1105 CMDT 2013 ENDOCRINE

CHAPTER 26 DISORDERS CMDT 2013 1105

may be administered, 150200 mg/m2 orally daily for 5 days
of each 28-day cycle; after three cycles, treatment efficacy is
determined by prolactin measurement and MRI scanning. A
minority of such patients respond to temozolomide.
Coker F et al. Antidepressant-induced hyperprolactinaemia:
incidence, mechanisms and management. CNS Drugs. 2010
Jul;24(7):56374. [PMID: 20527996]
Dekkers OM et al. Recurrence of hyperprolactinemia after with-
drawal of dopamine agonists: systematic review and meta-
analysis. J Clin Endocrinol Metab. 2010 Jan;95(1):4351.
[PMID: 19880787]
Kars M et al. Update in prolactinomas. Neth J Med. 2010
Mar;68(3):10412. [PMID: 20308704]
Klibanski A. Clinical practice. Prolactinomas. N Engl J Med.
2010 Apr 1;362(13):121926. [PMID: 20357284]
Melmed S et al. Diagnosis and treatment of hyperprolactinemia: an
Endocrine Society clinical practice guideline. J Clin Endocrinol
Metab. 2011 Feb;96(2):27388. [PMID: 21296991]
Milano W et al. Recent clinical aspects of hyperprolactinemia
induced by antipsychotics. Rev Recent Clin Trials. 2011
Jan;6(1):5263. [PMID: 20868350]
of total T4, resin T3 uptake (RT3U), and free thyroxine index
(FT4I). It is particularly important to determine free serum
levels (FT4 and FT3) in conditions associated with high cir-
culating levels of thyroxine-binding globulin, such as during
therapy with oral estrogen. Ultrasensitive assays for serum
TSH have largely replaced older TSH assays. Table 263
shows the appropriate use of thyroid tests.
HYPOTHYROIDISM & MYXEDEMA
`c ccc
EssEntials of diagnosis
`c ccccWeakness, fatigue, cold intolerance, constipa-
tion, weight change, depression, menorrhagia,
hoarseness.
`c ccccdry skin, bradycardia, delayed return of deep
tendon reflexes.
`c cccanemia, hyponatremia, hyperlipidemia.

`c cccft4 level is usually low.

`c ccctsH elevated in primary hypothyroidism.
cc
DISEASES OF THE THYROID GLAND
THYROID TESTING `cGeneral Considerations
Assays for FT4, total triiodothyronine (T3), and free tri- Hypothyroidism is common, affecting over 1% of the
iodothyronine (FT3) have largely supplanted measurements general population and about 5% of individuals over age

Table 263. appropriate use of thyroid tests.

Test Comment

Screening Serum thyroid-stimulating hormone (TSH) Most sensitive test for primary hypothyroidism and
(sensitive assay) hyperthyroidism
Free thyroxine (FT4) Excellent test
For hypothyroidism Serum TSH High in primary and low in secondary hypothyroidism
Antithyroglobulin and antithyroperoxidase Elevated in Hashimoto thyroiditis
antibodies
For hyperthyroidism Serum TSH (sensitive assay) Suppressed except in TSH-secreting pituitary tumor or pituitary
hyperplasia (rare)
Triiodothyronine (T3) or free triiodothyronine (FT3) Elevated
123I uptake and scan Increased uptake; diffuse versus hot areas on scan
Antithyroglobulin and antimicrosomal antibodies Elevated in Graves disease
Thyroid-stimulating immunoglobulin; TSH receptor Usually (65%) positive in Graves disease
antibody (TSH-R Ab [stim])
For thyroid nodules Fine-needle aspiration (FNA) biopsy Best diagnostic method for thyroid cancer
123I uptake and scan Cancer is usually cold; less reliable than FNA biopsy
99mTc scan Vascular versus avascular
Ultrasonography Useful to assist FNA biopsy. Useful in assessing the risk of
malignancy (multinodular goiter or pure cysts are less likely
to be malignant). Useful to monitor nodules and patients after
thyroid surgery for carcinoma.
 1106 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
60 years. Thyroid hormone deficiency affects almost all body
functions. The degree of severity ranges from mild and
unrecognized hypothyroid states to striking myxedema. The
fluid retention seen in myxedema is caused by the interstitial
accumulation of hydrophilic mucopolysaccharides, which
leads to lymphedema. Hyponatremia is the result of impaired
renal tubular sodium reabsorption due to reductions in
Na+K+-ATPase.
Hypothyroidism may be due to failure or resection of
the thyroid gland itself or deficiency of pituitary TSH (see
Hypopituitarism, above). The condition must be distin-
guished from the functional hypothyroidism that occurs in
severe nonthyroidal illness, which does not require treat-
ment with thyroxine (see Euthyroid Sick Syndrome).
Maternal hypothyroidism during pregnancy results in
offspring with IQ scores that are an average 7 points lower
than those of euthyroid mothers.
Goiter may be present with thyroiditis, iodide defi-
ciency, genetic thyroid enzyme defects, drug goitrogens
(lithium, iodide, propylthiouracil or methimazole, phe-
nylbutazone, sulfonamides, amiodarone, interferon-,
interferon-, interleukin-2), food goitrogens in iodide-
deficient areas (eg, turnips, cassavas) or, rarely, peripheral
resistance to thyroid hormone or infiltrating diseases (eg,
cancer, sarcoidosis). A hypothyroid phase occurs in sub-
acute (de Quervain) viral thyroiditis following initial
hyperthyroidism. Hashimoto thyroiditis is the most com-
mon cause of hypothyroidism (see Thyroiditis section).
Goiter is usually absent when hypothyroidism is due
to destruction of the gland by surgery, radiation therapy
(to the head, neck, chest, and shoulder region), or 131I.
Chemotherapy can reduce thyroid function, causing hypo-
thyroidism. Sunitinib, a protein-tyrosine kinase inhibitor
used to treat gastrointestinal stromal malignancies, causes
transient primary hypothyroidism in about 50% of treated
patients.
Amiodarone, because of its high iodine content, causes
clinically significant hypothyroidism in about 1520% of
patients who receive it. Hypothyroidism occurs most often
in patients with preexisting autoimmune thyroiditis and in
patients who are not iodine-deficient. The T4 level is normal
or low, and the TSH is elevated, usually over 20 ng/dL.
Another 17% of patients have milder elevations of TSH and
are asymptomatic. Low-dose amiodarone is less likely to
cause hypothyroidism. Cardiac patients with amiodarone-
induced symptomatic hypothyroidism are treated with just
enough thyroxine to relieve symptoms. Hypothyroidism
usually resolves over several months if amiodarone is dis-
continued. Hypothyroidism may also develop in patients
with a high iodine intake from other sources, especially if
they have underlying lymphocytic thyroiditis.
Hepatitis C is associated with an increased risk of auto-
immune thyroiditis, with 21% of affected patients having
antithyroid antibodies and 13% having hypothyroidism.
The risk of thyroid dysfunction is even higher when patients
are treated with interferon. Interferon- and interferon-
treatment can induce thyroid dysfunction (usually hypothy-
roidism, sometimes hyperthyroidism) in 6% of patients.
Spontaneous resolution occurs in over 50% of cases once
interferon is discontinued.
CMDT 2013 1106
`cClinical Findings
A. Symptoms and Signs
1. Common manifestationsMild hypothyroidism
often escapes detection without screening (ie, serum TSH).
Common symptoms of hypothyroidism include weight
gain, fatigue, lethargy, depression, weakness, dyspnea on
exertion, arthralgias or myalgias, muscle cramps, menor-
rhagia, constipation, dry skin, headache, paresthesias, car-
pal tunnel syndrome, cold intolerance, and Raynaud
syndrome. Physical findings can include bradycardia; dia-
stolic hypertension; thin, brittle nails; thinning of hair;
peripheral edema; puffy face and eyelids; and skin pallor or
yellowing (carotenemia). Delayed relaxation of deep ten-
don reflexes may be present. Patients often have a palpably
enlarged thyroid (goiter) that arises due to elevated serum
TSH levels or the underlying thyroid pathology, such as
Hashimoto thyroiditis.
2. Less common manifestationsLess common symp-
toms of hypothyroidism include diminished appetite and
weight loss, hoarseness, decreased sense of taste and smell,
and diminished auditory acuity. Some patients may com-
plain of dysphagia or neck discomfort. Although most
menstruating women have menorrhagia, some women
have scant menses or amenorrhea. Physical findings may
include thinning of the outer halves of the eyebrows; thick-
ening of the tongue; hard pitting edema; and effusions into
the pleural and peritoneal cavities as well as into joints.
Galactorrhea may also be present. Cardiac enlargement
(myxedema heart) and pericardial effusions may occur.
Psychosis (myxedema madness) can occur from severe
hypothyroidism or from toxicity of other drugs whose
metabolism is slowed in hypothyroidism. Hypothermia
and stupor or myxedema coma, which is often associated
with infection (especially pneumonia), may develop in
patients with severe hypothyroidism. Pituitary enlarge-
ment due to hyperplasia of TSH-secreting cells, which is
reversible following thyroid therapy, may be seen in long-
standing hypothyroidism.
Some hypothyroid patients with Hashimoto thyroiditis
have symptoms that are not due to hypothyroidism but
rather to other autoimmune disease. Some autoimmune
conditions that occur more commonly in patients with
Hashimoto thyroiditis include Addison disease, hypopara-
thyroidism, diabetes mellitus, pernicious anemia, Sjgren
syndrome, vitiligo, biliary cirrhosis, and celiac disease.
Celiac disease occurs in at least 5% of patients with
hypothyroidism due to Hashimoto thyroiditis. Affected
patients often have weight loss and gastrointestinal symp-
toms. However, many patients with celiac disease have
minimal gastrointestinal symptoms but may have systemic
manifestations such as fatigue, depression, osteoporosis
or osteomalacia, iron deficiency anemia, short stature,
delayed puberty, amenorrhea, or reduced fertility. Intestinal
malabsorption may cause vitamin deficiencies with bruis-
ing due to vitamin K deficiency, hyperkeratosis due to
vitamin A deficiency, bone pain due to vitamin D defi-
ciency, or neuropathy and ataxia due to vitamin E or
vitamin B12 deficiency.
 1107 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS CMDT 2013 1107

B. Laboratory Findings
Table 264. factors that may cause aberrations in
Hypothyroidism is a common disorder and thyroid func- laboratory tests that may be mistaken for primary
tion tests should be obtained for any patient with the non- hypothyroidism.1
specific symptoms or signs of hypothyroidism. The single
best screening test for hypothyroidism is the serum TSH Low Serum T4 or T3 High Serum TSH
(Table 263). Serum TSH is increased with primary hypo-
Laboratory error Laboratory error
thyroidism but is low or normal with pituitary insuffi-
Acute psychiatric problems Autoimmune disease
ciency. The FT4 may be low or low-normal. Other laboratory Cirrhosis (assay interference)
abnormalities may often be seen: increased serum LDL Nephrotic syndrome Heterophile antibodies
cholesterol, triglycerides, lipoprotein (a), liver enzymes, Familial thyroid-binding globulin Anti-mouse antibodies
and creatine kinase; increased serum PRL; and hypona- deficiency Strenuous exercise
tremia, hypoglycemia, and anemia (with normal or Severe illness (acute)
increased mean corpuscular volume). Semen analysis Drugs Androgens Sleep deprivation (acute)
shows an increase in abnormal sperm morphology. In Asparaginase Recovery from nonthyroidal
patients with autoimmune thyroiditis, titers of antibodies Carbamazepine illness (transient)
against thyroperoxidase and thyroglobulin are high; serum Chloral hydrate Acute psychiatric admissions
Corticosteroids (14% transient)
antinuclear antibodies (ANA) may be present and are not Elderlyespecially women
Diclofenac (T3)
usually indicative of lupus. Didanosine (10%, mild elevations)
The normal range for ultrasensitive TSH levels is gener- Fenclofenac
ally stated to be 0.44.0 mU/L. However, the normal range 5-Fluorouracil
of TSH varies with age such that newborns have a much Halofenate
higher normal range; children and elderly patients have a Mitotane
mildly higher normal range. Over 95% of normal adults Naproxen (T3)
have serum TSH concentrations under 3.0 mU/L. There is Nicotinic acid
a high risk of finding antithyroid antibodies in patients Oxcarbazepine
Phenobarbital
with serum TSH in the upper range of normal, but most Phenytoin (total T4 may be as
such patients are asymptomatic. TSH may be mildly ele- low as 2 mcg/dL)
vated in some euthyroid individuals, especially elderly Salicylateslarge doses
women (10% incidence). Such patients with normal FT4 (T3 and T4)
levels are considered to have subclinical hypothyroidism, Sertraline
but can have subtle manifestations of hypothyroidism (eg, Stavudine
fatigue, depression, hyperlipidemia) that may improve T3 therapy (T4)
with thyroid hormone replacement. Patients who are com-
pletely asymptomatic with a mildly elevated serum TSH 1True
and normal serum FT4 do not require levothyroxine primary hypothyroidism may coexist.
