Toxic Goiter in Pregnancy

INTRODUCTION

Goiter is an enlargement of the thyroid gland. It is termed as toxic or non-toxic depending on the
resultant changes in thyroxine (T3) and triidothyronine (T4) hormone levels.

TOXIC GOITER

Toxic goiter mainly occurs as a result of a hypersensitivity reaction to an auto-antibody of IgG type class
that acts on surface receptors for TSH (Thyroid Stimulating Hormone) on thyroid epithelium. In these patients, a
remarkable rise occurs in both T3 and T4 concentrations. The increase in thyroid hormone levels results in reduced
TSH release.

Toxic goiter occurs in three forms, namely Grave's disease, toxic adenoma, toxic nodular goiter. Grave's
disease mostly affects females and is commonly seen in families with a history of autoimmune diseases like
thyroiditis, pernicious anaemia. Exophthalmos (abnormal protrusion of the eye) is a prominent feature in this
disease. Toxic adenoma develops from only 1% of normal adenomas. A nodular goiter can become toxic, generally
in older patients, when a portion of the gland starts releasing high levels of T3 and T4.

The rise in T3 and T4 concentrations results in increased basal metabolic rate (BMR). This shows clinical
manifestations such as weakness, hyperkinesia and emotional instability. Patients suffer from loss of weight.
Glucose tolerance is diminished resulting in glycosuria. Skin becomes warm and sweaty (heat intolerance). Cardiac
arrhythmias are common in elderly patients suffering from toxic goiter. The enlargement of the gland is clearly
recognizable in most cases.

Toxic goiter needs prompt treatment with anti thyroid drugs, partial thyroidectomy and/or radioactive
iodine (I131) depending on patient's age and clinical status of the gland. Symptomatic treatment is also necessary
for toxic goiter.

TOXIC NODULAR GOITER (TNG)

Background
A toxic nodular goiter (TNG) is a thyroid gland that contains autonomously functioning thyroid nodules,
with resulting hyperthyroidism. TNG, or Plummer's disease, was first described by Henry Plummer in 1913. TNG is
the second most common cause of hyperthyroidism in the Western world, after Graves disease. In elderly
individuals and in areas of endemic iodine deficiency, TNG is the most common cause of hyperthyroidism.

Pathophysiology
Toxic nodular goiter (TNG) represents a spectrum of disease ranging from a single hyperfunctioning
nodule (toxic adenoma) within a multinodular thyroid to a gland with multiple areas of hyperfunction. The natural
history of a multinodular goiter involves variable growth of individual nodules; this may progress to hemorrhage
and degeneration, followed by healing and fibrosis. Calcification may be found in areas of previous hemorrhage.
Some nodules may develop autonomous function. Autonomous hyperactivity is conferred by somatic mutations of
the thyrotropin, or thyroid-stimulating hormone (TSH), receptor in 20-80% of toxic adenomas and some nodules of
multinodular goiters. Autonomously functioning nodules may become toxic in 10% of patients. Hyperthyroidism
predominantly occurs when single nodules are larger than 2.5 cm in diameter. Signs and symptoms of TNG are
similar to those of other types of hyperthyroidism.
Frequency
United States
Toxic nodular goiter accounts for approximately 15-30% of cases of hyperthyroidism in the United States,
second only to Graves disease.

International
In areas of endemic iodine deficiency, toxic nodular goiter (TNG) accounts for approximately 58% of cases
of hyperthyroidism, 10% of which are from solitary toxic nodules. Graves disease accounts for 40% of cases of
hyperthyroidism. In patients with underlying nontoxic multinodular goiter, initial iodine supplementation (or
iodinated contrast agents) can lead to hyperthyroidism (Jod-Basedow effect). Iodinated drugs, such as amiodarone,
may also induce hyperthyroidism in patients with underlying nontoxic multinodular goiter. Roughly 3% of patients
treated with amiodarone in the United States (more in areas of iodine deficiency) develop amiodarone-induced
hyperthyroidism.

Mortality/Morbidity
Morbidity and mortality from toxic nodular goiter (TNG) may be divided into problems related to
hyperthyroidism and problems related to growth of the nodules and gland. Local compression problems due to
nodule growth, although unusual, include dyspnea, hoarseness, and dysphagia.
TNG is more common in elderly adults; therefore, complications due to comorbidities, such as coronary artery
disease, are significant in the management of hyperthyroidism.

Sex
Toxic nodular goiter occurs more commonly in women than in men. In women and men older than 40
years, the prevalence rate of palpable nodules is 5-7% and 1-2%, respectively.

Age
Most patients with toxic nodular goiter (TNG) are older than 50 years.
Thyrotoxicosis often occurs in patients with a history of longstanding goiter. Toxicity occurs in a subset of
patients who develop autonomous function. This toxicity usually peaks in the sixth and seventh decades of life,
especially in persons with a family history of multinodular goiter or TNG, suggesting a genetic component

CLINICAL
History
• Thyrotoxic symptoms - Most patients with toxic nodular goiter (TNG) present with symptoms typical of
hyperthyroidism, including heat intolerance, palpitations, tremor, weight loss, hunger, and frequent
bowel movements.
• Elderly patients may have more atypical symptoms, including the following:
• Weight loss is the most common complaint in elderly patients with hyperthyroidism.
• Anorexia and constipation may occur, in contrast to frequent bowel movements often
reported by younger patients.
• Dyspnea or palpitations may be a common occurrence.
• Tremor also occurs but can be confused with essential senile tremor.
 • Cardiovascular complications occur commonly in elderly patients, and a history of atrial
fibrillation, congestive heart failure, or angina may be present.
• F Lahey, MD, first described apathetic hyperthyroidism in 1931; this is characterized by blunted
affect, lack of hyperkinetic motor activity, and slowed mentation in a patient who is thyrotoxic.
• Obstructive symptoms - A significantly enlarged goiter can cause symptoms related to mechanical
obstruction.
• A large substernal goiter may cause dysphagia, dyspnea, or frank stridor. Rarely, this goiter
results in a surgical emergency.
• Involvement of the recurrent or superior laryngeal nerve may result in complaints of hoarseness
or voice change.
• Asymptomatic - Many patients are asymptomatic or have minimal symptoms and are incidentally found to
have hyperthyroidism during routine screening. The most common laboratory finding is a suppressed TSH
with normal free thyroxine (T4) levels.

Physical
• Findings of hyperthyroidism may be more subtle than those of Graves disease. Features may include
widened, palpebral fissures; tachycardia; hyperkinesis; moist, smooth skin; tremor; proximal muscle
weakness; and brisk deep tendon reflexes.
• The size of the thyroid gland is variable. Large substernal glands may not be appreciable upon physical
examination.
• A dominant nodule or multiple irregular, variably sized nodules are typically present. In a small gland,
multinodularity may be apparent only on an ultrasonogram. Chronic Graves disease may present with
some nodularity; therefore, establishing the diagnosis is sometimes difficult.
• Hoarseness or tracheal deviation may be present upon examination.
• Mechanical obstruction may result in superior vena cava syndrome, with engorgement of facial and neck
veins (Pemberton sign).
• Stigmata of Graves disease (eg, orbitopathy, pretibial myxedema, acropachy) are not observed.

Causes
Functional autonomy of the thyroid gland appears to be related to iodine deficiency. Various mechanisms
have been implicated, but the molecular pathogenesis is poorly understood.

