibit a distinctive pattern of abnormalities. Acute

liver disease is associated with an initial rise in total (but not unbound)

T3

 and T4

 levels due to TBG release; these levels become subnormal

with progression to liver failure. A transient increase in total and

unbound T4

 levels, usually with a normal T3

 level, is seen in 5–30%

of acutely ill psychiatric patients. TSH values may be transiently low,

normal, or high in these patients. In the early stage of HIV infection, T3

and T4

 levels rise, even if there is weight loss. T3

 levels fall with progression to AIDS, but TSH usually remains normal. Renal disease is often

accompanied by low T3

 concentrations, but with normal rather than

increased rT3

 levels, due to an unknown factor that increases uptake

of rT3

 into the liver.

The diagnosis of NTI is challenging. Historic information may be

limited, and patients often have multiple metabolic derangements.

Useful features to consider include previous history of thyroid disease

and thyroid function tests, evaluation of the severity and time course

of the patient’s acute illness, documentation of medications that may

affect thyroid function or thyroid hormone levels, and measurements

of rT3

 together with unbound thyroid hormones and TSH. The diagnosis of NTI is frequently presumptive, given the clinical context and

pattern of laboratory values; only resolution of the test results with

clinical recovery can clearly establish this disorder. Treatment of NTI

with thyroid hormone (T4

 and/or T3

) is controversial, but most authorities recommend monitoring the patient’s thyroid function tests during

recovery, without administering thyroid hormone, unless there is

historic or clinical evidence suggestive of hypothyroidism. Sufficiently

large randomized controlled trials using thyroid hormone are unlikely

to resolve this therapeutic controversy in the near future, because clinical presentations and outcomes are highly variable.

AMIODARONE EFFECTS ON

THYROID FUNCTION

Amiodarone is a commonly used type III antiarrhythmic agent

(Chap. 252). It is structurally related to thyroid hormone and contains

39% iodine by weight. Thus, typical doses of amiodarone (200 mg/d)

are associated with very high iodine intake, leading to greater than fortyfold increases in plasma and urinary iodine levels. Moreover, because

amiodarone is stored in adipose tissue, high iodine levels persist for

>6 months after discontinuation of the drug. Amiodarone inhibits

deiodinase activity, and its metabolites function as weak antagonists

of thyroid hormone action. Amiodarone has the following effects on

thyroid function: (1) acute, transient suppression of thyroid function;

(2) inhibition of T4

 to T3

 conversion causing either euthyroid hyperthyroxinemia or increased dosage requirement in LT4-treated hypothyroid patients; (3) hypothyroidism in patients susceptible to the

inhibitory effects of a high iodine load; and (4) thyrotoxicosis that may

be caused by either a Jod-Basedow effect from the iodine load, in the

setting of MNG or incipient Graves’ disease, or a thyroiditis-like condition due to a toxic effect on thyroid follicular cells.

The initiation of amiodarone treatment is associated with a transient decrease of T4

 levels, reflecting the inhibitory effect of iodine

on T4

 release. Soon thereafter, most individuals escape from iodidedependent suppression of the thyroid (Wolff-Chaikoff effect), and the

inhibitory effects on deiodinase activity and thyroid hormone receptor

action become predominant. These events lead to the following pattern

of thyroid function tests: increased T4

, decreased T3

, increased rT3

, and

a transient TSH increase (up to 20 mIU/L). TSH levels normalize or are

slightly suppressed within 1–3 months.

The incidence of hypothyroidism from amiodarone varies geographically, apparently correlating with iodine intake. Hypothyroidism

occurs in up to 13% of amiodarone-treated patients in iodine-replete

countries, such as the United States, but is less common (<6% incidence) in areas of lower iodine intake, such as Italy or Spain. The

pathogenesis appears to involve an inability of the thyroid gland to

escape from the Wolff-Chaikoff effect in autoimmune thyroiditis. Consequently, amiodarone-associated hypothyroidism is more common

in women and individuals with positive TPO antibodies. It is usually

unnecessary to discontinue amiodarone for this side effect, because

LT4 can be used to normalize thyroid function. TSH levels should

be monitored, because T4

 levels are often increased for the reasons

described above. In addition, TSH levels need to be monitored in

LT4-replaced hypothyroid patients because a dosage increase is often

required.