T , levothyroxine; T , triiodothyronine; TSH, thyroid-stimulating
4 3
replacement; in fact, mildly decreased thyroid function was hormone.
associated with familial longevity in the Leiden Longevity
Study. About 18% of patients with subclinical hypothy- the absence of hypothyroidism (Table 264). The pituitary
roidism later become definitely hypothyroid; many such is often quite enlarged in primary hypothyroidism, due to
patients have Hashimoto thyroiditis. reversible hyperplasia of TSH-secreting cells; the concomi-
tant hyperprolactinemia seen in hypothyroidism can lead
C. Imaging to the mistaken diagnosis of a TSH-secreting or PRL-
Radiologic imaging is usually not necessary for patients secreting pituitary adenoma.
with hypothyroidism. However, on CT or MRI, a goiter Euthyroid sick syndrome should be considered in
may be noted in the neck or in the mediastinum (retroster- patients with abnormal thyroid function tests (eg, low
nal goiter). An enlarged thymus is frequently seen in the serum T4 and low levels of FT4) without thyroid disease;
mediastinum in cases of autoimmune thyroiditis. In pri- conditions that can result in this syndrome include severe
mary hypothyroidism with elevated serum TSH levels, illness, caloric deprivation, or major surgery. Patients who
MRI of the head will frequently show an enlargement of have undergone major surgery may have accelerated periph-
the pituitary gland from thyrotrophe hyperplasia; such eral metabolism of serum T4 to reverse T3 (rT3). Furthermore,
enlargement can be mistaken for a pituitary tumor. in most patients who are critically ill, there is a circulating
inhibitor of thyroid hormone binding to serum thyroxine-
binding proteins (TBPs). This causes the RT3U to be mis-
`cDifferential Diagnosis leadingly low, causing the computed FT4I to be very low.
Many clinical manifestations of hypothyroidism (see The presence of a very low serum T4 in severe nonthyroidal
illness indicates a poor prognosis. Serum TSH tends to be
above) are common in the general population without
suppressed in severe nonthyroidal illness, making the diag-
thyroid illness. The differential diagnoses are the condi-
nosis of concurrent primary hypothyroidism quite difficult,
tions and drugs that can cause aberrations in laboratory although the presence of a goiter suggests the diagnosis.
tests, resulting in a low serum T4 or T3 or high serum TSH in
 1108 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
The clinician must decide whether such severely ill
patients (with a low serum T4 but no elevated TSH) might
have hypothyroidism due to pituitary insufficiency. Patients
without symptoms of prior brain lesion or hypopituitar-
ism are very unlikely to suddenly develop hypopituitarism
during an unrelated illness. Patients with diabetes insipi-
dus, hypopituitarism, or other signs of a central nervous
system lesion may be given T4 empirically.
True secondary hypothyroidism due to direct dop-
amine suppression of TSH-secreting cells may develop in
patients receiving prolonged dopamine infusions.
Certain antiseizure medications cause low serum FT4
levels by accelerating hepatic conversion of T4 to T3; serum
TSH levels are normal.
`cComplications
Cardiac complications may occur as a result of preexistent
coronary artery disease and congestive heart failure, which
may be exacerbated by levothyroxine therapy. Patients with
severe hypothyroidism have an increased susceptibility to
bacterial pneumonia. Megacolon has been described in
long-standing hypothyroidism. Organic psychoses with
paranoid delusions may occur (myxedema madness).
Rarely, adrenal crisis may be precipitated by thyroid therapy.
Hypothyroidism is a rare cause of infertility, which may
respond to thyroid medication. Pregnancy in a woman with
untreated hypothyroidism often results in miscarriage. Sellar
enlargement and even well-defined TSH-secreting tumors
may develop in untreated cases. These tumors decrease in
size after replacement therapy is instituted.
Myxedema crisis refers to severe, life-threatening hypo-
thyroidism. The manifestations of hypothyroidism are pres-
ent and more severe. Affected patients have impaired
cognition, ranging from confusion to somnolence to coma
(myxedema coma). Convulsions and abnormal central ner-
vous system signs may occur. Patients have severe hypo-
thermia, hypoventilation, hyponatremia, hypoglycemia, and
hypotension. Rhabdomyolysis and acute kidney injury may
occur. Myxedema coma is most often seen in elderly women
who have had a stroke or who have stopped taking their
thyroxine medication. It is often induced by an underlying
infection; cardiac, respiratory, or central nervous system ill-
ness; cold exposure; or drug use. The mortality rate from
myxedema coma is high. Myxedematous patients are unusu-
ally sensitive to opioids and average doses may result in
death. Patients with severe myxedema may have hypona-
tremia that is severe and refractory to treatment.
`cTreatment
Before therapy with thyroid hormone is commenced, the
hypothyroid patient requires at least a clinical assessment
for adrenal insufficiency and angina, for which the patient
would require evaluation and treatment.
A. Beginning Treatment for Hypothyroidism
Levothyroxine is the preferred preparation for treating
hypothyroid patients. However, patients (as a group) receiv-
ing levothyroxine replacement do not have the same sense of
well-being as their peers. In response, some clinicians
CMDT 2013 1108
prescribe mixed T4/T3 preparations such as Armour thyroid,
but levothyroxine alone renders patients clinically euthyroid
as long as it is given in sufficient doses (see below).
Otherwise healthy young and middle-age adults with
hypothyroidism may be treated initially with levothyroxine
in doses of 2575 mcg orally daily. The lower doses are
used for very mild hypothyroidism, while higher doses are
given for more symptomatic hypothyroidism. Women who
are pregnant with significant hypothyroidism may begin
therapy with levothyroxine at higher doses of 100150 mcg
orally daily. The levothyroxine dosage may be increased
according to clinical response and serum TSH, initially
trying to keep the serum TSH level between 0.4 mU/L and
2.0 mU/L. The levothyroxine dose required to render
patients clinically euthyroid varies considerably, with
higher doses required during pregnancy and with certain
medications (see below). Since food interferes slightly with
the absorption of levothyroxine, it is advisable to take
levothyroxine with water in the morning after an overnight
fast. The selected time should become a regular daily habit
for the patient. After beginning daily administration, sig-
nificant increases in serum T4 levels are seen within 12
weeks, and near-peak levels are seen within 34 weeks.
Patients with coronary disease or those who are over
age 60 years are treated with smaller initial doses of
levothyroxine, 2550 mcg orally daily; higher initial doses
may be used if such patients are severely hypothyroid. The
dose can be increased by 25 mcg every 13 weeks until the
patient is euthyroid. Patients with hypothyroidism and
known ischemic heart disease may begin thyroxine therapy
following restoration of coronary perfusion by coronary
artery angioplasty or bypass.
Myxedema crisis requires larger initial doses of levothy-
roxine intravenously, since myxedema itself can interfere
with levothyroxine intestinal absorption. Levothyroxine
sodium 400 mcg is given intravenously as a loading dose,
followed by 50100 mcg intravenously daily; the lower
dose is given to patients with suspected coronary insuffi-
ciency. In patients with myxedema coma, liothyronine (T3,
Triostat) can be given intravenously in doses of 510 mcg
every 8 hours for the first 48 hours. The hypothermic
patient is warmed only with blankets, since faster warming
can precipitate cardiovascular collapse. Patients with
hypercapnia require intubation and assisted mechanical
ventilation. Infections must be detected and treated aggres-
sively. Patients in whom concomitant adrenal insufficiency
is suspected are treated with hydrocortisone, 100 mg intra-
venously, followed by 2550 mg every 8 hours.
B. Monitoring & Optimizing Treatment
of Hypothyroidism
Every hypothyroid patient requires regular clinical assess-
ments that must include interim histories and physical
examinations. Clinical judgment is critical to determine the
optimal levothyroxine dose for each patient. Laboratory
assays supplement clinical judgment. An elevated serum
TSH usually indicates the need for a higher dose of levothy-
roxine (see below). Unfortunately, normal serum TSH and
FT4 levels do not accurately determine that the patient is
euthyroid (see below). The patient should be prescribed
sufficient levothyroxine to restore a clinically euthyroid state,
 1109 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
while maintaining the serum T3 within the reference range.
For most patients with hypothyroidism, a stable mainte-
nance dose of levothyroxine can usually be found.
Levothyroxine doses may need to be titrated upward
after patients commence taking medications that increase
the hepatic metabolism of levothyroxine (eg, carbamazepine,
phenobarbital, primidone, phenytoin, rifabutin, rifampin,
sunitinib, and imatinib [Gleevec]). Amiodarone can cause
an increase or decrease in thyroxine dose requirements,
making it necessary to closely monitor serum TSH and
adjust the thyroxine dosage accordingly in these patients.
Malabsorption of thyroxine can be caused by coadministra-
tion of binding substances, such as iron preparations (includ-
ing iron found in multivitamins), fiber, raloxifene, sucralfate,
aluminum hydroxide antacids, sevelemer, orlistat, calcium
and magnesium supplements, and soy milk or soy protein
supplements. Bile acid-binding resins, such as cholestyramine
and colesevelam, can bind T4 and impair its absorption even
when administered 5 hours before the T4. Proton pump
inhibitors reduce gastric acidity, which interferes slightly
with the absorption of levothyroxine. Gastrointestinal disor-
ders can interfere with thyroxine absorption, including celiac
disease, inflammatory bowel disease, lactose intoler- ance,
Helicobacter pylori gastritis, and atrophic gastritis.
Different thyroxine preparations vary in their bioavail-
ability by up to 14%. Such differences in the bioavailability
of different T4 formulations may have a subtle but signifi-
cant clinical ct. It is therefore recommended that
impa
patients always continue to take the same brand name of
thyroxine or the same manufacturers generic thyroxine.
There is no standardized optimal dose of levothyroxine, so
each patients dose must be based on careful clinical assess-
ment. Although serum TSH levels can be helpful in deter-
mining optimal dosing, it is important to consider clinical
response and to not rely entirely on serum TSH levels to
determine the patients optimal thyroxine dosage.
Women with hypothyroidism typically require increased
doses of T4 during therapy with oral estrogen as well as
during pregnancy (see below). Conversely, T4 dosage
requirements for women often decrease with delivery,
cessation of oral estrogen, and menopause.
1. During pregnancyAdministering adequate levothy-
roxine to a hypothyroid woman is critical. The fetus is at
least partially dependent on maternal T for central nervous
4 thyroid despite a normal serum TSH may have a subopti-
system developmentparticularly in the second trimester.
It is therefore important to carefully monitor hypothyroid
women with serum TSH (FT4I or FT4 concentrations in
hypopituitarism) determinations every 46 weeks and to
increase T4 replacement progressively as required (see
Chapter 19).
There is considerable individual variation in the
requirement for additional T4 replacement during preg-
nancy. An increase in levothyroxine requirement has been
noted as early as the fifth week of pregnancy. Therefore,
for women receiving replacement thyroxine, it is prudent
to increase levothyroxine dosages by approximately 30%
as soon as pregnancy is confirmed. By mid pregnancy,
CMDT 2013 1109
levels during pregnancy increase thyroxine binding glob-
ulin (TBG) serum concentrations, reducing FT4 levels.
(2) Placental deiodinase promotes the turnover of T4.
(3) Supplemental iron and prenatal multivitamins contain-
ing iron can bind to oral T4 and reduce its intestinal absorp-
tion. Similarly, supplemental calcium can also reduce T4
absorption. Therefore, it is important that patients take their
T4 replacement at least 4 hours before or after such dietary
supplements. Postpartum, T4 replacement requirements
ordinarily return to prepregnancy levels.
Serum TSH levels normally drop while FT4I rises dur-
ing the first trimester of pregnancy. This probably results
from high levels of hCG (with structural homology to
TSH) that stimulates thyroid hormone production. Most
women with a low serum TSH in the first trimester are
euthyroid. Serum FT4I is helpful in evaluating the thyroid
status of pregnant women, particularly in the first
trimester. Following delivery, levothyroxine dose require-
ments decline.
2. Elevated serum TSH levelsThis usually indicates
underreplacement with levothyroxine. However, before
increasing the T4 dosage, it is important to confirm that the
patient is indeed taking the medication as directed and
does not have angina. It is also important to consider the
following: A high TSH in a patient receiving standard
replacement doses of T4 may indicate malabsorption of
levothyroxine due to concurrent administration with bind-
ing substances (see above) or with food (instead of fasting).
Malabsorption of T4 can also occur in short bowel syn-
drome; therapy with medium chain triglyceride oil may
improve absorption. Impaired absorption of T4 can also be
caused by diarrhea of any cause or malabsorption due to
concurrent celiac disease (sprue), regional enteritis, liver
disease, or pancreatic exocrine insufficiency. Serum TSH
may be elevated transiently in acute psychiatric illness and
during recovery from nonthyroidal illness. Autoimmune
disease can cause false elevations of TSH by interfering
with the assay. A high TSH can also be caused by thyrotro-
pin-secreting pituitary tumors. TSH may be increased by
phenothiazines and atypical antipsychotics.
3. Normal serum TSH levelsPatients are treated with
sufficient levothyroxine to achieve normal serum TSH
levels of 0.42.0 mU/L. Patients who continue to feel hypo-
mal serum T3; they may respond well to higher replacement
doses of levothyroxine.
women require an average of 47% increase in their
levothyroxine dosage.