• The sequence of events leading to toxic multinodular goiter is as follows:

• Iodine deficiency leads to low levels of T4; this induces thyroid cell hyperplasia to compensate for
the low levels of T4.
• Increased thyroid cell replication predisposes single cells to somatic mutations of the TSH
receptor. Constitutive activation of the TSH receptor may generate autocrine factors that
promote further growth, resulting in clonal proliferation. Cell clones then produce multiple
nodules.
• Somatic mutations of the TSH receptors and G α protein confer constitutive activation to the cyclic
adenosine monophosphate (cAMP) cascade of the inositol phosphate pathways. These mutations may be
responsible for functional autonomy of the thyroid in 20-80% of cases. 1
 • These mutations are found in autonomously functioning thyroid nodules, solitary and within a
multinodular gland. Nonfunctioning thyroid nodules within the same gland lack these mutations.
• The reported frequency of these mutations varies widely, ranging from 10-80%. Higher incidence
is reported in patients with iodine deficiency.
• In addition to somatic mutations, polymorphisms of the TSH receptor have been studied in patients with
toxic nodular goiter (TNG); notably, polymorphisms involving the carboxyl-terminal tail of the human TSH
receptor have been found in nodular and genomic deoxyribonucleic acid (DNA).
• Unlike the somatic mutations found in autonomously functioning nodules, these mutations have
also been found in other cell lines, indicating a germline mutation. One of these, D727E, was
present with greater frequency in patients with TNG than in healthy individuals; this suggests
that this polymorphism may be associated with the disease.
• The presence of the heterozygous state for the D727E variant of the human TSH receptor alone is
not sufficient for the development of the TNG. Approximately 10% of healthy individuals have
this polymorphism.
• Possible mediators in growth include the following:
• Endothelin-1 (ET-1) production is increased in rat thyroid glands that have undergone
hyperplasia; this suggests that ET-1 production may be involved in thyroid gland growth and
vascularity. In contrast to normal thyroid tissue and papillary thyroid cancer, thyroid tissue in
patients with TNG shows markedly positive staining of the stroma but absent staining of the
follicular cells. The significance of this finding is unclear, but ET-1 is, in addition to being a
vasoconstrictor, a mitogen for vascular endothelium, smooth muscle cells, and thyroid follicular
cells.
• In vitro systems have shown stimulation of thyroid follicular cell proliferation with insulinlike
growth factor-1, epidermal growth factor, and fibroblast growth factor. Reduced concentrations
of transforming growth factor-β 1 or resistance to transforming growth factor-β have also been
associated with follicular cell growth. The role of these multiple factors in the growth and
secretory function of TNG needs further investigation.

OTHER PROBLEMS TO BE CONSIDERED

Subclinical hyperthyroidism
Substernal goiter
Amiodarone-associated thyroid disease
Iodine-induced hyperthyroidism

WORKUP
Laboratory Studies
• Thyroid function tests6 - Evidence of hyperthyroidism must be present in order to consider a diagnosis of
toxic nodular goiter (TNG).
• Third-generation TSH assays are generally the best initial screening tool for hyperthyroidism.
Patients with TNG will have suppressed TSH levels.
• Free T4 levels or surrogates of free T4 levels (ie, free T4 index) may be elevated or within the
reference range. An isolated increase in T4 is observed in iodine-induced hyperthyroidism or in
the presence of agents that reduce peripheral conversion of T4 to triiodothyronine (T3) (eg,
propranolol, corticosteroids, radiocontrast agents, amiodarone).
 • Some patients may have normal free T4 levels (or free T4 index) with an elevated T3 level (T3
toxicosis); this may occur in 5-46% of patients with toxic nodules. Note that the total T3 and T4
levels may often be within the reference range but may be higher than the normal range for a
particular individual; this is especially true in patients with nonthyroidal illness in which T3 levels
are decreased.
• Subclinical hyperthyroidism - Some patients may have suppressed TSH levels with normal free T4 and
total T3 levels.

Imaging Studies
• Nuclear scintigraphy
• Nuclear scans should be performed on patients with biochemical hyperthyroidism. Nuclear
medicine scans can be performed with radioactive iodine-123 ( 123 I) or with technetium-99m (99m
Tc). These isotopes are chosen for their shorter half-life and because they provide lower
radiation exposure to the patient when compared with sodium iodide-131 (Na 131 I).
99m
• Tc is trapped in the thyroid but is not organified. Although convenient, 99m Tc scanning may
provide misleading results. Some nodules that appear hot or warm on 99m TC scan results may be
cold on123 I scan results. Nodules with discordant 99m Tc and123 I scan results may be malignant;
therefore,123 I scanning is preferred.
• Nuclear scans allow determination of the cause of hyperthyroidism. Patients with Graves disease
usually have homogeneous diffuse uptake. Glands with thyroiditis have low uptake.
• In patients with toxic nodular goiter (TNG), the scan results usually reveal patchy uptake, with
areas of increased and decreased uptake. The uptake rate of radioiodine in 24 hours averages
approximately 20-30%. Radioactive Na131 I ablation of the thyroid gland may be considered if the
thyroid uptake value is elevated. Several therapeutic modalities have been suggested to increase
uptake (eg, low iodine diet, lithium, recombinant TSH, propylthiouracil [PTU]).
• Thyroid scanning is also useful for helping to determine the presence of substernal extension of
the thyroid gland, which may contain toxic nodules.

• Ultrasonography
• Ultrasonography is a highly sensitive procedure for delineating discrete nodules that are not
palpable during thyroid examination. Ultrasonography is helpful when correlated with nuclear
scans to determine the functionality of nodules.
• Dominant cold nodules should be considered for fine-needle aspiration biopsy prior to definitive
treatment of a TNG.
• This technique may be used to serially examine the size of thyroid nodules.

• Other imaging modalities

• In the workup of patients with compressive or obstructive symptoms, computed tomography
(CT) scanning of the neck may help to establish whether the trachea is patent and if tracheal
deviation or the impingement of other structures is caused by a nodular goiter.
• Multinodular goiters, especially those with a substernal component, are often incidental findings
on chest radiographs, CT scans, or magnetic resonance imaging (MRI) scans. CT scans with
iodinated contrast may induce thyrotoxicosis in individuals with an underlying nontoxic,
multinodular goiter by supplying an iodine load (Jod-Basedow effect). This type of thyrotoxicosis
is self-limited but may last longer if areas of autonomy already exist within the goiter.
Procedures
• Fine-needle aspiration
• Fine-needle aspiration is not usually indicated in an autonomously functioning (ie, hot) thyroid
nodule. The risk of malignancy is quite low. Interpretation of the cytology specimen is difficult,
because it is likely to demonstrate a follicular neoplasm (ie, sheets of follicular cells with little or
no colloid), and distinguishing between a benign lesion and a malignant lesion is not possible
without histologic sectioning to examine for the presence of vascular or capsular invasion.
• Perform a fine-needle aspiration biopsy if a dominant cold nodule is present in a multinodular
goiter. A clinically significant nodule is larger than 1 cm in maximum diameter, based on either
palpation or ultrasonographic images, unless there is an increased risk of malignancy.
Nonpalpable nodules may be biopsied with the assistance of ultrasonography.
• A history of head or neck irradiation during childhood increases the risk of malignancy. Head or
neck irradiation in an adult increases the frequency of toxic nodular goiter and of carcinoma of
the thyroid. Patients from iodine-replete areas have the same risk of malignancy as persons from
iodine-deficient areas.