The management of amiodarone-induced thyrotoxicosis (AIT) is

complicated by the fact that there are different causes of thyrotoxicosis

and because the increased thyroid hormone levels exacerbate underlying arrhythmias and coronary artery disease. Amiodarone treatment

causes thyrotoxicosis in 10% of patients living in areas of low iodine

intake and in 2% of patients in regions of high iodine intake. There

are two major forms of AIT, although some patients have features of

both. Type 1 AIT is associated with an underlying thyroid abnormality

(preclinical Graves’ disease or nodular goiter). Thyroid hormone synthesis becomes excessive as a result of increased iodine exposure (JodBasedow phenomenon). Type 2 AIT occurs in individuals with no

intrinsic thyroid abnormalities and is the result of drug-induced

lysosomal activation leading to destructive thyroiditis with histiocyte accumulation in the thyroid; the incidence rises as cumulative

amiodarone dosage increases. Mild forms of type 2 AIT can resolve

spontaneously or can occasionally lead to hypothyroidism. Color-flow

Doppler ultrasonography shows increased vascularity in type 1 AIT

but decreased vascularity in type 2 AIT. Thyroid scintiscans are difficult to interpret in this setting because the high endogenous iodine

levels diminish tracer uptake. However, the presence of normal or

rarely increased uptake favors type 1 AIT.

In AIT, the drug should be stopped, if possible, although this is often

impractical because of the underlying cardiac disorder. Discontinuation of amiodarone will not have an acute effect because of its storage

and prolonged half-life. High doses of antithyroid drugs can be used

in type 1 AIT but are often ineffective. Potassium perchlorate, 200 mg

every 6 h, has been used to reduce thyroidal iodide content. Perchlorate

treatment has been associated with agranulocytosis, although the risk

appears relatively low with short-term use. Glucocorticoids, as administered for subacute thyroiditis, have modest benefit in type 2 AIT and

are generally initiated as prednisone 40 mg PO daily. Lithium blocks

thyroid hormone release and can also provide some benefit. Near-total

thyroidectomy rapidly decreases thyroid hormone levels and may be

the most effective long-term solution if the patient can undergo the

procedure safely.

■ FURTHER READING

Biondi B, Cooper DS: Subclinical hyperthyroidism. N Engl J Med

378:2411, 2018.

De Leo S et al: Hyperthyroidism. Lancet 388:906, 2016.

Kitahara CM et al: Association of radioactive iodine treatment with

cancer mortality in patients with hyperthyroidism. JAMA Intern Med

179:1034, 2019.

Ross DS et al: 2016 American Thyroid Association guidelines for

diagnosis and management of hyperthyroidism and other causes of

thyrotoxicosis. Thyroid 26:1343, 2016.

Smith TJ et al: Teprotumumab for the treatment of active thyroid eye

Disease. N Engl J Med 382:341, 2020.

2946 PART 12 Endocrinology and Metabolism

■ GOITER AND THYROID NODULAR DISEASE

Goiter refers to an enlarged thyroid gland. Biosynthetic defects, iodine

deficiency, autoimmune disease, and nodular diseases can each lead

to goiter, although by different mechanisms. Biosynthetic defects and

iodine deficiency are associated with reduced efficiency of thyroid

hormone synthesis, leading to increased thyroid-stimulating hormone

(TSH), which stimulates thyroid growth as a compensatory mechanism to overcome the block in hormone synthesis. Graves’ disease

and Hashimoto’s thyroiditis are also associated with goiter. In Graves’

disease, the goiter results mainly from the TSH-R–mediated effects of

thyroid-stimulating immunoglobulins. The goitrous form of Hashimoto’s thyroiditis occurs because of acquired defects in hormone synthesis, leading to elevated levels of TSH and its consequent growth effects.

Lymphocytic infiltration and immune system–induced growth factors

also contribute to thyroid enlargement in Hashimoto’s thyroiditis.

Thyroid nodular disease is characterized by the disordered growth

of thyroid cells, which can be either hyperplastic or neoplastic. A

patient may have a multinodular goiter (MNG) in which thyroid nodules (generally hyperplastic) replace the majority of the normal thyroid

parenchyma; this presentation is more common in areas of borderline

iodine deficiency. Or, the thyroid gland may be normal in size and

contain discrete thyroid nodules. Because the management of goiter

depends on the etiology, the detection of thyroid enlargement on physical examination should prompt further evaluation to identify its cause.

Nodular thyroid disease is common, occurring in about 3–7% of

adults when assessed by physical examination. Using ultrasound, nodules are present in up to 50% of adults, with the majority being <1 cm

in diameter. Thyroid nodules may be solitary or multiple, and they may

be functional or nonfunctional.

■ DIFFUSE NONTOXIC (SIMPLE) GOITER

Etiology and Pathogenesis When diffuse enlargement of the

thyroid occurs in the absence of nodules and hyperthyroidism, it is

referred to as a diffuse nontoxic goiter. This is sometimes called simple

goiter, because of the absence of nodules, or colloid goiter, because of

the presence of uniform follicles that are filled with colloid. Worldwide, diffuse goiter is most commonly caused by iodine deficiency

and is termed endemic goiter when it affects >5% of the population. In

nonendemic regions, sporadic goiter occurs, and the cause is usually

unknown. Thyroid enlargement in teenagers is sometimes referred to

as juvenile goiter. In general, goiter is more common in women than

men, probably because of the greater prevalence of underlying autoimmune disease and the increased iodine demands associated with

pregnancy.