The increased T4 dosage requirements during pregnancy
are believed to be due to several factors: (1) Rising estrogen
 1110 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS CMDT 2013 1110

4. Low or suppressed serum TSH levelsSerum TSH

levels (using a sensitive assay) that are below the reference
range (0.44.0 mU/L) are considered low (0.040.4 mU/L)
or suppressed ( 0.03 mU/L). It has generally been
assumed that since TSH is a sensitive test for hyperthyroid-
ism in Graves disease, a low serum TSH in patients taking
levothyroxine reliably indicates overreplacement; that
assumption is proving incorrect. Certainly, if a patient taking
levothyroxine has a suppressed serum TSH and manifesta-
tions of hyperthyroidism, the dosage of levothyroxine must
be reduced. However, many patients with low serum TSH
levels exhibit no symptoms of hyperthyroidism. For such
patients, it is important to determine whether hypopituitar-
ism or severe nonthyroidal illness is present, which can result
 1111 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
in low serum TSH levels without hyperthyroidism. TSH can
also be reduced by certain medications, such as nonsteroidal
anti-inflammatory drugs; opioids; nifedipine; verapamil;
and high-dose, short-term administration of corticosteroids.
Absent such conditions, a clinically euthyroid patient with a
suppressed serum TSH should be given a lower dosage of
levothyroxine. Patients who exhibit hypothyroid symptoms
on the reduced dosage of levothyroxine may have the higher
dose resumed.
Some hypothyroid patients receiving levothyroxine
have hypothyroid-type symptoms, particularly persistent
fatigue or weight gain, despite having low serum TSH
levels. Such patients require careful assessment for concur-
rent illnesses such as adrenal insufficiency, hypogonadism,
anemia, celiac disease, or depression. If such conditions
are not present or are treated and hypothyroid-type symp-
toms persist despite low-normal or low TSH levels, a
serum T3 level (FT3 in pregnancy and women receiving
oral estrogens) is often helpful. If the serum T3 level is
low or low normal, the patient may benefit from an increase
in levothyroxine dosage; if a definite clinical benefit is
achieved, the higher dose is continued. Patients with a low
serum TSH (0.040.4 mU/L) on replacement levothyroxine
do not have any long-term increased risk of cardiovascular
disease, dysrhythmias, or fractures. However, patients with
suppressed serum TSH ( 0.03 mU/L) do have an increased
risk of such side effects and long-term monitoring for
atrial arrhythmias and osteoporosis is recommended.
`cPrognosis
Hypothyroidism caused by interferon- resolves within 17
months of stopping the drug in 50% of patients. Patients
with mild hypothyroidism caused by Hashimoto thyroidi-
tis have a remission rate of 11%. With early treatment of
hypothyroidism, striking transformations take place both
in appearance and mental function. Return to a normal
state is usually the rule, but relapses will occur if treatment
is interrupted. On the whole, response to thyroid treatment
is most satisfactory. However, untreated hypothyroid
patients with myxedema crisis have a mortality rate
approaching 100%. Even with optimal treatment, patients
with myxedema crisis have a mortality rate of 2050%.
Kim BW et al. For some: L-thyroxine replacement might not be
enough: a genetic rationale. J Clin Endocrinol Metab. 2009
May;94(5):15213. [PMID: 19420275]
Liwanpo L et al. Conditions and drugs interfering with thyroxine
absorption. Best Pract Res Clin Endocrinol Metab. 2009
Dec;23(6):78192. [PMID: 19942153]
Nygaard B et al. Effect of combination therapy with thyroxine
(T4) and 3,5,3-triiodothyronine versus T4 monotherapy in
patients with hypothyroidism, a double-blind, randomized
cross-over study. Eur J Endocrinol. 2009 Dec;161(6):895902.
[PMID: 19666698]
OReilly DS. Thyroid hormone replacement: an iatrogenic problem.
Int J Clin Pract. 2010 Jun;64(7):9914. [PMID: 20584231]
Padmanabhan H. Amiodarone and thyroid dysfunction. South
Med J. 2010 Sep;103(9):92230. [PMID: 20689491]
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roidism in pregnancy. Cochrane Database Syst Rev. 2010
Jul 7;(7):CD007752. [PMID: 20614463]
CMDT 2013 1111
HYPERTHYROIDISM (THYROTOXICOSIS)
`c ccc
EssEntials of diagnosis
`c ccccsweating, weight loss or gain, anxiety, palpita-
tions, loose stools, heat intolerance, irritability,
fatigue, weakness, menstrual irregularity.
`c ccctachycardia; warm, moist skin; stare; tremor.
`c cccin graves disease: goiter (often with bruit);
ophthalmopathy.
`c cccsuppressed tsH in primary hyperthyroidism;
increased t4, ft4, t3, ft3.
`cGeneral Considerations
The term thyrotoxicosis refers to the clinical manifesta-
tions associated with serum levels of T4 or T3 that are exces-
sive for the individual (hyperthyroidism). Serum TSH
levels are suppressed in primary hyperthyroidism. However,
certain drugs and conditions can affect laboratory tests and
lead to the erroneous diagnosis of hyperthyroidism in
euthyroid individuals (Table 265). The causes of hyper-
thyroidism are many and diverse, as described below.
A. Graves Disease
Graves disease (known as Basedow disease in Europe) is
the most common cause of thyrotoxicosis. It is an autoim-
mune disorder affecting the thyroid gland, characterized by
an increase in synthesis and release of thyroid hormones.
Graves disease is much more common in women than
in men (8:1), and its onset is usually between the ages of
20 and 40 years. It may be accompanied by infiltrative oph-
thalmopathy (Graves exophthalmos) and, less commonly,
by infiltrative dermopathy (pretibial myxedema). The thy-
mus gland is typically enlarged and serum ANA levels are
usually elevated, reflecting the underlying autoimmunity.
Graves disease has a familial tendency, and many patients
have a family history of Graves disease or hypothyroidism
from Hashimoto thyroiditis. Histocompatibility studies
have shown an association with group HLA-B8 and HLA-
DR3. The pathogenesis of the hyperthyroidism of Graves
disease involves the formation of autoantibodies that bind
to the TSH receptor in thyroid cell membranes and stimu-
late the gland to hyperfunction. Such antibodies are called
thyroid-stimulating immunoglobulins (TSI) or TSH recep-
tor antibodies (TSHrAb).
Dietary iodine supplementation can trigger Graves
disease. An increased incidence of Graves disease occurs in
countries that have embarked on national programs to for-
tify commercial salt with potassium iodide; the increase in
Graves disease lasts about 4 years. Similarly, patients being
treated with potassium iodide or amiodarone (which con-
tains iodine) have an increased risk of developing Graves
disease.
Patients with Graves disease have an increased risk of
other systemic autoimmune disorders. Affected patients are
at increased risk for Sjgren syndrome, pernicious anemia,
 1112 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS CMDT 2013 1112

followed by hypothyroidism. Patients taking lithium may

Table 265. factors that can cause aberrations in rarely experience thyrotoxicosis due to silent thyroiditis.
laboratory tests that may be mistaken for spontane- Symptoms mimic a manic episode such that the diagnosis
ous clinical primary hyperthyroidism.1 is often missed.
High Serum T4 or T3 Low Serum TSH D. Thyrotoxicosis Factitia
Laboratory error Laboratory error Thyrotoxicosis factitia is due to ingestion of excessive
Collecting serum in vial with gel Autonomous thyroid or
amounts of exogenous thyroid hormone. Isolated epi-
barrier for T3 thyroid nodule
Acute psychiatric problems (30%) Acute corticosteroid
demics of thyrotoxicosis have been caused by consumption
Acute medical illness (eg, acute administration of ground beef contaminated with bovine thyroid gland.
intermittent porphyria) Elderly euthyroid
AIDS (increased thyroid-binding Nonthyroidal illness E. Struma Ovarii
globulin) (severe)
Thyroid tissue is contained in about 3% of ovarian der-
Autoimmunity Pregnancy (especially
Hepatitis: acute or chronic active with morning sickness) moid tumors and teratomas. This thyroid tissue may
Primary biliary cirrhosis hCG-secreting trophoblastic autonomously secrete thyroid hormone due to a toxic nod-
Pregnancy (especially with morning tumors ule or in concert with the womans thyroid gland in Graves
sickness) Drugs disease or toxic multinodular goiter.
Hyperemesis gravidarum Thyroid hormone
Familial thyroid-binding Amphetamines F. Pituitary Tumor
abnormalities Dopamine
Familial generalized resistance to Dopamine agonists TSH hypersecretion by the pituitary may be caused by a
thyroid (Refetoff syndrome) Calcium channel tumor or thyrotrophe cell hyperplasia and is a rare cause of
Drugs Amiodarone blockers (nifedipine, hyperthyroidism. Serum TSH is elevated or normal in the
Amphetamines verapamil) presence of true thyrotoxicosis. Pituitary hyperplasia may
Clofibrate be detected on MRI scan as pituitary enlargement without
Estrogens (oral) a discrete adenoma being visible. This condition appears to
Heparin (dialysis method) be due to a diminished feedback effect of T4 upon the pitu-
Heroin
itary. Some cases are familial. Prolonged untreated hypo-
Thyroid hormone therapy
Methadone thyroidism causes pituitary enlargement due to thyrotrophe
Perphenazine hyperplasia; thyrotrophe tumors are rare.
Tamoxifen
G. Thyroiditis
1True clinical hyperthyroidism may coexist. Hashimoto thyroiditis may cause transient hyperthyroidism
hCG, human chorionic gonadotropin; NSAIDs, nonsteroidal anti- during the initial destructive phase. This is also seen in
inflammatory drugs; T4, levothyroxine; T3, triiodothyronine; TSH, some patients receiving interferon-, interferon-, and
thyroid-stimulating hormone. interleukin-2. Postpartum thyroiditis refers to Hashimoto
thyroiditis that occurs in the first 6 months after delivery. It
is common, occurring postpartum in 510% of women in
Addison disease, alopecia areata, vitiligo, celiac disease, auto- the United States. Hyperthyroidism results from the release
immune diabetes mellitus type 1, hypoparathyroidism, of stored thyroid hormone following damage to the thyroid.
myasthenia gravis, and cardiomyopathy. Thyroiditis and hyperthyroidism can also develop in patients
receiving sunitinib chemotherapy.
B. Toxic Multinodular Goiter
and Thyroid Adenomas H. Pregnancy and Trophoblastic Tumors
The prevalence of hyperthyroidism in pregnancymost
Autonomous toxic adenomas of the thyroid may be single
commonly due to Graves diseaseis about 0.2%. Struma
(Plummer disease) or multiple (toxic multinodular goiter).
ovarii is rare. Newborns have an increased risk of intra-
Jod-Basedow disease, or iodine-induced hyperthyroidism,
uterine growth retardation, prematurity, and transient
may occur in patients with multinodular goiters after
thyrotoxicosis from transplacental transfer of thyrotropin
intake of large amounts of iodine in the diet or in the form
receptor antibody (TRAb).
of radiographic contrast materials or drugs, especially
Although hCG generally has a low affinity for the thy-
amiodarone. This condition is not associated with infiltra-
roids TSH receptors, very high serum levels of hCG may
tive ophthalmopathy or dermopathy.
cause sufficient receptor activation to cause thyrotoxicosis.
C. Subacute (de Quervain) Thyroiditis Mild gestational hyperthyroidism may occur during the
first 4 months of pregnancy, when hCG levels are very high.
Subacute thyroiditis typically presents with a moderately Pregnant women are more likely to have thyrotoxicosis and
enlarged, tender thyroid, and hyperthyroidism. It is thought hyperemesis gravidarum if they have high serum levels of
to be due to a viral infection. If the gland is nontender, the asialo-hCG, a subfraction of hCG with greater affinity for
disorder is called silent thyroiditis. Hyperthyroidism is TSH receptors.
 1113 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
High levels of hCG can also cause thyrotoxicosis in
some cases of molar pregnancy, choriocarcinoma, and
testicular malignancies.
I. Thyroid Carcinoma
Metastatic functioning thyroid carcinoma is a rare cause of
thyrotoxicosis. Hyperthyroidism can be induced by recom-
binant human thyroid-stimulating hormone (rhTSH) that
is given prior to radioiodine therapy or scanning. (See
Thyroid Cancer section.)
J. Iodine-Induced Hyperthyroidism
Iodine-induced hyperthyroidism is also known as Jod-
Basedow disease. The recommended iodine intake for
nonpregnant adults is 150 mcg/d. Higher iodine intake can
precipitate hyperthyroidism, particularly in patients with
nodular goiters, autonomous thyroid nodules, or asymp-
tomatic Graves disease. Iodine-induced hyperthyroidism
also occurs in patients with no detectable underlying thy-
roid disorder. Common sources of excess iodine include
intravenous iodinated radiocontrast dye, certain foods (eg,
kelp, nori), topical iodinated antiseptics (eg, povidine
iodine), and medications (eg, potassium iodide or amio-
darone). Intravenous iodinated radiocontrast dye can also
precipitate thyrotoxicosis by inducing a destructive sub-
acute thyroiditis that may be painful and is similar to type
2 amiodarone-induced thyrotoxicosis.