Histologic Findings
Autonomous nodules may be monoclonal or polyclonal. Many nodules studied in multinodular goiters
may actually be monoclonal, even in the setting of histologically marked phenotypic variation.
The histologic appearance of a multinodular goiter can be highly variable and may involve the presence of
normal-sized follicles, microfollicles, or macrofollicles, all coexisting within the same gland. Early goiters display
micronodular growth patterns. Actively proliferating follicular cells can be observed within some thyroid follicles,
resulting in budding intraluminal projections, while other cells within the same follicle appear to be in the resting
phase. Conversely, some follicles show a more uniform appearance of cells. Periods of alternating active and
quiescent growth appear to occur within the goiter. Areas of fresh and old hemorrhage with calcification are also
occasionally present.

TREATMENT
Medical Care
The optimal therapy for treatment of toxic nodular goiter (TNG) remains controversial. Unlike Graves disease,
TNG is not an autoimmune disease and rarely, if ever, remits. Therefore, patients who have autonomously
functioning nodules should be treated definitely with radioactive iodine or surgery. Patients with subclinical
hyperthyroidism should be monitored closely for overt disease. Some suggest that elderly patients, women with
osteopenia, and patients with risk factors for atrial fibrillation should be treated, even those who have subclinical
disease.
• Na131 I treatment - In the United States and Europe, radioactive iodine is considered the treatment of
choice for TNG. Except for pregnancy, there are no absolute contraindications to radioiodine therapy.
• Much debate exists regarding optimal dosing of radioactive iodine. Patients with TNG tend to
have less uptake than do patients with Graves disease; therefore, they are generally considered
to need higher doses of Na131 I. However, studies by Allahabadia and colleagues suggest that
fixed doses of radioiodine do not demonstrate any difference in response in these 2 groups of
patients (using a fixed dose of 370 megabecquerels).
• A single dose of radioiodine therapy has a success rate of 85-100% in patients with TNG.
Radioiodine therapy may reduce the size of the goiter by up to 40%.
 • Failure of initial treatment with radioactive iodine has been associated with increased goiter size
and higher T3 and free T4 levels, which suggests that these factors may present a need for higher
doses of Na131 I.
• A positive correlation exists between radiation dose to the thyroid and decrease in thyroid
volume. In patients with uptake of less than 20%, pretreatment with lithium, PTU, or
recombinant TSH can increase the effectiveness of iodine uptake and treatment. This treatment
may be valuable in elderly patients in whom surgery is considered high risk.
• Complications
• Hypothyroidism occurs in 10-20% of patients; this is similar to the incidence rate after
surgery and is substantially less than in the treatment of Graves disease.
• Tracheal compression due to thyroid swelling after radiation therapy is no longer
thought to be a risk.
• Mild thyrotoxic symptoms after radioiodine occur in about one-third of patients, and
about 4% of patients develop a clinically significant radiation-induced thyroiditis. These
patients should be treated symptomatically with beta blockers.
• Elderly patients may have exacerbation of congestive heart failure and atrial fibrillation.
Pretreat elderly patients with antithyroid drugs.
• Thyroid storm is a rare complication, particularly in patients with rapidly enlarging
goiters or high total T3 levels. Patients with these conditions should receive
pretreatment with antithyroid drugs.
• Pharmacotherapy - Antithyroid drugs and beta blockers are used for short courses in the treatment of
TNG; they are important in rendering patients euthyroid in preparation for radioiodine or surgery and in
treating hyperthyroidism while awaiting full clinical response to radioiodine. Patients with subclinical
disease at high risk of complications (eg, atrial fibrillation, osteopenia) may be given a trial of low dose
methimazole (5-15 mg/d) or beta blockers and should be monitored for a change in symptoms or for
disease progression that requires definitive treatment.
• Thioamides - The role of therapy with thioamides (eg, PTU, methimazole) is to achieve
euthyroidism prior to definitive treatment with either surgery or radioiodine therapy. Data
suggest that pretreated patients have decreased response to radioiodine. The general
recommendation is to stop antithyroid agents at least 4 days prior to radioiodine therapy in
order to maximize the radioiodine effect.
• Antithyroid drugs are often administered for 2-8 weeks before radioiodine therapy in
order to avoid the risk of precipitating thyroid storm. Although many physicians no
longer consider this treatment necessary, the general consensus is that elderly patients
or patients with high risk of cardiac complications should receive this treatment.
• Antithyroid drugs and beta blockers have side effects, the most common being pruritic
rash, fever, gastrointestinal upset, and arthralgias. More serious potential side effects
include agranulocytosis, drug-induced lupus and other forms of vasculitis, and liver
damage.
• The US Food and Drug Administration (FDA) added a boxed warning, the strongest warning
issued by the FDA, to the prescribing information for PTU. The boxed warning emphasizes the
risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed
warning also states that PTU should be reserved for use in patients who cannot tolerate other
treatments, such as methimazole, radioactive iodine, or surgery.
• The decision to include a boxed warning was based on the FDA's review of
postmarketing safety reports and on meetings held with the American Thyroid
 Association, the National Institute of Child Health and Human Development, and the
pediatric endocrine clinical community.
• The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury
associated with PTU. Of the adults, 12 deaths and 5 liver transplants occurred, and
among the pediatric patients, 1 death and 6 liver transplants occurred. PTU is indicated
for hyperthyroidism due to Graves disease. These reports suggest an increased risk for
liver toxicity with PTU compared with methimazole. Serious liver injury has been
identified with methimazole in 5 cases (3 resulting in death).
• PTU is considered to be a second-line drug therapy, except in patients who are allergic
to or intolerant of methimazole, or in women who are in the first trimester of
pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with
methimazole during pregnancy. The FDA recommends the following criteria be
considered for prescribing PTU:
• Reserve PTU use during first trimester of pregnancy, or in patients who are
allergic to or intolerant of methimazole.
• Closely monitor PTU therapy for signs and symptoms of liver injury, especially
during the first 6 months after initiation of therapy.
• For suspected liver injury, promptly discontinue PTU therapy, evaluate the
patient for evidence of liver injury, and provide supportive care.
• PTU should not be used in pediatric patients unless the patient is allergic to or
intolerant of methimazole and no other treatment options are available.
• Counsel patients to promptly contact their health care provider for the
following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of
appetite, itching, easy bruising, or yellowing of the eyes or skin.
• Beta-adrenergic receptor antagonists - These drugs remain useful in the treatment of symptoms
of thyrotoxicosis; they may be used alone in patients with mild thyrotoxicosis or in conjunction
with thioamides for treatment of more severe disease.
• Propranolol, a nonselective beta blocker, may help to lower the heart rate, control
tremor, reduce excessive sweating, and alleviate anxiety. Propranolol is also known to
reduce the conversion of T4 to T3.
• In patients with underlying asthma, beta-1 selective antagonists, such as atenolol or
metoprolol, would be safer options.
• In patients with contraindications to beta blockers (eg, moderate to severe asthma),
calcium channel antagonists (eg, diltiazem) may be used to help control the heart rate.