In iodine-deficient areas, thyroid enlargement reflects a compensatory effort to trap iodide and produce sufficient hormone under conditions in which hormone synthesis is relatively inefficient. Somewhat

surprisingly, TSH levels are usually normal or only slightly increased,

suggesting increased sensitivity to TSH or activation of other pathways

that lead to thyroid growth. Iodide appears to have direct actions on

thyroid vasculature and may indirectly affect growth through vasoactive

substances such as endothelins and nitric oxide. Endemic goiter may

also be caused by exposure to environmental goitrogens such as cassava

root, which contains a thiocyanate; vegetables of the Cruciferae family

(known as cruciferous vegetables) (e.g., Brussels sprouts, cabbage, and

cauliflower); and milk from regions where goitrogens are present in

grass. Although relatively rare, inherited defects in thyroid hormone

synthesis lead to a diffuse nontoxic goiter. Abnormalities at each step

of hormone synthesis, including iodide transport (sodium/iodide

385 Thyroid Nodular Disease

and Thyroid Cancer

J. Larry Jameson, Susan J. Mandel,

Anthony P. Weetman

symporter [NIS]), thyroglobulin (Tg) synthesis, organification and

coupling (thyroid peroxidase [TPO]), and the regeneration of iodide

(dehalogenase), have been described.

■ CLINICAL MANIFESTATIONS AND DIAGNOSIS

If thyroid function is preserved, most goiters are asymptomatic. Examination of a diffuse goiter reveals a symmetrically enlarged, nontender,

generally soft gland without palpable nodules. Goiter is defined, somewhat arbitrarily, as a lateral lobe with a volume greater than the thumb

of the individual being examined. On ultrasound, total thyroid volume

exceeding 30 mL is considered abnormal. If the thyroid is markedly

enlarged, it can cause tracheal or esophageal compression. These

features are unusual, however, in the absence of nodular disease and

fibrosis. Substernal goiter may obstruct the thoracic inlet. Pemberton’s

sign refers to facial and neck congestion due to jugular venous obstruction when the arms are raised above the head, a maneuver that draws

the thyroid into the thoracic inlet. Respiratory flow measurements and

CT or MRI should be used to evaluate substernal goiter in patients with

obstructive signs or symptoms.

Thyroid function tests should be performed in all patients with

goiter to exclude thyrotoxicosis or hypothyroidism. It is not unusual,

particularly in iodine deficiency, to find a low total T4

, with normal T3

and TSH, reflecting enhanced T4 → T3

 conversion. A low TSH with a

normal free T3

 and free T4

, particularly in older patients, suggests the

possibility of thyroid autonomy or undiagnosed Graves’ disease, and

is termed subclinical thyrotoxicosis. The benefit of treatment (typically

with radioiodine) in subclinical thyrotoxicosis, versus follow-up and

implementing treatment if free T3

 or free T4

 levels become abnormal,

is unclear, but treatment is increasingly recommended in the elderly to

reduce the risk of atrial fibrillation and bone loss. Low urinary iodine

levels (<50 μg/L) support a diagnosis of iodine deficiency. Thyroid

scanning is not generally necessary but will reveal increased uptake in

iodine deficiency and most cases of dyshormonogenesis.

TREATMENT

Diffuse Nontoxic (Simple) Goiter

Iodine replacement induces variable regression of goiter in iodine

deficiency, depending on duration and the degree of hyperplasia, with accompanying fibrosis, and autonomous function that

may have developed. Surgery is rarely indicated for diffuse goiter.

Exceptions include documented evidence of tracheal compression

or obstruction of the thoracic inlet, which are more likely to be

associated with substernal MNGs (see below). Subtotal or near-total

thyroidectomy for these or cosmetic reasons should be performed

by an experienced surgeon to minimize complication rates. Surgery

should be followed by replacement with levothyroxine (LT4).

■ NONTOXIC MULTINODULAR GOITER

Etiology and Pathogenesis Depending on the population studied, MNG or the presence of nodules in a thyroid of normal size

occurs in up to 12% of adults. MNG should be distinguished from the

presence of nodules in a normal-size thyroid gland (see “Approach to

the Patient with Thyroid Nodules”). MNG is more common in women

than men and increases in prevalence with age. It is more common in

iodine-deficient regions but also occurs in regions of iodine sufficiency,

reflecting multiple genetic, autoimmune, and environmental influences

on the pathogenesis.

There is typically wide variation in nodule size. Histology reveals

a spectrum of morphologies ranging from hypercellular, hyperplastic

regions to cystic areas filled with colloid. Fibrosis is often extensive,

and areas of hemorrhage or lymphocytic infiltration may be seen.

Using molecular techniques, most nodules within an MNG are polyclonal in origin, suggesting a hyperplastic response to locally produced

growth factors and cytokines. TSH, which is usually not elevated, may

play a permissive or contributory role. Monoclonal neoplastic lesions

may also occur, reflecting mutations in genes that confer a selective

growth advantage to the progenitor cell.