K. Amiodarone-Induced Thyrotoxicosis
Amiodarone is a widely used antiarrhythmic drug. The
half-life of amiodarone and its metabolites is about
100 days. By weight, amiodarone is 37% iodine and thyroid
dysfunction develops in about 1520% of patients taking
amiodarone. In the United States, amiodarone-induced
thyrotoxicosis develops in about 3% of patients taking the
drug; the incidence of amiodarone-induced thyrotoxicosis
is higher in Europe and in iodine-deficient geographic
areas (20%). Hyperthyroidism can occur 4 months to
3 years after initiation of amiodarone and may develop
several months after amiodarone has been discontinued.
Type 1 amiodarone-induced thyrotoxicosis is caused by
active elaboration of excessive thyroid hormone and may
occur by either of two mechanisms: (1) Free iodine may
cause toxic multinodular goiter in iodine-deficient patients
with preexisting autonomous thyroid nodules. Thyroid
radioactive iodine (RAI) uptake ranges from low to high.
(2) Excessive free iodine can trigger an immunologic attack
on the thyroid; this may cause Graves disease, commonly
with diffuse thyroid enlargement and antithyroid peroxidase
antibodies (70%). Color flow Doppler sonography shows
increased vascularity and blood flow velocity. Thyroidal
radioiodine uptake may be low, normal, or increased.
Type 2 amiodarone-induced thyrotoxicosis is caused by
destructive thyroiditis, which releases stored thyroid hormone
from damaged cells; hyperthyroidism can last 13 months
and may be followed by hypothyroidism. On ultrasound, the
thyroid gland is normal in size, and on color flow Doppler
sonography there is no increase in vascularity. Thyroidal
radioiodine uptake is usually very low (< 3%).
CMDT 2013 1113
`cClinical Findings
A. Symptoms and Signs
Thyrotoxicosis due to any cause produces many different
manifestations of variable intensity among different indi-
viduals. Patients may complain of nervousness, restless-
ness, heat intolerance, increased sweating, pruritus, fatigue,
weakness, muscle cramps, frequent bowel movements, or
weight change (usually loss). There may be palpitations or
angina pectoris. Women frequently report menstrual irreg-
ularities.
Signs of thyrotoxicosis also include fine resting finger
tremors, moist warm skin, fever, hyperreflexia, fine hair,
and onycholysis. Chronic thyrotoxicosis may cause osteo-
porosis. Clubbing and swelling of the fingers (acropachy)
develop in a small number of patients.
In patients with Graves disease, physical examination
usually reveals a diffusely enlarged thyroid, frequently
asymmetric, often with a bruit. However, some patients
have no palpable thyroid enlargement. The thyroid gland
in subacute thyroiditis is usually moderately enlarged
and tender. In patients with toxic multinodular goiter, the
thyroid usually has palpable nodules.
Cardiopulmonary manifestations of thyrotoxicosis
commonly include a forceful heartbeat, premature atrial
contractions, and sinus tachycardia. Patients often have exer-
tional dyspnea. Atrial fibrillation or atrial tachycardia occurs
in about 8% of patients with thyrotoxicosis, more commonly
in men, the elderly, and those with ischemic or valvular heart
disease. The ventricular response from the atrial fibrillation
may be difficult to control. Thyrotoxicosis itself can cause a
thyrotoxic cardiomyopathy, and the onset of atrial fibrillation
can precipitate congestive heart failure. Echocardiogram
reveals pulmonary hypertension in 49% of patients with
hyperthyroidism; of these, 71% have pulmonary artery
hypertension while 29% have pulmonary venous hyperten-
sion. Hemodynamic abnormalities and pulmonary hyper-
tension are reversible with restoration of euthyroidism.
Graves eye manifestations, which can occur with
hyperthyroidism of any etiology, include upper eyelid
retraction (Dalrymple sign), lid lag with downward gaze
(von Graefe sign), and a staring appearance (Kocher sign).
Ophthalmopathy is clinically apparent in 2040%
of patients with Graves disease and type 1 amiodarone-
induced thyrotoxicosis, but in no other conditions causing
hyperthyroidism. It usually consists of conjunctival edema
(chemosis), conjunctivitis, and mild exophthalmos (prop-
tosis). About 510% of patients experience more severe
exophthalmos, with the eye being pushed forward by
increased retro-orbital fat and eye muscles that have been
thickened by lymphocytic infiltration. Such patients can
experience diplopia from extraocular muscle entrapment.
There may be weakness of upward gaze (Stellwag sign).
The optic nerve may be compressed in severe cases, causing
progressive loss of color vision, visual fields, and visual
acuity. Corneal drying may occur with inadequate lid
closure. Eye changes may sometimes be asymmetric or uni-
lateral. The severity of the eye disease is not closely corre-
lated with the severity of the thyrotoxicosis. Some patients
with Graves ophthalmopathy are clinically euthyroid.
 1114 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
Exophthalmometry should be performed on all patients
with Graves disease to document their degree of exophthal-
mos and detect progression of orbitopathy. The protrusion of
the eye beyond the orbital rim is measured with a prism
instrument (Hertel exophthalmometer). Maximum normal
eye protrusion varies between kindreds and races, being about
22 mm for blacks, 20 mm for whites, and 18 mm for Asians.
The differential diagnosis for Graves ophthalmopathy
includes diplopia caused by coexistent ocular myasthenia
gravis, which is more common in Graves disease and is
usually mild, often with selective eye involvement.
Acetylcholinesterase receptor antibody (AChR Ab) levels
are elevated in only 36% of such patients, and a thymoma
is present in 9%. Orbital lymphoma can also masquerade
as Graves ophthalmopathy.
Graves dermopathy (pretibial myxedema) occurs in about
3% of patients with Graves disease, usually in the pretibial
region. It is more common in patients with high levels of
serum thyroid-stimulating immunoglobulin and in those
with severe Graves ophthalmopathy. Glycosaminoglycans
accumulation and lymphoid infiltration occur in affected
skin, which becomes erythematous with a thickened, rough
texture. Elephantiasis of the legs is a rare complication.
Thyroid acropachy is an extreme and unusual manifesta-
tion of Graves disease. It presents with digital clubbing, swell-
ing of fingers and toes, and a periosteal reaction of extremity
bones. It is ordinarily associated with ophthalmopathy and
thyroid dermopathy. Most patients are smokers. The pres-
ence of thyroid acropachy is an indication of the severity of
the autoimmunity; most patients have high serum titers of
thyroid-stimulating immunoglobulin. Patients with thyroid
acropachy are at greater risk for having concurrent Graves
dermopathy and severe ophthalmopathy. However, acropachy
itself does not usually cause clinical complaints.
Tetany is a rare presenting feature. In hyperthyroidism,
the renal excretion of magnesium is increased and hypo-
magnesemia is common. Severe magnesium depletion
causes hypoparathyroidism that can result in hypocalcemia.
Hyperthyroidism during pregnancy shares many of
the features of normal pregnancy: tachycardia, warm skin,
heat intolerance, increased sweating, and a palpable thy-
roid. Pregnancy can have a beneficial effect on the thyro-
toxicosis of Graves disease. However, there is an increased
risk of thyroid storm, preeclampsiaeclampsia, congestive
heart failure, premature delivery, and abruptio placentae.
TSI (or TSHrAb) crosses the placenta; if maternal serum
TSI (or TSHrAb) levels reach > 500% in the third trimester,
the risk of transient neonatal Graves disease in the new-
born is increased.
Hypokalemic periodic paralysis occurs in about 15%
of Asian or Native American men with thyrotoxicosis. It
usually presents abruptly with symmetric flaccid paralysis
(and few thyrotoxic symptoms), often after intravenous
dextrose, oral carbohydrate, or vigorous exercise. Attacks
last 772 hours.
B. Laboratory Findings
Serum FT4, T3, FT3, T4, thyroid resin uptake, and FT4 index
are all usually increased. Sometimes the FT4 level may be
CMDT 2013 1114
normal but with an elevated serum T3 (T3 toxicosis). Serum
T3 can be misleadingly elevated when blood is collected in
tubes using a gel barrier, which causes certain immunoas-
says (eg, Immulite but not Axsym analyzers) to report
serum total T3 levels that are falsely elevated in 24% of
normal patients. Serum T4 or T3 can be elevated in other
nonthyroidal conditions (Table 265).
Serum TSH is suppressed in hyperthyroidism, except in
the very rare cases of pituitary inappropriate secretion of
thyrotropin. Serum TSH may be misleadingly low in other
nonthyroidal conditions (Table 265). The term subclinical
hyperthyroidism is used to describe asymptomatic indi-
viduals with a low serum TSH but normal serum levels of FT4
and T3; progression to symptomatic thyrotoxicosis occurs
at a rate of 12% per year in patients without a goiter and at
a rate of 5% per year in patients with a multinodular goiter.
Hyperthyroidism can cause other laboratory abnor-
malities, including hypercalcemia, increased alkaline
phosphatase, anemia, and decreased granulocytes.
Hypokalemia and hypophosphatemia occur in thyrotoxic
periodic paralysis.
Problems of diagnosis occur in patients with acute psy-
chiatric disorders; about 30% of these patients have ele-
vated serum T4 levels without clinical thyrotoxicosis. The
TSH is not usually suppressed, distinguishing psychiatric
disorder from true hyperthyroidism. T4 levels return to
normal gradually.
In Graves disease, serum TSI (or TSHrAb) is usually
detectable (65%). Antithyroglobulin or antithyroperoxi-
dase antibodies are usually elevated but are nonspecific.
Serum ANA and anti-double-stranded DNA antibodies are
also usually elevated without any evidence of lupus erythe-
matosus or other collagen-vascular disease.
With subacute thyroiditis, patients often have an
increased erythrocyte sedimentation rate (ESR) but anti-
thyroid antibodies are usually not present in the plasma,
and tests for TSI (or TSHrAb) are negative. Patients with
iodine-induced hyperthyroidism also have undetectable
serum TSI (or TSHrAb), an absence of serum anti-
thyroperoxidase antibodies, and an elevated urinary iodine
concentration. In thyrotoxicosis facticia, serum thyro-
globulin levels are low, distinguishing it from other causes
of hyperthyroidism.
With hyperthyroidism during pregnancy, women have
an elevated FT4 while the TSH is suppressed. However,
apparent lack of full TSH suppression can be seen due to
misidentification of hCG as TSH in certain assays. Although
the total T4 is elevated in most pregnant women, values over
20 mcg/dL are encountered only in hyperthyroidism. The
T3 resin uptake, which is low in normal pregnancy because
of high TBG concentration, is normal or high in thyrotoxic
persons. Pregnancy can have a beneficial effect on the thyro-
toxicosis of Graves disease, with decreasing antibody titers
and decreasing FT4 levels as the pregnancy advances.
Since high levels of T4 and FT4 are normally seen in
patients taking amiodarone, suppressed TSH (sensitive
assay) must be present along with a greatly elevated T4
(> 20 mcg/dL) or T3 (> 200 ng/dL) in order to diagnose
hyperthyroidism. (Note: Hypothyroidism occurs in an
additional 6% of patients receiving amiodarone after
 1115 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
239 weeks of therapy.) In type 1 amiodarone-induced
thyrotoxicosis, the presence of proptosis, thyroid-
stimulating immunoglobulin is diagnostic. In type 2
amiodarone-induced thyrotoxicosis, serum levels of
interleukin-6 (IL-6) are usually quite elevated.
C. Imaging
RAI should never be administered to pregnant women. In
others, RAI scanning and uptake may be helpful to deter-
mine the cause for hyperthyroidism. RAI uptake and scan-
ning is not necessary for patients with obvious Graves
disease who have elevated serum thyroid-stimulating immu-
noglobulin or associated Graves ophthalmopathy. Women
with hyperthyroidism due to Graves disease should ideally
have the RAI scan extended to include the pelvis in order to
screen for concomitant struma ovarii (rare). A high RAI
uptake is seen in Graves disease and toxic nodular goiter.
Patients with type 1 amiodarone-induced thyrotoxicosis
have RAI uptake that is usually detectable but typically
below the normal range, although some patients may have
elevated RAI uptake. A low RAI uptake is characteristic of
subacute thyroiditis and iodine-induced hyperthyroidism.
Low RAI uptake is also seen with interleukin-2 therapy and
after neck surgery for hyperparathyroidism. In type 2
amiodarone-induced thyrotoxicosis, thyroid RAI uptake is
usually below 3%.
Thyroid ultrasound can be helpful in patients with
hyperthyroidism, particularly in patients with palpable thy-
roid nodules. Color flow Doppler sonography is helpful to
distinguish type 1 amiodarone-induced thyrotoxicosis, with
its increased blood flow velocity and vascularity, from type
2 amiodarone-induced thyrotoxicosis (reduced vascularity).
MRI and CT scanning of the orbits are the imaging
methods of choice to visualize Graves ophthalmopathy
affecting the extraocular muscles. Imaging is required only
in severe or unilateral cases or in euthyroid exophthalmos
that must be distinguished from orbital pseudotumor,
tumors, and other lesions.
`cDifferential Diagnosis
True thyrotoxicosis must be distinguished from those con-
ditions that elevate serum T4 and T3 or suppress serum
TSH without affecting clinical status (see Table 265).
Some states of hypermetabolism without thyrotoxico-
sisnotably severe anemia, leukemia, polycythemia, and
cancerr arely cause confusion. Pheochromocy toma
is often associated with hypermetabolism, tachycardia,
weight loss, and profuse sweating. Acromegaly may also
produce tachycardia, sweating, and thyroid enlarge-
ment. Appropriate laboratory tests will easily distinguish
these entities.