Surgical Care
Surgical therapy is usually reserved for young individuals, patients with 1 or more large nodules or with
obstructive symptoms, patients with dominant nonfunctioning or suspicious nodules, patients who are pregnant,
patients in whom radioiodine therapy has failed, or patients who require a rapid resolution of the thyrotoxic state.
Subtotal thyroidectomy results in rapid cure of hyperthyroidism in 90% of patients and allows for rapid
relief of compressive symptoms.
• Restoring euthyroidism prior to surgery is preferable.
• Complications of surgery include the following:
• In patients who are treated surgically, the frequency of hypothyroidism is similar to that found in
patients treated with radioiodine (15-25%).
 • Complications include permanent vocal cord paralysis (2.3%), permanent hypoparathyroidism
(0.5%), temporary hypoparathyroidism (2.5%), and significant postoperative bleeding (1.4%).
• Other postoperative complications include tracheostomy, wound infection, wound hematoma,
myocardial infarction, atrial fibrillation, and stroke.
• The mortality rate is almost zero.

Consultations
• Consult an endocrinologist for hyperthyroidism that has not responded to medical therapy or if other
comorbid conditions are complicating the patient's condition. Refer patients with amiodarone-associated
hyperthyroidism to an endocrinologist. In a multinodular goiter with cold and hot areas on thyroid scan
findings, fine-needle aspiration may be required to determine the histologic nature of the cold lesions.
• Consult an endocrine surgeon if medical therapy fails to maintain the euthyroid state, if compromise of
the trachea is noted on imaging studies, or if the patient requests surgical removal.
• Consult a thoracic surgeon in the case of a toxic substernal goiter, because the surgeon may be helpful in
further diagnostic and therapeutic measures.

Activity
• Activity should be restricted to maintain a heart rate of less than 90 beats per minute.

MEDICATION
The goals of pharmacotherapy are to reduce morbidity, prevent complications, and provide a bridge to
definitive therapy.

Antithyroid agents
Inhibition thyroid hormone production. PTU and methimazole are thionamide derivatives. PTU is a
thiourea antithyroid drug that blocks the production of thyroid hormones. A high doses, this drug also inhibits the
peripheral deiodination of T4 to T3 and is used (1) in the management of hyperthyroidism, including treatment of
Graves disease; (2) in the preparation of patients who are hyperthyroid for thyroidectomy; (3) as an adjunct to
radioiodine therapy; and (4) as treatment for thyroid storm. Unlike PTU, methimazole lacks the ability to block
peripheral conversion of T4 to T3.

Propylthiouracil
Thiourea agent that blocks the synthesis of thyroid hormones and inhibits peripheral deiodination of T4 to
T3.
Dosing

Adult
Note: Only available in 50-mg size
Initial: 100-150 mg PO q8h; not to exceed 900-1200 mg/d (except in treatment of thyroid storm)
Maintenance: 100-300 mg/d PO
Thyroid storm: 200mg q6h for first 24 hours; may be given via NG tube or PR if unable to tolerate PO
Pediatric
Disease not observed in children
Interactions

Monitor aPTT; hyperthyroidism increases metabolism of vitamin K – dependent clotting factors, resulting
in increased sensitivity to oral anticoagulants; antithyroid drugs reduce hyperthyroidism and decrease metabolism
of clotting factors, thus reducing effects of oral anticoagulants.
Contraindications
Documented hypersensitivity; breastfeeding; pediatric patients (unless allergic or intolerant to
methimazole and no other treatment is an option)
Precaution

Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Commonly used in pregnancy, but close monitoring required for prevention of fetal goiter and
hypothyroidism; aplasia cutis not identified with use, thus, preferred antithyroid medication during
pregnancy; smallest dose to control disorder should be used because drug does cross the placenta and
may result in hypothyroidism of fetus with possible goiter; fever, rash, agranulocytosis, leukopenia,
aplastic anemia, hemolytic anemia, DIC, and acute myelocytic anemia; vasculitis; galactorrhea; CNS
toxicity; nausea, vomiting, and dysgeusia; rarely, acute hepatitis or liver failure.
Risk of serious liver injury, including liver failure and death, has been reported in adults and
children by the FDA (carefully consider drug therapy, and, if PTU initiated, monitor for symptoms and
signs of liver injury, especially during first 6 mo of therapy)

Methimazole (Tapazole)
Active moiety of parent compound carbimazole. A thiourea agent that blocks production of thyroid
hormones.
Dosing

Adult
Mild hyperthyroidism: 30 mg/d PO divided q8-12h initially
Moderate or severe hyperthyroidism: 60 mg/d PO divided q8h initially
Maintenance or treatment of subclinical hyperthyroidism: 5-15 mg/d PO
Pediatric
Disease not observed in children
Interaction

Monitor aPTT if patient is on anticoagulants; hyperthyroidism increases metabolism of vitamin K –

dependent clotting factors, resulting in increased sensitivity to oral anticoagulants; antithyroid drugs reduce
hyperthyroidism and decrease metabolism of clotting factors, thus reducing effects of oral anticoagulants;
coadministration with amiodarone leads to a greater decline in T4 and T3 levels than with methimazole therapy
alone, possibly related to increased iodide release and inhibition of T4-to-T3 conversion.
Contraindication
Documented hypersensitivity; breastfeeding; pregnancy or planned pregnancy
Precaution

Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Aplasia cutis reported in infants born to women taking methimazole in pregnancy; liver disease;
leukopenia, agranulocytosis, rash, signs or symptoms of infection, fever, sore throat; CNS toxicity; nausea,
vomiting, dysgeusia

Radioactive iodines
Radioisotopes that decay by beta and gamma emissions are used to destroy autonomously functioning
follicular cells of the thyroid gland.

Sodium iodide-131 (Na131 I; Iodotope)

Used to treat hyperthyroidism by destroying follicular cells of the thyroid gland. The dose is determined
by radioactivity calibration system just prior to administration.
Dosing

Adult
Hyperthyroidism: Total amount to achieve clinical remission without destroying entire thyroid varies
widely; usual dose range is 4-20 MCi PO; TNG and other special situations require even larger doses, depending on
the size and activity of the gland; decay by beta and gamma emissions with half-life of 8.04 d; following PO
administration, approximately 40% of activity has half-life of 0.34 d and 60% has half-life of 7.61 d
Pediatric
Disease not observed in children
Interactions
Increases lithium toxicity by producing additive hypothyroid effects; uptake is affected by stable iodine,
iodinated contrast, thyroid hormone, and antithyroid agents; amiodarone may block radioactive iodine uptake into
goiter; many herbal products contain iodine and should be discontinued prior to radioactive iodine uptake and
therapy.
Contraindications
Critical obstruction from goiter (edema after treatment and radiation thyroiditis theoretically may worsen
condition); pregnancy and breast-feeding (drug may pass through placenta and is secreted in milk)
Precautions

Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
May cause bone marrow depression, acute leukemia, anemia, blood dyscrasias, leukopenia,
thrombocytopenia, radiation sickness, angina, sinus tachycardia, pruritus, skin rash, or hives; high doses
 may cause radiation thyroiditis with painful thyroid or release of stored thyroid hormone, causing
temporary thyrotoxicosis

Beta-adrenergic receptor antagonists

These inhibit chronotropic, inotropic, and vasodilatory responses to beta-adrenergic activity observed in
hyperthyroidism.

Propranolol (Inderal)

Nonselective, competitive beta-receptor antagonist with no intrinsic sympathetic activity.

Propranolol treats cardiac arrhythmias resulting from hyperthyroidism, controls cardiac and psychomotor
manifestations immediately, and blocks conversion of T4 to T3.

Dosing

Adult
Initial: 40 mg PO bid, titrate dose for heart rate less than 90 beats/min

Maintenance dose: 120-240 mg PO qd; rarely, 640 mg/d may be required

Life-threatening arrhythmias: 1-3 mg IV; rate of administration should not exceed 1 mg/min; wait 4 h
before administering additional dose

Pediatric

Disease not observed in children

Interaction

Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine,
and rifampin may decrease effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase
toxicity; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase.

Contraindication

Low-output congestive heart failure, bronchospasm, diabetes mellitus with risk of hypoglycemia
unawareness, and Wolff-Parkinson-White syndrome

Precaution
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus

Precautions
May mask some clinical signs of thyrotoxicosis (withdraw slowly to avoid exacerbation of clinical
symptoms or thyroid storm); caution in patients with impaired renal or hepatic function; may lower
intraocular pressure and, therefore, interfere with measurements for glaucoma
Atenolol (Tenormin)

Selectively blocks beta-1 receptors with little or no effect on beta-2 types. Atenolol treats cardiac
arrhythmias resulting from hyperthyroidism and controls cardiac and psychomotor manifestations within minutes.
Dosing
Adult
25 mg PO qd; increase to 100 mg/d as symptoms of palpitations, tremor, or pulse rate dictate

Pediatric
Disease not observed in children

Interaction

Coadministration with aluminum salts, barbiturates, calcium salts, cholestyramine, NSAIDs, penicillins,
and rifampin may decrease effects; haloperidol, hydralazine, loop diuretics, and MAOIs may increase toxicity

Contraindications

Documented hypersensitivity; low-output congestive heart failure, bronchospasm, diabetes mellitus with
risk of hypoglycemia unawareness, Wolff-Parkinson-White syndrome

Precaution

Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions
May mask some clinical signs of thyrotoxicosis (withdraw slowly to avoid exacerbation of clinical
symptoms or thyroid storm); caution in patients with impaired renal or hepatic function; may lower
intraocular pressure and, therefore, interfere with measurements for glaucoma

Metoprolol, metoprolol succinate, metoprolol tartrate (Lopressor, Toprol XL)

Selective beta-1 – adrenergic receptor blocker that decreases automaticity of contractions. Helps to treat cardiac
arrhythmias resulting from hyperthyroidism. Controls cardiac and psychomotor manifestations within minutes.

Dosing

Adult
PO: 25-50 mg bid, may need to increase to 100 mg bid or higher as symptoms of palpitations, tremor, or
pulse rate dictate IV (metoprolol tartrate): 5 mg, may repeat at 3-min intervals, not to exceed 15 mg in a
patient with thyroid storm; during IV administration, carefully monitor blood pressure, heart rate, and
ECG

Pediatric
Disease not observed in children
Interactions

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may
decrease bioavailability and plasma levels, possibly resulting in decreased pharmacologic effects; toxicity may
increase with coadministration of sparfloxacin, phenothiazines, astemizole, calcium channel blockers, quinidine,
flecainide, and contraceptives; may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine,
prazosin, verapamil, and lidocaine

Contraindications

Documented hypersensitivity; low-output congestive heart failure, bronchospasm, diabetes mellitus with
risk of hypoglycemia unawareness, and Wolff-Parkinson-White syndrome

Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus

Precautions
Abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm;
monitor patient closely and withdraw drug slowly; during IV administration, carefully monitor blood
pressure, heart rate, and ECG

DIFFUSE TOXIC GOITER

Background
This condition was first described by the English physician Caleb H. Parry (1755-1822). The disorder is
known as Graves disease (after Robert J. Graves) in the English-speaking world and as Basedow disease (after Karl
A. von Basedow) in the rest of Europe. 

In diffuse toxic goiter, the thyroid gland is diffusely hyperplastic and excessively overproduces thyroid
hormone. This results in accelerated metabolism in most body organs. The clinical response and its manifestations
are variable in intensity, distribution, and are modified by age, gender, and associated premorbid medical
problems. When the diffuse toxic goiter is associated with clinical evidence of oculopathy, or rarely with
dermopathy/acropachy, the term Graves’ disease is often applied. Awareness is needed regarding the atypical
clinical presentations.

Pathophysiology
The thyroid gland is usually enlarged to a variable degree and is vascular and diffusely affected. This
results in a smooth, rubbery-firm consistency, and often a bruit is heard on auscultation. Microscopically, the
thyroid follicular cells are hypertrophic and hyperplastic, and they contain little colloid (stored hormone) and show
evidence of hypersecretion. Lymphocytes and plasma cells infiltrate into the thyroid gland and may aggregate into
lymphoid follicles.
 This condition is an autoimmune disorder whereby the thyroid gland is overstimulated by antibodies
directed to the thyroid-stimulating hormone (TSH) receptor on the thyroid follicular cells. This antibody stimulates
iodine uptake, thyroid hormonogenesis and release, and thyroid gland growth. Although mainly produced within
the thyroid gland, these antibodies reach the circulation and can be measured by various assays in most, but not
all, cases.

The association with another autoimmune thyroid disease, Hashimoto thyroiditis, and to a lesser degree,
with other autoimmune diseases in other endocrine glands and other systems in the same person is high. A strong
familial association exists with the same diffuse toxic goiter or the associated disorders, especially Hashimoto
thyroiditis. The presence of Hashimoto thyroiditis, which has more of a destructive effect on the thyroid gland, or
the presence of another antibody, TSH-receptor blocking antibody, results in a variable natural history of the
course of diffuse toxic goiter.

Frequency
United States
Diffuse toxic goiter is the most common cause of spontaneous hyperthyroidism. A Minnesota study found
0.3 new cases per 1000 per year.

In late childhood, the incidence rate is 3 per 100,000 in girls and 0.5 per 100,000 in boys. Prevalence
studies show a rate of 2.7% in women and 0.23% in men.

A marked increase in familial incidence is noted.

International
Prewar Copenhagen found 0.2 new cases per 1000 per year.

British studies found 0.08-0.2 new cases per 1000 per year.

Mortality/Morbidity
The natural history is usually of a benign course, which may vary in intensity of the symptoms and even
spontaneously remit. The intensity of the symptoms and effect on quality of life are variable from person to person
and are affected by age and gender.

Mortality is rare but is due to cardiovascular problems such as heart failure, arrhythmias, or myocardial
infarction. Debility and infection may occur. Thyroid storm is rare but may be fatal from dehydration,
hyperthermia, and organ failure.

Morbidity may result from increased bone turnover and osteoporosis, especially in postmenopausal
women, or from atrial fibrillation and its sequelae, such as thromboembolism, especially in older men. Personality
changes and psychopathology, muscular weakness, and systemic symptoms all lead to quality of life changes.
Associated oculopathy may be symptomatic, especially with double vision. Rarely it may progress to affect the
integrity of the cornea and may even endanger vision.