Cardiac disease (eg, atrial fibrillation, angina) refractory
to treatment suggests the possibility of underlying (apa-
thetic) hyperthyroidism. Other causes of ophthalmoplegia
(eg, myasthenia gravis) and exophthalmos (eg, orbital
tumor, pseudotumor) must be considered. Thyrotoxicosis
must also be considered in the differential diagnosis of
muscle weakness and osteoporosis. Diabetes mellitus and
Addison disease may coexist with thyrotoxicosis.
CMDT 2013 1115
`cComplications
Hypercalcemia, osteoporosis, and nephrocalcinosis may
occur. Decreased libido, erectile dysfunction, diminished
sperm motility, and gynecomastia may be noted in
men with hyperthyroidism. Other complications include
cardiac arrhythmias and heart failure, thyroid crisis, oph-
thalmopathy, dermopathy, and thyrotoxic hypokalemic
periodic paralysis (see below.)
`cTreatment
A. Graves Disease
The treatment of Graves disease involves a choice of meth-
ods rather than a method of choice.
1. PropranololPropranolol is generally used for symp-
tomatic relief until the hyperthyroidism is resolved. It
effectively relieves the tachycardia, tremor, diaphoresis, and
anxiety that occur with hyperthyroidism due to any cause.
It is the initial treatment of choice for thyroid storm. The
periodic paralysis seen in association with thyrotoxicosis is
also effectively treated with -blockade. It has no effect on
thyroid hormone secretion. Treatment is usually begun
with propranolol ER 60 mg orally once or twice daily, with
dosage increases every 23 days to a maximum daily dose
of 320 mg. Propranolol ER is initially given every 12 hours
for patients with severe hyperthyroidism, due to acceler-
ated metabolism of the propranolol; it may be given once
daily as hyperthyroidism improves.
2. Thiourea drugsMethimazole or propylthiouracil is
generally used for young adults or patients with mild thy-
rotoxicosis, small goiters, or fear of isotopes. Carbimazole
is another thiourea that is converted to methimazole in
vivo and is available outside the United States. Elderly
patients usually respond particularly well. These drugs are
also useful for preparing hyperthyroid patients for surgery
and elderly patients for RAI treatment. The drugs do not
permanently damage the thyroid and are associated with a
lower chance of posttreatment hypothyroidism (compared
with RAI or surgery). When thiourea therapy is discontin-
ued, there is a high recurrence rate for hyperthyroidism
(about 50%). A better likelihood of long-term remission is
seen in patients with small goiters or mild hyperthyroidism
and those requiring small doses of thiourea. Patients whose
thyroperoxidase and thyroglobulin antibodies remain high
after 2 years of therapy have been reported to have only a
10% rate of relapse. Thiourea therapy may be continued
long-term for patients who are tolerating it well.
Agranulocytosis occurs in about 0.3% of patients tak-
ing methimazole and about 0.4% of patients taking propy-
lthiouracil. Agranulocytosis usually occurs in the first
60 days of therapy, and it develops in a few patients after
5 months of therapy. There is a genetic tendency to develop
agranulocytosis with thiourea therapy; if a close relative
has had this adverse reaction, other therapies should be
considered for the patient. Patients are warned that if a sore
throat or febrile illness develops, they should seek medical
attention and have a WBC determined immediately. The
agranulocytosis is generally reversible; recovery is not
 1116 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
improved by filgrastim (granulocyte colony-stimulating
factor [G-CSF]). Periodic surveillance of the WBC during
treatment has been advocated, but the onset of agranulocy-
tosis is generally abrupt.
Other side effects common to thiourea drugs include
pruritus, allergic dermatitis, nausea, and dyspepsia. Anti-
histamines may control mild pruritus without discontinu-
ation of the drug. Since the two thiourea drugs are similar,
patients who have had a major allergic reaction from one
should not be given the other.
Primary hypothyroidism may occur. The patient may
become clinically hypothyroid for 2 weeks or more before
TSH levels rise, having been suppressed by the preceding
hyperthyroidism. Therefore, the patients changing thyroid
status is best monitored clinically and with serum levels of
FT4. Rapid growth of the goiter usually occurs if prolonged
hypothyroidism is allowed to develop; the goiter may
sometimes become massive but usually regresses rapidly
with reduction or cessation of thiourea therapy or with
thyroid hormone replacement.
A. MethimazoleMethimazole is generally preferred
over propylthiouracil since methimazole is more convenient
to use and is less likely to cause fulminant hepatic necrosis.
Methimazole therapy is also less likely to cause 131I treatment
failure. Rare complications peculiar to methimazole include
serum sickness, cholestatic jaundice, loss of taste, alopecia,
nephrotic syndrome, and hypoglycemia. Methimazole is
given orally in initial doses of 3060 mg once daily. Some
patients with very mild hyperthyroidism may respond well
to smaller initial doses of methimazole (1020 mg daily).
Methimazole may also be administered twice daily to reduce
the likelihood of gastrointestinal upset. Methimazole use in
pregnancy has been associated with a possibly increased risk
of fetal anomalies such as aplasia cutis, esophageal atresia,
and coanal atresia. However, methimazole may be used if the
patient cannot tolerate propylthiouracil (see below). If
methimazole is used during pregnancy or breastfeeding, the
dose should not exceed 20 mg daily. The dosage is reduced
as manifestations of hyperthyroidism resolve and as the FT4
level falls toward normal. For patients who have elected to
receive 131I therapy, methimazole is discontinued 4 days
prior to receiving the 131I and is resumed at a lower dose
3 days afterwards to avoid recurrence of hyperthyroidism.
About 4 weeks after 131I therapy, methimazole may be dis-
continued if the patient is euthyroid.
B. PropylthiouracilPropylthiouracil has been the
drug of choice during breastfeeding since it is not concen-
trated in the milk as much as methimazole. Propylthiouracil
is also favored during pregnancy, possibly causing fewer
problems in the newborn. Rare complications peculiar to
propylthiouracil include arthritis, lupus, aplastic anemia,
thrombocytopenia, and hypoprothrombinemia. Acute
hepatitis occurs rarely and is treated with prednisone but
may progress to liver failure. Propylthiouracil is given
orally in initial doses of 300600 mg daily in four divided
doses. The dosage and frequency of administration are
reduced as symptoms of hyperthyroidism resolve and the
FT4 level approaches normal. During pregnancy, the dose
of propylthiouracil is kept below 200 mg/d to avoid goitrous
CMDT 2013 1116
hypothyroidism in the infant; the patient may be switched
to methimazole in the second trimester.
3. Iodinated contrast agentsThese agents provide
effective temporary treatment for thyrotoxicosis of any
cause. Iopanoic acid (Telepaque) or ipodate sodium
(Bilivist, Oragrafin) is given orally in a dosage of 500 mg
twice daily for 3 days, then 500 mg once daily. These agents
inhibit peripheral 5-monodeiodination of T4, thereby
blocking its conversion to active T3. Within 24 hours,
serum T3 levels fall an average of 62%. For patients with
Graves disease, methimazole is begun first to block iodine
organification; the next day, ipodate sodium or iopanoic
acid may be added. The iodinated contrast agents are par-
ticularly useful for patients who are very symptomatically
thyrotoxic (see Thyroid Storm). They offer a therapeutic
option for patients with T4 overdosage, subacute thyroid-
itis, and amiodarone-induced thyrotoxicosis and for those
intolerant to thioureas and for newborns with thyrotoxico-
sis (due to maternal Graves disease). Treatment periods of
8 months or more are possible, but efficacy tends to wane
with time. In Graves disease, thyroid RAI uptake may be
suppressed during treatment but typically returns to pre-
treatment uptake by 7 days after discontinuation of the
drug, allowing 131I treatment.
4. Radioactive iodine (131I, RAI)The administration of
131
I is an excellent method of destroying overactive thyroid
tissue (either diffuse or toxic nodular goiter). There are
ample data to conclude that patients who are treated with
RAI in adulthood do not have an increased risk of subse-
quent thyroid cancer, leukemia, or other malignancies.
Similarly, individuals who were treated with RAI as teenag-
ers have not shown any increased risk of malignancy in a
36-year retrospective study. Children born to parents pre-
viously treated with 131I show normal rates of congenital
abnormalities.
Because fetal radiation is harmful, RAI should not be
given to pregnant women. A sensitive pregnancy test (serum
-hCG) should be obtained on all women of reproductive
age prior to 131I therapy.
Most patients may receive 131I while being symptomati-
cally treated with propranolol ER, which is then reduced in
dosage as hyperthyroxinemia resolves. However, some
patients (those with coronary disease, the elderly, or those
with severe hyperthyroidism) are usually rendered euthy-
roid with a thiouracil drug (see above) while the dosage of
propranolol is reduced. A higher rate of 131I treatment fail-
ure has been reported in patients with Graves disease who
have been receiving methimazole or propylthiouracil.
However, therapy with 131I will usually be effective if the
methimazole is discontinued at least 4 days before RAI
therapy and if the therapeutic dosage of 131I is adjusted
(upward) according to RAI uptake on the pretherapy scan.
Prior to 131I therapy, patients are instructed against receiv-
ing intravenous iodinated contrast or ingesting large quan-
tities of dietary iodine, but severe restriction of dietary
iodine is not usually necessary.
Following 131I treatment for hyperthyroidism, Graves
ophthalmopathy appears or worsens in 15% of patients
(23% in smokers and 6% in nonsmokers) and improves in
 1117 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
none, whereas during treatment with methimazole, oph-
thalmopathy worsens in 3% and improves in 2% of
patients. Among patients receiving prednisone following
131
I treatment, preexistent ophthalmopathy worsens in
none and improves in 67%. Therefore, patients with Graves
ophthalmopathy who are to be treated with radioiodine
should be considered for prophylactic prednisone (2040
mg/d) for 2 months following administration of 131I, par-
ticularly in patients who have severe orbital involvement.
Smoking increases the risk of having a flare in ophthal-
mopathy following 131I treatment and also reduces the
effectiveness of prednisone treatment. Therefore, patients
who smoke are strongly encouraged to quit prior to 131I
treatment.
FT4 levels may sometimes drop within 2 months after
131
I treatment, but then rise again to thyrotoxic levels, at
which time thyroid RAI uptake is low. This phenomenon is
caused by a release of stored thyroid hormone from injured
thyroid cells and does not indicate a treatment failure. In
fact, serum FT4 then falls abruptly to hypothyroid levels.
There is a high incidence of hypothyroidism in the
months to years after 131I, even when small doses are given.
Patients with Graves disease treated with 131I also have an
increased lifetime risk of developing hyperparathyroidism,
particularly when radioiodine therapy was administered in
childhood or adolescence. Lifelong clinical follow-up is
mandatory, with measurements of serum TSH, FT4, and
calcium when indicated.
5. Thyroid surgeryThyroidectomy may be performed
for pregnant women whose thyrotoxicosis is not controlled
with low doses of thioureas, and for women who desire to
become pregnant in the very near future. Surgery is also an
option for nodular goiters, when there is a suspicion for
malignancy.
The HartleyDunhill operation is the procedure of
choice for patients with Graves disease having surgery; this
operation consists of a total resection of one lobe and a
subtotal resection of the other lobe, leaving about 4 g of
thyroid tissue. Subtotal thyroidectomy of both lobes is
often used, but ultimately results in a 9% recurrence rate
for hyperthyroidism. Total thyroidectomy of both lobes
poses an increased risk of hypoparathyroidism and damage
to the recurrent laryngeal nerves.
Patients are ordinarily rendered euthyroid preopera-
tively with a thiourea drug. Ipodate sodium or iopanoic
acid (500 mg orally twice daily) may be used in addition to
a thiourea to accelerate the decline in serum T3. Propranolol
ER is given orally at initial doses of 6080 mg twice daily
and increased every 23 days until the heart rate is < 90
beats per minute. Propranolol is continued until the serum
T3 (or free T3) is normal preoperatively. Thyroid vascular-
ity is reduced by preoperative treatment with either ipo-
date sodium or iopanoic acid (500 mg twice orally daily for
3 days) or iodine (eg, Lugol solution, two or three drops
orally daily for several days). If a patient undergoes surgery
while thyrotoxic, larger doses of propranolol are given
perioperatively to reduce the likelihood of thyroid crisis.
Morbidity includes possible damage to the recurrent
laryngeal nerve, with resultant vocal cord paralysis. If both
recurrent laryngeal nerves are damaged, airway obstruction
CMDT 2013 1117
may develop, and the patient may require intubation and
tracheostomy. Hypoparathyroidism also occurs, which
means that calcium levels must be checked postoperatively.
When a competent, experienced neck surgeon performs a
thyroidectomy, surgical complications are uncommon.
Thyroid surgery should be performed as an inpatient, with
at least an overnight observational period.