Associated dermopathy is uncommon and is usually minimally symptomatic, but it may be symptomatic to
become debilitating.
 Associated hypokalemic periodic paralysis, most commonly seen in Asian males, may be sudden,
dramatic, and concerning but usually runs a benign course of recovery after a few hours of skeletal muscle
paralysis.

A higher risk of associated immunologic diseases, such as adrenal insufficiency, each has their own
associated morbidity and mortality, especially if undiagnosed.

Race
No racial predilection exists.

Sex
Diffuse toxic goiter is 7-10 times more common in women than in men. It is often associated with or
following a pregnancy.

Age
Diffuse toxic goiter can occur in all ages, but it is rare in children younger than 10 years  and unusual in
elderly persons. The peak incidence is in third and fourth decades.

Incidence is increased in postpartum women, often the first presentation of disease.

CLINICAL

History
Symptoms of the hyperthyroidism, the goiter itself, and of comorbid conditions are present. The
symptoms may be present for weeks, months, or even years before diagnosis.

The hyperthyroid symptoms may be multisystemic or predominate in a single organ system and mask the
correct diagnosis in this manner. Many symptoms are adrenergic in origin and may be misdiagnosed as an anxiety
disorder.

Elderly patients may have no adrenergic symptoms and present as weight loss (malignancy), atrial
fibrillation (cardiac), or apathy (depression), and this presentation is referred to as apathetic thyrotoxicosis.

The presenting symptoms may be modified by preexisting medical or psychiatric disorders, which may be
modified or worsened. Symptoms are described below.

 Hypermetabolism with heat generation and protein catabolism - Weight loss with good appetite,
heat intolerance, sweating, muscle weakness (proximal more than distal), osteoporosis
 Adrenergic - Palpitations, tremor, emotional lability, insomnia, restlessness, hyperdefecation
 Other - Gynecomastia, lighter menses, insomnia, decreased concentration, fatigue, shortness of
breath on exertion, and decreased exercise tolerance
 Goiter - May be mildly tender, may have difficulty swallowing if large
 Associated oculopathy (clinically present in about 25% of cases) - Tearing, pain, puffiness,
grittiness, double vision, prominent appearance, rarely visual loss
Physical
General physical examination findings may include restless appearance, evidence of weight loss, pruritus,
palmar erythema, and onycholysis of the finger nails.

 Hypermetabolism with protein catabolism - Warm hands, often with heat radiation, velvety skin,
proximal muscle weakness in the arms and legs compared with distal muscle strength  
 Hyperadrenergic - Bounding and fast pulse, wide pulse pressure with higher systolic and lower
diastolic blood pressure, active precordium and abdominal aorta to palpation; lid retraction
(upper eyelid more than halfway from pupil to top of iris) and lid lag or globe lag, tremor of
fingers, brisk reflexes  
 Organ decompensation - Atrial fibrillation, congestive heart failure, jaundice  
 Oculopathy - Periorbital puffiness, chemosis, conjunctival redness, proptosis (sclera visible below
iris), double vision with eye movements, loss of color vision (rare), or papilledema (rare)  
 Thyroid gland - Mildly enlarged (but may be normal in size, many times normal in size, or difficult
to palpate); smooth, rubbery firm in texture; nontender or mildly tender; systolic bruit on
auscultation  
 Miscellaneous - Pretibial myxedema (uncommon), rare may be finger clubbing, diffuse
lymphadenopathy, and splenomegaly

Causes
Diffuse toxic goiter and its hyperthyroidism are caused by TSH-receptor stimulating antibodies. Although
the exact cause is not understood, it has been suggested that there is a genetic lack of suppressor T cells that
results in the unregulated production of the antibody, resulting in the autoimmune disease. The antibody may pass
the placenta and result in fetal and neonatal hyperthyroidism.

As with most such disorders, usually a combination of genetic and environmental factors is present. The
familial association indicates a strong genetic factor. Predisposing factors include genetic susceptibility (including
HLA factors); female gender; mental stress; viral infection; surgery; postpartum state; iodine administration; drugs
such as lithium and iodine-containing agents, such as amiodarone, interferons and interleukins, and antiretroviral
agents.

Associated ophthalmopathy is not well understood, but it is a related but separate autoimmune disorder
directed toward the extraocular muscles. It may run a course similar to or different from the hyperthyroidism.
Smoking is an environmental aggravating factor. The presence and degree of clinical ophthalmopathy does
correlate with the degree of elevation of the anti-TSH receptor antibodies.

Dermopathy (pretibial myxedema) may be brought on or aggravated by local trauma.

TREATMENT

Medical Care
Even though the natural history of diffuse toxic goiter is to possibly spontaneously remit (and perhaps
later relapse), or even progress into hypothyroidism, observation without intervention, even in minimally
symptomatic people, is not recommended. The risk of bone loss and atrial fibrillation occur, especially in older
women and men, even in subclinical cases.

The goals of therapy are to resolve hyperthyroid symptoms and to restore the euthyroid state. 
 Each therapeutic choice has advantages and disadvantages, so treatment should be individualized. Patient
input into the treatment choice is important and must be discussed and considered. 

Therapy may be by subtotal thyroidectomy, administration of radioiodine, antithyroid drugs, or a

combination of these. In North America, radioiodine is the most common treatment and is available for all ages.
Adjunctive symptomatic therapy, such as beta-blockers, may help adrenergic symptoms. Nonsurgical therapy
occurs in the outpatient setting. Surgical therapy requires first normalization of the hyperthyroid state by
medication. 

Cardiac decompensation or arrhythmias may require hospitalization.

Thyroid storm is a rare emergency requiring intensive care support and therapy.

Surgical Care
Subtotal thyroidectomy may be considered if it is the choice of the patient, second trimester of
pregnancy, failure (resistance or intolerance) of drug therapy, or poor compliance to drug therapy. Risks are low
with experienced surgeons but include anesthetic risks, hemorrhage, hypoparathyroidism, and vocal cord paralysis.
Patients should be made euthyroid prior to surgery to minimize anesthetic risks, cardiovascular/hemodynamic
complications, and risk of thyroid storm. If normalizing with antithyroid drugs is not possible, then beta-blockers
and potassium iodide 4 drops/day for 10 days will decrease vascularity of the thyroid gland.

Consultations
Oculopathy usually requires ophthalmologic consultation, and dermopathy may require dermatologic
consultation.

Diet
Diet must include caloric intake to meet the energy expenditure of the hypermetabolism. High iodine-
containing substances, such as kelp, should be avoided.

Activity
Physical activity is limited by the presence of symptoms, until recovery occurs. Usually, shortness of
breath on exertion, fatigue, and palpitations are the limiting symptoms.

MEDICATION

No standard treatment protocols exist; individualization of treatment based on clinical experience is

protocol. Patient preference after informed consent affects all therapeutic decisions.

Beta-blockers

Beta-blockers are used if symptomatic tremor or palpitations require their use. They may be used even as
investigation is ongoing because they have no effect on thyroid gland function, but they block the beta-adrenergic
peripheral manifestations of the hyperthyroid state. Propranolol has an effect in decreasing the peripheral
conversion of T4 to T3, but this is of unknown clinical significance with the usual doses. The dose may be decreased
and then stopped when the euthyroid state occurs. They should not be used in the presence of bronchospasm,
even the beta1-selective agents. Calcium channel blockers may be substituted.

Thionamides
 Thionamide drugs, propylthiouracil (PTU) and methimazole (MTZ), inhibit hormonogenesis within the
thyroid gland. PTU has an effect in decreasing the peripheral conversion of T4 to T3, but this is of unknown added
clinical significance. Other than in pregnancy and breastfeeding, MTZ has advantages over PTU by a longer half-life
with once-a-day dosing, and possibly more rapid return to the euthyroid state. Although rare, agranulocytosis,
lupuslike vasculitis, and hepatitis are more commonly associated with PTU than with MTZ. Agranulocytosis occurs
in less that 0.1% of cases but is unpredictable; it may occur at any time. Routine monitoring of WBC count is not
useful. Should any infection occur, such as a sore throat, the WBC count should then be measured. Discontinuation
of the drug results in a rise of WBC within a few days.

Granulocyte colony-stimulating factor may need to be administered. Skin rash may perhaps be more
common with MTZ; incidence is about 3%, and it usually occurs within the first few weeks of therapy. Methimazole
is the drug of choice

The US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the
FDA, to the prescribing information for PTU. The boxed warning emphasizes the risk for severe liver injury and
acute liver failure, some of which have been fatal. The boxed warning also states that PTU should be reserved for
use in patients who cannot tolerate other treatments, such as methimazole, radioactive iodine, or surgery.

The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports
and on meetings held with the American Thyroid Association, the National Institute of Child Health and Human
Development, and the pediatric endocrine clinical community.

The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with PTU. Of
the adults, 12 deaths and 5 liver transplants occurred, and among the pediatric patients, 1 death and 6 liver
transplants occurred. PTU is indicated for hyperthyroidism due to Graves disease. These reports suggest an
increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with
methimazole in 5 cases (3 resulting in death).

PTU is considered to be a second-line drug therapy, except in patients who are allergic to or intolerant of
methimazole, or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including
aplasia cutis, have been reported with methimazole during pregnancy. The FDA recommends the following criteria
be considered for prescribing PTU:

 Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of
methimazole.
 Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months
after initiation of therapy.
 For suspected liver injury, promptly discontinue PTU therapy, evaluate the patient for evidence of liver
injury, and provide supportive care.
 PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole
and no other treatment options are available.
 Counsel patients to promptly contact their health care provider for the following signs or symptoms:
fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes
or skin.

Monitor the serum thyroid indices monthly until euthyroid, and then the dose of the drug may be
decreased for maintenance. The lowest dose needed to maintain the euthyroid state is then used for long-term
therapy.
 Normalization of thyroid function with these drugs must occur for some time, at least 6 months and
perhaps for 1-2 years, to maximize the remission rate after drug discontinuation. Despite this, the relapse rate is
50-70%, usually within the first few weeks or months, but occasionally after a few years. Remission is weakly
predicted by a short duration of symptoms, age younger than 40 years, minimal enlargement of the thyroid gland,
and concomitant presence of Hashimoto thyroiditis.

Relapse after discontinuation of the drug requires a decision regarding radioiodine therapy or surgery for
more definitive therapy, or return to the antithyroid drug. Although general practice is not to use these drugs long-
term, there is no reason why this cannot occur, if that is what the patient chooses.

Iodine

In severe cases, such as thyroid storm, iodine in the form of potassium iodide (SSKI) 10 drops twice a day
or iopanoic acid 1-3 g/d may be given. They inhibit the release of thyroxin from the gland and inhibit peripheral
conversion of T4 to T3. They help render a euthyroid state more rapidly in response to antithyroid drugs, or
prepare for surgery, but will eliminate the use of radioiodine for many months due to expansion of the iodine pool
and thus decrease the delivery of radioiodine to the thyroid gland.

Radioiodine

Oral administration of I 131 is incorporated into the thyroid follicular cells, and the beta emission results
in cell destruction and glandular fibrosis. The effect is seen in 1 and a half to 4 months. Off medications, the thyroid
hormone levels become normal (requiring continued monitoring), fall below normal (requiring thyroid hormone
replacement therapy, likely for life), or remain elevated (requiring another administration of radioiodine). In those
becoming euthyroid, the chance every year of becoming hypothyroid due to ongoing disease in the gland is 5%;
occasionally, hyperthyroidism may reoccur. The usual dose is 6-8 mCi. The dose is adjusted based on size of the
thyroid gland, age of the patient, and severity of the clinical picture. Resistance is increased by age older than 40
years, large goiters, prior therapy with PTU, and nodularity (not seen with diffuse toxic goiter). Recent reviews
confirm the safety of the use of radioiodine.

Radioiodine therapy is not used in clinically severe hyperthyroidism or thyroid storm until the
hyperthyroid state is medically controlled.

Because of transplacental transfer and lactation transfer, it is contraindicated in women who are pregnant
or breastfeeding. For the theoretical ovarian exposure, conception in treated women is empirically discouraged for
3-6 months.

It may be administered to children, if clinically indicated. Long-term safety data in children are not
available.

Worsening of the hyperthyroid state may occur after radioiodine therapy due to release of prestored
hormone. Gland tenderness and swelling is uncommon and may be treated with nonsteroidal anti-inflammatory
drugs (NSAIDs) (not aspirin), and they rarely require steroid administration.

Radioiodine administration has been associated with worsening or progression of symptomatic

ophthalmopathy. Either radioiodine is avoided in very symptomatic individuals or corticosteroids (prednisone 0.5
mg/kg) are used beginning the day after the radioiodine administration for 1-3 months, or they are administered if
any worsening of the ophthalmopathy occurs after radioiodine administration. Cessation of smoking and
avoidance of hypothyroidism also help the course of ophthalmopathy.
 The return to the euthyroid state, regardless of therapy, is best monitored by serum free thyroxin, or its
equivalent, because the pituitary is suppressed and TSH secretion may remain low for some time after a normal or
hypothyroid state occurs. Relapse from a euthyroid state to hyperthyroidism is first monitored by new suppression
of the serum TSH, and often the serum T3 then increases above normal before the serum T4 increases above
normal.

Pregnancy and breastfeeding

Pregnancy often has an effect on improving the immunologic disease state during the pregnancy and then
often relapses following delivery. The treatment of choice is PTU, which has less placental transfer than MTZ. Rare
congenital anomalies reported with MTX (eg, aplasia cutis) are even less associated with PTU. Overall, the
congenital abnormality rate with these drugs is similar to background normal rate. MTZ may be used if a problem
exists with PTU.

The goal is to keep the free thyroxin in the upper part of normal to minimize fetal drug exposure. Monthly
monitoring of serum free thyroxin usually allows the dose of PTU to be decreased and often discontinued in the
third trimester. Both PTU and MTZ may be used in breastfeeding mothers. A small amount of drug does enter the
milk, but neonatal thyroid levels generally remain normal. PTU and MTZ are not contraindicated in pregnancy or
lactation.

Antithyroid agents
These agents may either inhibit hormonogenesis within the thyroid gland or inhibit release of thyroid
hormone from the gland.

Propylthiouracil (PTU)

Actively transported into the thyroid gland and inhibits incorporation of iodine to thyroid hormones, and
inhibits peripheral conversion of T4 to T3. Drug recommended in pregnancy and lactation with dose adjustment to
minimum needed. Laboratory monitoring of free T4 to adjust dose therapy. The serum TSH may lag behind the
changes in free T4. Long-term experience with this drug.