B. Toxic Solitary Thyroid Nodules
Toxic solitary thyroid nodules are usually benign but may
rarely be malignant. If a nonsurgical therapy is elected, the
nodule should be evaluated with a fine-needle aspiration
biopsy (FNA). Hyperthyroidism caused by a single hyper-
functioning thyroid nodule may be treated symptomatically
with propranolol ER and methimazole or propylthiouracil,
as in Graves disease (see above). Patients who tolerate
methimazole well may elect to continue it for long-term
therapy. The dose of methimazole should be adjusted to keep
the TSH slightly suppressed, so the risk of TSH-
stimulated growth of the nodule is reduced. For patients
under age 40 years and for healthy older patients, surgery is
usually recommended; patients are made euthyroid with a
thiourea preoperatively and given several days of iodine,
ipodate sodium, or iopanoic acid before surgery as in Graves
disease (see above). Transient postoperative hypothyroidism
resolves spontaneously. Permanent hypothyroidism occurs
in about 14% of patients by 6 years after surgery. Patients
with a toxic solitary nodule who are over age 40 years or in
poor health may be offered 131I therapy. If the patient has
been receiving methimazole preparatory to 131I, the TSH
should be kept slightly suppressed in order to reduce the
uptake of 131I by the normal thyroid. Nevertheless, perma-
nent hypothyroidism occurs in about one-third of patients
after 8 years of 131I therapy. The nodule remains palpable in
50% and may grow in 10% of patients after 131I.
C. Toxic Multinodular Goiter
Hyperthyroidism caused by a toxic multinodular goiter
may also be treated with propranolol ER and methimazole,
as in Graves disease. Methimazole does reverse hyperthy-
roidism, but there is a 95% recurrence rate if it is stopped.
Definitive treatment for large multinodular goiters is sur-
gery, prior to which patients are rendered euthyroid.
Surgery is particularly indicated to relieve pressure symp-
toms or for cosmetic indications. Patients with toxic mul-
tinodular goiter are prepared for surgery the same as those
with Graves disease. Patients who are to receive 131I treat-
ment are rendered nearly euthyroid with methimazole,
which is stopped at least 4 days before RAI treatment.
Meanwhile, the patient follows a low-iodine diet; this is
done to enhance the thyroid glands uptake of RAI, which
may be relatively low in this condition (compared to
Graves disease). Relatively high doses of 131I are usually
required; recurrent thyrotoxicosis and hypothyroidism are
common, so patients must be monitored closely. Peculiarly,
in about 5% of patients with diffusely nodular toxic goiter,
the administration of 131I therapy may induce Graves dis-
ease. Also, Graves eye disease has occurred rarely following
131
I therapy for multinodular goiter.
 1118 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
D. Subacute (de Quervain) Thyroiditis
Patients with hyperthyroidism due to subacute thyroiditis
are treated symptomatically with oral propranolol ER at
initial doses of about 6080 mg twice daily and increased
every 23 days until the heart rate is < 90 beats per minute.
Ipodate sodium or iopanoic acid, 500 mg orally daily,
promptly corrects elevated T3 levels and is continued for
1560 days until the serum FT4 level normalizes. The condi-
tion subsides spontaneously within weeks to months.
Thioureas are ineffective, since thyroid hormone production
is actually low in this condition. RAI is ineffective, since the
thyroids iodine uptake is low. Since periods of hypothyroid-
ism may occur following the initial inflammatory episode,
patients should have close clinical follow-up, with serum FT4
measurement when necessary. Prompt treatment of the
transient hypothyroidism may reduce the incidence
of recurrent thyroiditis. Pain can usually be managed with
non-aspirin nonsteroidal anti-inflammatory drugs.
E. Hashimoto Thyroiditis (Hashitoxicosis)
Rarely, hyperthyroidism develops as a result of release of
stored thyroid hormone during severe Hashimoto thyroidi-
tis. Serum thyroperoxidase or thyroglobulin antibodies are
usually high, but RAI uptake is low, thus distinguishing it
from Graves disease. This is especially common in postpar-
tum women, in whom it may be transient. Treatment is
with propranolol ER. Ipodate sodium or iopanoic acid may
also be used as described above. Patients are monitored
carefully for the development of hypothyroidism and
treated.
F. Hyperthyroidism during Pregnancy
and Lactation
There may be a slightly increased risk of fetal anomalies
associated with methimazole in the first trimester.
Therefore, pregnant women with hyperthyroidism are
treated with propylthiouracil in the first trimester and then
may be switched to methimazole. Either thiourea should be
given in the smallest dose possible, permitting mild sub-
clinical hyperthyroidism to occur since it is usually well
tolerated. Both propylthiouracil and methimazole cross the
placenta and can induce hypothyroidism, with fetal TSH
hypersecretion and goiter. Thyroid hormone administra-
tion to the mother does not prevent hypothyroidism in the
fetus, since T4 and T3 do not freely cross the placenta. Fetal
hypothyroidism is rare if the mothers hyperthyroidism is
controlled with small daily doses of propylthiouracil (50
150 mg/d orally) or methimazole (515 mg/d orally).
Thyroidectomy is reserved for women who are allergic or
resistant to antithyroid drugs (usually due to noncompli-
ance) or who have very large goiters. Fetal ultrasound at
32 weeks gestation can visualize any fetal goiter, so fetal
thyroid dysfunction can be diagnosed and treated.
Both methimazole and propylthiouracil are secreted in
breast milk, but not in amounts that affect the infants
thyroid hormone levels. No adverse reactions to these
drugs (eg, rash, hepatic dysfunction, leukopenia) have been
reported in breast-fed infants. Recommended doses are
20 mg orally daily or less for methimazole and 450 mg
CMDT 2013 1118
orally daily or less for propylthiouracil. It is recommended
that the medication be taken just after breast-feeding.
G. Treatment of Other Causes of
Hyperthyroidism
Patients with thyrotoxicosis from thyrotrophe pituitary
hyperplasia are treated with propranolol ER as described
above. Definitive treatment is with RAI or thyroid surgery.
Patients with thyrotoxicosis caused by a thyrotrophe
pituitary adenoma are treated with propranolol ER and
methimazole, followed by transsphenoidal resection of the
pituitary tumor, when possible.
Patients with type 1 amiodarone-induced thyrotoxico-
sis usually require propranolol ER. Therapy with 131I may
be successful in some patients with sufficient RAI uptake.
If radioiodine therapy is not an option (due to insufficient
RAI uptake), treatment with methimazole is begun. If
radioiodine is administered, methimazole may be started
several days afterward. After two doses of methimazole,
iopanoic acid or sodium ipodate may be added to the regi-
men to further block conversion of T4 to T3; the recom-
mended dosage for each is 500 mg orally twice daily for
3 days, followed by 500 mg once daily until thyrotoxicosis
is resolved. If iopanoic acid or sodium ipodate is not avail-
able, the alternative is potassium perchlorate; it is given in
doses of 1000 mg daily (in divided doses) for a course not
to exceed 30 days in order to avoid the complication of
aplastic anemia. Amiodarone may be withdrawn but this
does not have a significant therapeutic effect for several
months. Thyroidectomy is reserved for resistant cases.
Patients with type 2 amiodarone-induced thyrotoxico-
sis usually require propranolol ER. Prednisone is given at
an initial dose of about 0.50.7 mg/kg; that dose of predni-
sone is continued for about 2 weeks and then slowly
tapered and finally withdrawn after about 3 months.
Iopanoic acid or ipodate sodium may also be used (see
above). Withdrawal of amiodarone is not usually necessary.
Methimazole is ineffective. Thyroidectomy is rarely
required, since the condition is transient. Most patients
become euthyroid within 3040 days, except in cases of
very severe thyrotoxicosis.
Some cases of amiodarone-induced thyrotoxicosis
cannot be strictly categorized as either type 1 or type 2.
Such patients usually have negligible radioiodine uptake,
so treatment is usually commenced with propranolol ER
and a 1-month trial of methimazole. Iopanoic acid or ipo-
date sodium can be added to methimazole as noted above.
Prednisone is given for severe thyrotoxicosis or when
methimazole fails to correct the thyrotoxicosis. Amiodarone
is discontinued, when feasible.
H. Treatment of Complications
1. Graves ophthalmopathyThe risk of having a flare
of ophthalmopathy following 131I treatment for hyperthy-
roidism is about 6% for nonsmokers and 23% for smokers.
Graves ophthalmopathy can also be aggravated by thiazoli-
dinediones (eg, pioglitazone, rosiglitazone); these oral
diabetic agents should be avoided or withdrawn in patients
with Graves disease. Patients with mild ophthalmopathy
 1119 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
may be treated with selenium 100 mcg orally twice daily,
which slows the progression of the disease. For acute, pro-
gressive exophthalmos, intravenous methylprednisolone,
begun promptly, is superior to oral prednisone, possibly
due to improved compliance. Methylprednisolone is given
intravenously, 500 mg weekly for 6 weeks, then 250 mg
weekly for 6 weeks. If oral prednisone is chosen for treat-
ment, it must be given promptly in daily doses of 4060
mg/d orally, with dosage reduction over several weeks.
Higher initial prednisone doses of 80120 mg/d are used
when there is optic nerve compression. Prednisone allevi-
ates acute eye symptoms in 64% of nonsmokers, but only
14% of smokers respond well.
Progressive active exophthalmos may be treated with
retrobulbar radiation therapy using a supervoltage linear
accelerator (46 MeV) to deliver 20 Gy over 2 weeks to the
extraocular muscles, avoiding the cornea and lens. Prednisone
in high doses is given concurrently. Patients who respond
well to orbital radiation include those with signs of acute
inflammation, recent exophthalmos (< 6 months), or optic
nerve compression. Patients with chronic proptosis and
orbital muscle restriction respond less well. Retrobulbar
radiation does not cause cataracts or tumors; however, it can
cause radiation-induced retinopathy (usually subclinical) in
about 5% of patients overall, mostly in diabetics.
For severe cases, orbital decompression surgery may
save vision, though diplopia often persists postoperatively.
General eye protective measures include wearing glasses to
protect the protruding eye and taping the lids shut during
sleep if corneal drying is a problem. Methylcellulose drops
and gels (artificial tears) may also help. Tarsorrhaphy or
canthoplasty can frequently help protect the cornea and
provide improved appearance. Hypothyroidism and hyper-
thyroidism must be treated promptly.
2. Cardiac complications
A. Sinus tachycardiaTreatment consists of treating
the thyrotoxicosis. A -blocker (as described above) such as
propranolol is used in the interim unless there is an associ-
ated cardiomyopathy.
B. Atrial fibrillationHyperthyroidism must be
treated immediately (see above). Other drugs, including
digoxin, -blockers, anticoagulants, may be required.
Electrical cardioversion is unlikely to convert atrial fibrilla-
tion to normal sinus rhythm while the patient is thyrotoxic.
Spontaneous conversion to normal sinus rhythm occurs in
62% of patients with return of euthyroidism, but that like-
lihood decreases with age. Following conversion to euthy-
roidism, there is a 60% chance that atrial fibrillation will
recur, despite normal thyroid function tests. Those with
persistent atrial fibrillation may have elective cardioversion
4 months after resolution of hyperthyroidism.
(1) DigoxinDigoxin is used to slow a fast ventricular
response to thyrotoxic atrial fibrillation; it must be used in
larger than normal doses because of increased clearance
and an increased number of cardiac cellular sodium pumps
requiring inhibition. Digoxin doses are reduced as hyper-
thyroidism is corrected.
(2) -Blockers-Blockers may also reduce the ventricu-
lar rate, but they must be used with cautionparticularly
CMDT 2013 1119
in patients with cardiomegaly or signs of heart failure
since their negative inotropic effect may precipitate con-
gestive heart failure. Therefore, an initial trial of a
short-duration -blocker should be considered, such as
esmolol intravenously. If a -blocker is used, doses of
digoxin must be reduced.
(3) AnticoagulantsAnticoagulation is indicated in the
following situations: left atrial enlargement on echocardio-
gram, global left ventricular dysfunction, recent congestive
heart failure, hypertension, recurrent atrial fibrillation, or a
history of previous thromboembolism. The doses of war-
farin required in thyrotoxicosis are smaller than normal
because of an accelerated plasma clearance of vitamin
Kdependent clotting factors. Higher warfarin doses are
usually required as hyperthyroidism subsides.
C. Heart failureHeart failure due to thyrotoxicosis
may be caused by extreme tachycardia, cardiomyopathy, or
both. Very aggressive treatment of the hyperthyroidism is
required in either case (see Thyroid Crisis, below). The
tachycardia from atrial fibrillation is treated with digoxin
as above. Intravenous furosemide is typically required.
Oral spironolactone or eplerenone may be helpful. If tachy-
cardia appears to be the main cause of the failure, -blockers
are administered cautiously as described above.
Congestive heart failure may occur as a result of low-
output dilated cardiomyopathy in the setting of hyperthy-
roidism. It is uncommon and may be caused by an
idiosyncratic severe toxic effect of hyperthyroidism upon
certain hearts. Cardiomyopathy may occur at any age and
without preexisting cardiac disease. -Blockers and
calcium channel blockers are avoided. Emergency treat-
ment may include afterload reduction, diuretics, digoxin,
and other inotropic agents while the patient is being ren-
dered euthyroid. Heart failure usually persists despite cor-
rection of hyperthyroidism.
D. Apathetic hyperthyroidismApathetic hyperthy-
roidism may present with angina pectoris. Treatment is
directed at reversing the hyperthyroidism as well as provid-
ing standard antianginal therapy. Coronary angioplasty or
bypass grafting can often be avoided by prompt diagnosis
and treatment.