Dosing
Adult
Not first-line agent
200-400 mg/d PO divided q8-12h initially, then 50-300 mg/d PO divided bid; minimize dose needed to
maintain euthyroid state
Pediatric
Not first-line agent

5-7 mg/kg/d PO divided tid, daily maintenance dose (one half to two thirds of initial dose) PO divided bid

Interactions

Has activity against vitamin K; may potentiate action of oral anticoagulants

Contraindications
 Documented hypersensitivity; liver impairment; pediatric patients (unless allergic or intolerant to
methimazole and no other treatment is an option)

Precaution

Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions
Warn patient of common adverse effects (eg, skin rash) and rare but severe adverse effect,
agranulocytosis (fever and sore throat); monitor TFTs at intervals and use lower maintenance dose once
TSH level rises; warn of relapse of hyperthyroidism after drug discontinuation, and monitor patient
accordingly.

Risk of serious liver injury, including liver failure and death, has been reported in adults and
children by the FDA (carefully consider drug therapy, and, if PTU initiated, monitor for symptoms and
signs of liver injury, especially during first 6 mo of therapy)

Methimazole (Tapazole)

Actively transported in thyroid gland and inhibits thyroid synthesis by preventing oxidation of trapped
iodine. Ten times more potent than PTU, and once-a-day dose is effective. Euthyroid state is achieved in 4-6 wk,
and maintenance treatment continued for 12-24 mo. Relapse may be observed 1-6 months after stopping therapy,
occasionally later.

Less desirable than propylthiouracil in pregnancy and lactation but may be used if propylthiouracil cannot
be used.

Dosing

Adult
10-40 mg PO qd; decrease dose once euthyroid; minimize dose needed to maintain euthyroid state

Pediatric
0.4 mg/kg/d PO divided tid initially, 0.2 mg/kg/d PO divided tid maintenance; not to exceed 30 mg qd

Interaction

Has activity against vitamin K; may potentiate action of oral anticoagulants

Contraindication

Documented hypersensitivity

Precaution

Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions
 Rashes occur in about 3%; agranulocytosis is a rare but severe complication; measure WBC if sore
throat or fever occurs; monitor TFTs during therapy, and adjust dose once patient is euthyroid.

Lugol solution (Pima, Thyro-Block)

Inhibits thyroid hormone secretion. Contains 8 mg of iodide per gtt. May be mixed with juice or water for
intake.

May decrease thyroid gland secretion and vascularity for a short time, such as 2 wk; may be used in
severe cases of hyperthyroidism, such as thyroid storm, or to prepare patient for thyroidectomy

Dosing

Adult
4-10 gtt (1 mL) PO q8h

Pediatric
Administer as in adults

Interaction

Increases lithium toxicity by inducing additive hypothyroid effects

Contraindication

Documented hypersensitivity; tuberculosis; bronchitis; pulmonary edema; hyperkalemia; renal failure.

Precaution

Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals.

Precautions
Prolonged use may result in hypothyroidism; caution in renal failure or GI obstruction

Supersaturated potassium iodide (SSKI)

Contains 50 mg of iodide per drop. May be mixed with juice or water for ingestion. Inhibits thyroid
hormone release.

Dosing

Adult
1-5 gtt PO q8h

Pediatric
Administer as in adults
Interaction

Increases lithium toxicity by producing additive hypothyroid effects

Contraindication

Documented hypersensitivity; tuberculosis; pulmonary edema; bronchitis; hyperkalemia

Precaution

Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions
Prolonged use may result in hypothyroidism; caution in renal failure or GI obstruction

Corticosteroids
These agents have profound and varied metabolic effects.

Dexamethasone (Decadron)

Steroids block peripheral conversion of T4 to T3. Used as adjunct in management of thyroid storm and
symptomatic progressive Graves ophthalmopathy.

Dosing

Adult
0.5-2 mg PO/IV q6h

Pediatric
Administer as in adults

Interaction

Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; decreases effects of
salicylates and vaccines used for immunization

Contraindication

Documented hypersensitivity; active bacterial or fungal infection

Precaution

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus

Precautions
Increased risk of multiple complications, including severe infections; monitor adrenal
insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis;
 hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, osteoporosis, euphoria, psychosis,
myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Radiopharmaceuticals
These agents are used to destroy thyroid cells.

Radioiodine (I-131)

Agent of choice because it is selectively taken up by the thyroid gland. Causes dysfunction or death of
thyroid cells over time. Long-term experience suggests good safety profile.

Dosing

Adult
Dosage is calculated based on size of goiter and percentage of uptake; usual dose is 5-8 mCi PO; may
increase dose if clinically indicated

Repeat administration occasionally needed

Pediatric
Not established

Interaction

None reported; if iodine has been administered to patient, such as contrast agents, radioiodine will lose
effectiveness until iodine pool has returned to normal over a few months

Contraindication

Documented hypersensitivity; pregnant or lactating patients; uncontrolled thyroid storm/crisis

Precaution

Pregnancy
X - Contraindicated; benefit does not outweigh risk

Precautions
Women of childbearing age; latent period can last 3 wk to 3 mo; beta-blockers are used
adjunctively to suppress symptoms; hypothyroidism occurs in more than 50% of patients during first year
and occurs in 2-3% each year thereafter; risk of worsening ophthalmopathy can be reduced by treatment
with glucocorticoid 1 day after administration of radioiodine; administer pregnancy test before treatment
begins, and advise patient to use contraception for the first 6 mo after treatment.

Beta-adrenergic receptor blockers

Relief of adrenergic symptoms, especially cardiac and neurologic. Propranolol blocks peripheral
conversion of T4 to T3, but this is of unknown clinical significance.

Propanolol (inderal)
 Nonselective beta-adrenergic receptor blocker. Also blocks peripheral conversion of T4 to T3. Used along
with antithyroid drugs, before and after radioiodine treatment. Useful in thyroid crisis/storm, or in cardiac
complications such as atrial fibrillation. Oral or intravenous use controls cardiac and psychomotor manifestations
within minutes. Continue until euthyroid state is achieved.

Dosing

Adult
40-80 mg PO q6h, long-acting formulations 80 mg q12h

Pediatric
2-4 mg/kg/d PO divided bid

Interaction

Has synergistic effect with calcium channel blockers; barbiturate, aluminium salts, calcium salts,
cholestyramine, NSAIDs, penicillins, and rifampin may decrease plasma levels and possibly pharmacologic effect;
MAOIs, hydralazine, loop diuretics, and haloperidol may increase metoprolol level; severe hypotension has been
reported with haloperidol

Contraindication

Documented hypersensitivity; cardiogenic shock; sinus bradycardia; second- and third-degree heart block;
congestive heart failure; bronchial asthma

Precaution

Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use
if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions
Pregnancy category D in second and third trimesters of pregnancy; liver and renal disease; may
mask signs of hypoglycemia; abrupt withdrawal may worsen symptoms of hyperthyroidism; withdraw
drug slowly when euthyroid and monitor closely
TOXIC GOITER IN PREGNANCY

Submitted by:

PALLINGAYAN, Jerrence May P.

2–C

November 23, 2010

Reference:

Book:
 Katzung. Basic Pharmacology.

Website:

http://emedicine.medscape.com/article/

http://www.mythyroid.com/toxicmultinodulargoiter.html