3. Thyroid crisis or stormThis disorder, rarely seen
today, is an extreme form of thyrotoxicosis that may be
triggered by stressful illness, thyroid surgery, or RAI
administration. Its manifestations often include marked
delirium, severe tachycardia, vomiting, diarrhea, dehydra-
tion and very high fever. The mortality rate is high.
A thiourea drug is given (eg, methimazole, 1525 mg
orally every 6 hours or propylthiouracil, 150250 mg orally
every 6 hours). Ipodate sodium (500 mg/d orally) can be
helpful if begun 1 hour after the first dose of thiourea.
Iodide is given 1 hour later as Lugol solution (10 drops
three times daily orally) or as sodium iodide (1 g intrave-
nously slowly). Propranolol is given (cautiously in the pres-
ence of heart failure; see above) in a dosage of 0.52 mg
intravenously every 4 hours or 20120 mg orally every
6 hours. Hydrocortisone is usually given in doses of 50 mg
orally every 6 hours, with rapid dosage reduction as the
clinical situation improves. Aspirin is avoided since it
 1120 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
displaces T4 from TBG, raising FT4 serum levels. Definitive
treatment with 131I or surgery is delayed until the patient is
euthyroid.
4. Hyperthyroidism from postpartum thyroiditis
Propranolol ER is given during the hyperthyroid phase
followed by levothyroxine during the hypothyroidism
phase (see Thyroiditis, below).
5. Graves dermopathyTreatment involves application
of a topical corticosteroid (eg, fluocinolone) with noctur-
nal plastic occlusive dressings.
6. Thyrotoxic hypokalemic periodic paralysisSudden
symmetric flaccid paralysis, along with hypokalemia and
hypophosphatemia can occur with hyperthyroidism. There
are often few classic signs of thyrotoxicosis. It is most preva-
lent in Asian and Native Americans with hyperthyroidism
and is 30 times more common in men than women.
Therapy with oral propranolol, 3 mg/kg, normalizes the
serum potassium and phosphate levels and reverses the
paralysis within 23 hours. No intravenous potassium or
phosphate is ordinarily required. Intravenous dextrose and
oral carbohydrate aggravate the condition and are to be
avoided. Therapy is continued with propranolol, 6080 mg
orally every 8 hours (or sustained-action propranolol ER
daily at equivalent daily dosage), along with a thiourea drug
such as methimazole to treat the hyperthyroidism.
`cPrognosis
Graves disease may rarely subside spontaneously, particu-
larly when it is mild or subclinical. Graves disease that
presents in early pregnancy has a 30% chance of spontane-
ous remission before the third trimester. The ocular, car-
diac, and psychological complications can become serious
and persistent even after treatment. Permanent hypopara-
thyroidism and vocal cord palsy are risks of surgical thyroi-
dectomy. Recurrences are common following thiourea
therapy but also occur after low-dose 131I therapy or subto-
tal thyroidectomy. With adequate treatment and long-term
follow-up, the results are usually good. However, despite
treatment for their hyperthyroidism, women experience an
increased long-term risk of death from thyroid disease,
cardiovascular disease, stroke, and fracture of the femur.
Posttreatment hypothyroidism is common. It may occur
within a few months or up to several years after RAI ther-
apy or subtotal thyroidectomy. Malignant exophthalmos
has a poor prognosis unless treated aggressively.
Subclinical hyperthyroidism refers to a condition in
which asymptomatic individuals have a low serum TSH
and normal FT4 and T3. Most such patients do well without
treatment. In one series, clinical hyperthyroidism devel-
oped in only one of seven patients after 2 years. In most
patients, the serum TSH may revert to normal within
2 years. Most such patients do not have accelerated bone
loss. However, if a baseline bone density shows significant
osteopenia, bone densitometry may be performed periodi-
cally. In persons over age 60 years, serum TSH is very low
(< 0.1 mU/L) in 3% and mildly low (0.10.4 mU/L) in 9%.
The chance of developing atrial fibrillation is 2.8% yearly
in elderly patients with very low TSH and 1.1% yearly in
those with mildly low TSH. Asymptomatic persons with
CMDT 2013 1120
very low TSH are monitored closely but are not treated
unless atrial fibrillation or other manifestations of hyper-
thyroidism develop.
Bahn RS et al. Hyperthyroidism and other causes of thyrotoxi-
cosis: management of guidelines of the American Thyroid
Association and American Association of Clinical
Endocrinologists. Thyroid. 2011 Jun;21(6):593646. [PMID:
21510801]
Bogazzi F et al. Approach to the patient with amiodarone-
induced thyrotoxicosis. J Clin Endocrinol Metab. 2010 Jun;
95(6):252935. [PMID: 20525904]
Calvi L et al. Acute thyrotoxicosis secondary to destructive thy-
roiditis associated with cardiac catheterization contrast dye.
Thyroid. 2011 Apr;21(4):4439. [PMID: 21385076]
Ghandour A et al. Hyperthyroidism: a stepwise approach to
management. J Fam Pract. 2011 Jul;60(7):38895. [PMID:
21731916]
Kim TD et al. Thyroid dysfunction caused by second-generation
tyrosine kinase inhibitors in Philadelphia chromosome-
positive chronic myeloid leukemia. Thyroid. 2010 Nov;20(11):
120914. [PMID: 20929406]
Marococci C et al; European Group on Graves Orbitophathy.
Selenium and the course of mild Graves orbitopathy. N Engl
J Med. 2011 May 19;364(20):192031. [PMID: 21591944]
Pantalone KM et al. Approach to a low TSH level: patience is a
virtue. Cleve Clin J Med. 2010 Nov;77(11):80311. [PMID:
21048053]
Pramyothin P et al. Clinical problem solving. A hidden solution.
N Engl J Med. 2011 Dec;365(22):21237. [PMID: 22129257]
Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J
Med. 2011 Feb 10;364(6):54250. [PMID: 21306240]
THYROIDITIS
`c ccc
EssEntials of diagnosis
Acute and subacute forms: thyroid gland swell-
`c cccc
ing, sometimes causing pressure symptoms.
Chronic form: thyroid gland may or may not be
`c cccc
enlarged with rubbery firmness.
`c cccthyroid function tests variable.
serum antithyroperoxidase and antithyroglobulin
`c cccc
antibody levels usually elevated in Hashimoto
thyroiditis.
`cGeneral Considerations
Thyroiditis may be classified as follows: (1) chronic lym-
phocytic thyroiditis due to autoimmunity (also called
Hashimoto thyroiditis), (2) subacute thyroiditis, (3) sup-
purative thyroiditis, and (4) Riedel thyroiditis.
Hashimoto thyroiditis is an autoimmune condition and
the most common thyroid disorder in the United States.
B-lymphocytes invade the thyroid gland, such that the con-
dition is also known as chronic lymphocytic thyroiditis.
Detectable levels of antithyroid antibodies are usually pres-
ent: antithyroperoxidase (antimitochondrial) antibodies or
antithyroglobulin antibodies, or both. Elevated serum levels
of antithyroid antibodies are found in 3% of men and 13%
of women. Women over the age of 60 years have a 25%
 1121 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
incidence of elevated serum levels of antithyroid antibodies.
However, only a small subset of individuals with elevated
antithyroid antibody levels ever develops thyroid dysfunc-
tion. One percent of the population has serum antithyroid
antibody titers > 1:6400 and they are at particular risk for
thyroid dysfunction. The incidence of Hashimoto thyroiditis
varies by kindred, race, and by sex; in persons older than 12
years of age in the United States, elevated levels of antithy-
roid antibodies are found in 14.3% of whites, 10.9% of
Mexican-Americans, and 5.3% of blacks.
Hashimoto thyroiditis tends to be familial and is
six times more common in women than in men. Its fre-
quency is increased by dietary iodine supplementation.
Certain drugs (amiodarone, interferon-, interferon-,
interleukin-2, G-CSF) frequently induce thyroid autoanti-
bodies. Childhood or occupational exposure to headneck
external beam radiation increases the lifetime risk of
Hashimoto thyroiditis. Subclinical thyroiditis is extremely
common, as evidenced in autopsy series that have found
focal thyroiditis in about 40% of women and 20% of men.
Hashimoto thyroiditis often progresses to hypothy-
roidism, which may be linked to thyrotropin receptor
blocking antibodies, detected in 10% of patients with
Hashimoto thyroiditis. Hypothyroidism is more likely to
develop in smokers than in nonsmokers, possibly due to
the thiocyanates in cigarette smoke. High serum levels of
thyroid peroxidase antibody also predict progression from
subclinical hypothyroidism to symptomatic hypothyroid-
ism. Although the hypothyroidism is usually permanent,
up to 11% of patients experience a remission after several
years. There are two possible causes for such remissions:
(1) the Hashimoto thyroiditis may improve spontane-
ously; and (2) thyroid-stimulating immunoglobulin is
produced in sufficient quantities to overwhelm the
destructive effects of concurrent Hashimoto thyroiditis,
causing the thyroid to produce more thyroid hormone.
Rarely, if the thyroid gland goes on to produce excessive
thyroid hormone, the result is an autoimmune hyperthy-
roidism (see Graves disease).
Hashimoto thyroiditis is sometimes associated with
other endocrine deficiencies as part of polyglandular auto-
immunity (PGA). Adults with type 2 PGA are prone to
autoimmune thyroiditis, diabetes mellitus type 1, autoim-
mune gonadal failure, hypoparathyroidism, and adrenal
insufficiency (see Adrenal Insufficiency). Thyroiditis is asso-
ciated with other autoimmune conditions, such as perni-
cious anemia, Sjgren syndrome, vitiligo, inflammatory
bowel disease, and celiac disease. The incidence of celiac
disease in patients with Hashimoto thyroiditis is about 5%.
Hashimoto thyroiditis is very rarely associated with other
autoimmune conditions such as myocarditis, hypophysitis,
alopecia areata, encephalitis, primary pulmonary hyperten-
sion, or membranous nephropathy. Women with gonadal
dysgenesis (Turner syndrome) have a 15% incidence of sig-
nificant thyroid dysfunction by age 40 years. Thyroiditis is
also commonly seen in patients with hepatitis C.
Painless postpartum thyroiditis refers to autoimmune
thyroiditis that occurs soon after delivery in 7.2% of
women. There is some evidence that the autoimmunity
may be triggered by the accumulation of fetal cells in the
maternal thyroid during pregnancy, a condition known as
CMDT 2013 1121
microchimerism. Women in whom postpartum thyroiditis
develops have a 70% chance of recurrence after subsequent
pregnancies. It occurs most commonly in women who
have high levels of thyroid peroxidase antibody in the first
trimester of pregnancy or immediately after delivery. It is
also more common in women with other autoimmunity or
a family history of Hashimoto thyroiditis.
Painless sporadic thyroiditis is thought to be a sub-
acute form of Hashimoto thyroiditis that is similar to pain-
less postpartum thyroiditis (see above), except that it is not
related to pregnancy. It accounts for about 1% of cases of
thyrotoxicosis.
Subacute thyroiditisalso called de Quervain thyroidi-
tis, granulomatous thyroiditis, and giant cell thyroiditisis
relatively common. It is believed to be caused by a viral
infection and often follows an upper respiratory tract infec-
tion. Its incidence peaks in the summer. It accounts for up to
5% of clinical thyroid disease and young and middle-aged
women are most commonly affected.
Suppurative thyroiditis refers to a nonviral infection of
the thyroid gland. It is usually bacterial. However, myco-
bacterial, fungal, and parasitic infections can occur, par-
ticularly in immunosuppressed individuals. Suppurative
thyroiditis is quite rare, since the thyroid is resistant to
infection, largely due to its high iodine content. It tends to
affect patients with preexistent thyroid disease. Congenital
pyriform sinus fistulas are a cause for recurrent suppura-
tive thyroiditis in otherwise normal individuals.
Riedel thyroiditis is also called invasive fibrous thy-
roiditis, Riedel struma, woody thyroiditis, ligneous thy-
roiditis, and invasive thyroiditis. It is the rarest form of
thyroiditis and is found most frequently in middle-aged or
elderly women. It is usually a manifestation of a multifocal
systemic fibrosis syndrome.
`cClinical Findings
A. Symptoms and Signs
In Hashimoto thyroiditis, the thyroid gland is usually dif-
fusely enlarged, firm, and finely nodular. One thyroid lobe
may be asymmetrically enlarged, raising concerns about
neoplasm. Although patients may complain of neck tight-
ness, pain and tenderness are not usually present. About
10% of cases are atrophic, the gland being fibrotic, particu-
larly in elderly women.
Systemic manifestations are mostly related to ambient
levels of thyroid hormone. However, depression and
chronic fatigue are more common in such patients, even
after correction of hypothyroidism. About one-third of
patients have mild dry mouth (xerostomia) or dry eyes
(keratoconjunctivitis sicca) of an autoimmune nature
related to Sjgren syndrome. It may be associated with
myasthenia gravis, which is usually of mild severity, mainly
affecting the extraocular muscles and having a relatively
low incidence of detectable AChR Ab or thymic disease.
Associated celiac disease can produce fatigue or depression,
often in the absence of gastrointestinal symptoms.
Postpartum thyroiditis is typically manifested by hyper-
thyroidism that begins 16 months after delivery and persists
for only 12 months. Then, hypothyroidism tends to develop
in affected women beginning 48 months after delivery.
 1122 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
Thyrotoxic symptoms in painless sporadic thyroiditis
are usually mild; a small, nontender goiter may be palpated
in about 50% of such patients. High serum thyroid peroxi-
dase antibody concentrations are found in only 50% of
such patients. The course is similar to painless postpartum
thyroiditis.
Subacute thyroiditis presents with an acute, usually
painful enlargement of the thyroid gland, often with dys-
phagia. The pain may radiate to the ears. Patients usually
have a low-grade fever and fatigue. The manifestations may
persist for weeks or months and may be associated with
malaise. If there is no pain, it is called silent thyroiditis.
Thyrotoxicosis develops in 50% of affected patients and
tends to last for several weeks. Subsequently, hypothyroid-
ism develops that lasts 46 months. Normal thyroid func-
tion typically returns within 12 months, but persistent
hypothyroidism develops in 5% of patients.
Patients with suppurative thyroiditis usually are febrile
and have severe pain, tenderness, redness, and fluctuation
in the region of the thyroid gland. In Riedel thyroiditis,
thyroid enlargement is often asymmetric; the gland is stony
hard and adherent to the neck structures, causing signs of
compression and invasion, including dysphagia, dyspnea,
pain, and hoarseness. Related conditions include retroperi-
toneal fibrosis, fibrosing mediastinitis, sclerosing cervicitis,
subretinal fibrosis, and biliary tract sclerosis. It may respond
to therapy with tamoxifen (see Treatment).
B. Laboratory Findings
In Hashimoto thyroiditis with clinically evident disease,
there are usually increased circulating levels of antithyroid
peroxidase (90%) or antithyroglobulin (40%) antibodies.
Antithyroid antibodies decline during pregnancy and are
often undetectable in the third trimester. Once Hashimoto
thyroiditis has been diagnosed, monitoring of these anti-
body levels is not necessary. The serum TSH level is ele-
vated if thyroid hormone is not elaborated in adequate
amounts by the thyroid gland.
Patients with Hashimoto thyroiditis have a 15% inci-
dence of having serum antibodies associated with celiac
disease (sprue, gluten-sensitive enteropathy). At least 5% of
patients with Hashimoto thyroiditis are found to have
clinically significant celiac disease. Although most patients
with celiac disease have gastrointestinal complaints such as
bloating or diarrhea, vague symptoms such as fatigue or
ennui may predominate. Serum levels of IgA endomysial
antibody or IgA tissue transglutaminase (tTG) antibody
may be elevated. However, these antibody levels decline on
a low gluten diet. Many patients with mild celiac disease
have negative serology and a trial of a gluten-free diet is the
most sensitive test.
In subacute thyroiditis, the ESR is markedly elevated
while antithyroid antibody titers are low, distinguishing it
from autoimmune thyroiditis. In suppurative thyroiditis,
both the leukocyte count and ESR are usually elevated.
With hyperthyroidism due to Hashimoto thyroiditis or
subacute thyroiditis, serum FT4 levels tend to be propor-
tionally higher than T3 levels, since the hyperthyroidism is
due to the passive release of stored thyroid hormone, which
is predominantly T4; this is in contrast to Graves disease
CMDT 2013 1122
and toxic nodular goiter, where T3 is relatively more ele-
vated. Because T4 is less active than T3, the hyperthyroidism
seen in thyroiditis is usually less severe. Serum levels of
TSH are suppressed in hyperthyroidism due to thyroiditis.
C. Imaging
Ultrasound in cases of Hashimoto thyroiditis typically shows
a gland with characteristic diffuse heterogeneous density and
hypoechogenicity. Ultrasonography of the thyroid helps dis-
tinguish thyroiditis from multinodular goiter or thyroid
nodules that are suspicious for malignancy. It is also helpful
in guiding FNA biopsy of small suspicious thyroid nodules.
Color-flow Doppler ultrasonography can help distinguish
thyroiditis from Graves disease, since patients with Graves
disease have a hypervascular thyroid gland, whereas in thy-
roiditis there is normal or reduced vascularity.
RAI uptake and scan may be helpful in determining the
cause of hyperthyroidism, distinguishing thyroiditis from
Graves disease, since patients with subacute thyroiditis
exhibit a very low RAI uptake. In patients with chronic
Hashimoto thyroiditis (euthyroid or hypothyroid), RAI
uptake may be normal or high with uneven uptake on the
scan; scanning is not useful in making the diagnosis.
[18F]Fluorodeoxyglucose positron emission tomogra-
phy (18FDG-PET) scanning frequently shows diffuse thy-
roid uptake of isotope in cases of thyroiditis. About 3% of
all 18FDG-PET scans shows such uptake. However, discrete
thyroid nodules can also be discovered on 18FDG-PET
scanning and are known as thyroid PET incidentalomas,
of which 50% are malignant.
D. Fine-Needle Aspiration Biopsy
Patients with Hashimoto thyroiditis who have a thyroid
nodule should have an ultrasound-guided FNA biopsy,
since the risk of papillary thyroid cancer is about 8% in
such nodules. When suppurative thyroiditis is suspected,
an FNA biopsy with Gram stain and culture is required.
FNA biopsy is usually not required for subacute thyroiditis
but shows characteristic giant multinucleated cells.
`cComplications
Hashimoto thyroiditis may lead to hypothyroidism or
transient thyrotoxicosis. Perimenopausal women with high
serum levels of antithyroperoxidase antibodies have a
higher relative risk of depression independently of ambient
thyroid hormone levels.
Pregnant women with Hashimoto thyroiditis have an
increased risk of spontaneous miscarriage in the first trimes-
ter of pregnancy. Hyperthyroidism may develop in patients
with Hashimoto thyroiditis, either due to the emergence of
Graves disease or due to the release of stored thyroid hor-
mone, which is caused by inflammation. The latter condi-
tion has variably been termed hashitoxicosis or painless
sporadic thyroiditis; it is known as postpartum painless
thyroiditis when it occurs in women after delivery.
Patients with Hashimoto thyroiditis have an increased
risk of other autoimmune conditions, such as Addison
disease, hypoparathyroidism, diabetes, pernicious anemia,
biliary cirrhosis, vitiligo, and celiac disease.
 1123 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
In the suppurative forms of thyroiditis, any of the com-
plications of infection may occur; the subacute and chronic
forms of the disease are complicated by the effects of pres-
sure on the neck structures: dyspnea and, in Riedel struma,
vocal cord palsy. Papillary thyroid carcinoma or thyroid
lymphoma may rarely be associated with chronic thyroidi-
tis and must be considered in the diagnosis of uneven pain-
less enlargements that continue in spite of treatment; such
patients require FNA biopsy.
`cDifferential Diagnosis
Thyroiditis must be considered in the differential diagnosis
of all types of goiters, especially if enlargement is rapid.
The very low RAI uptake in subacute thyroiditis with ele-
vated T4 and T3 is helpful. Thyroid autoantibody tests have
been of help in the diagnosis of Hashimoto thyroiditis, but
the tests are not specific and may also be positive in
patients with multinodular goiters, malignancy (eg, thy-
roid carcinoma, lymphoma), and concurrent Graves dis-
ease. The subacute and suppurative forms of thyroiditis
may resemble any infectious process in or near the neck
structures. Chronic thyroiditis, especially if the enlarge-
ment is uneven and if there is pressure on surrounding
structures, may resemble carcinoma, and both disorders
may be present in the same gland.
`cTreatment
A. Hashimoto Thyroiditis
If hypothyroidism is present, levothyroxine should be given
in the usual replacement doses (0.050.2 mg orally daily).
In patients with a large goiter and normal or elevated serum
TSH, an attempt is made to shrink the goiter by administer-
ing levothyroxine in doses sufficient to drive the serum TSH
below the reference range while maintaining clinical euthy-
roidism. Suppressive doses of T4 tend to shrink the goiter an
average of 30% over 6 months. If the goiter does not regress,
lower replacement doses of levothyroxine may be given. If
the thyroid gland is only minimally enlarged and the patient
is euthyroid, regular observation is in order, since hypothy-
roidism may develop subsequentlyoften years later. (See
Hypothyroidism section.)
In one study involving 21 patients with Hashimoto
thyroiditis and subclinical hypothyroidism, simvastatin
(20 mg orally daily) improved thyroid function over
8 weeks, possibly by stimulating apoptosis of certain types
of lymphocytes. In another study, selenium (200 mcg daily
orally for 3 months) reduced the serum levels of anti-
thyroperoxidase antibodies by 49% versus a 10% reduction
in the placebo arm. The long-term effectiveness of simvas-
tatin or selenium therapy on the course of Hashimoto
thyroiditis is unknown.
B. Subacute Thyroiditis
All treatment is empiric and must be continued for several
weeks. Recurrence is common. The drug of choice is
aspirin, which relieves pain and inflammation. Thyrotoxic
symptoms are treated with propranolol, 1040 mg every
6 hours. Iodinated contrast agents cause a prompt fall in
CMDT 2013 1123
serum T3 levels and a dramatic improvement in thyrotoxic
symptoms. Sodium ipodate (Oragrafin, Bilivist) or iopanoic
acid (Telepaque) is given orally in doses of 500 mg orally
daily until serum FT4 levels return to normal. Transient
hypothyroidism is treated with T4 (0.050.1 mg orally
daily) if symptomatic.
C. Suppurative Thyroiditis
Treatment is with antibiotics and with surgical drainage
when fluctuation is marked.
D. Riedel Struma
The treatment of choice is tamoxifen, 20 mg orally twice
daily, which must be continued for years. Tamoxifen can
induce partial to complete remissions in most patients
within 36 months. Its mode of action appears to be unre-
lated to its antiestrogen activity. Short-term corticosteroid
treatment may be added for partial alleviation of pain and
compression symptoms. Surgical decompression usually
fails to permanently alleviate compression symptoms; such
surgery is difficult due to dense fibrous adhesions, making
surgical complications more likely.
`cPrognosis
Hashimoto thyroiditis is occasionally associated with other
autoimmune disorders (diabetes mellitus, Addison disease,
pernicious anemia, etc). In general, however, patients with
Hashimoto thyroiditis have an excellent prognosis, since
the condition either remains stable for years or progresses
slowly to hypothyroidism, which is easily treated. Although
80% of women with postpartum thyroiditis subsequently
recover normal thyroid function, permanent hypothyroid-
ism eventually develops in about 50% within 7 years.
Permanent hypothyroidism is more common in women
who are multiparous or who have had a spontaneous abor-
tion. In subacute thyroiditis, spontaneous remissions and
exacerbations are common; the disease process may smol-
der for months. Papillary thyroid carcinoma carries a rela-
tively good prognosis when it occurs in patients with
Hashimoto thyroiditis.
Boelaert K et al. Prevalence and relative risk of other autoim-
mune diseases in subjects with autoimmune thyroid disease.
Am J Med. 2010 Feb;123(2):183.e19. [PMID: 20103030]
Desailloud R et al. Viruses and thyroiditis: an update. Virol J.
2009 Jan 12;6:5. [PMID: 19138419]
Duntas LH. Environmental factors and autoimmune thyroiditis.
Nat Clin Pract Endocrinol Metab. 2008 Aug;4(8):45460.
[PMID: 18607401]
Eschler DC et al. Cutting edge: the etiology of autoimmune
thyroid disease. Clin Rev Allergy Immunol. 2011 Oct;41(2):
1907. [PMID: 21234711]
Li Y et al. Hashimotos thyroiditis: old concepts and new insights. Curr
Opin Rheumatol. 2011 Jan;23(1):1027. [PMID: 21124092]
Tomer Y. Genetic susceptibility to autoimmune thyroid disease:
past, present, and future. Thyroid. 2010 Jul;20(7):71525.
[PMID: 20604685]
Tran HA et al. The natural history of interferon-alpha induced
thyroiditis in chronic hepatitis C patients: a long term study.
Thyroid Res. 2011 Jan 8;4(1):2. [PMID: 21214950]
 1124 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
THYROID NODULES & MULTINODULAR GOITER
`c ccc
EssEntials of diagnosis
single or multiple thyroid nodules are commonly
`c cccc
found with careful thyroid examinations.
`c cccthyroid function tests mandatory.
`c cccthyroid biopsy for single or dominant nodules or
for a history of prior headneck or chestshoulder
radiation.
`c cccUltrasound examination useful for biopsy and
follow-up.
`c cccClinical follow-up required.
`cGeneral Considerations
Thyroid nodules are extremely common. In Germany, neck
ultrasound screening of adults found a 20% incidence of
thyroid nodules > 1 cm in diameter. Palpable nodules are
found in 5% of women and 1% of men in iodine-sufficient
areas of the world. Palpable thyroid nodules are even more
common in iodine-deficient geographic areas (see Iodine
Deficiency Disorder & Endemic Goiter). Each year in the
United States, about 275,000 thyroid nodules are detected
by palpation, of which 10% are malignant. Palpable thy-
roid nodules are increasingly prevalent with age. On high-
resolution thyroid ultrasound, about 50% of palpable
solitary nodules are found to be just one nodule in a
multinodular goiter.
In recent years, an increased general use of scanning
(CT, MRI, ultrasound, PET) has led to an increased rate of
incidentally detecting nonpalpable thyroid nodules. In fact,
thyroid ultrasound detects thyroid nodules in about 20%
of randomly screened healthy adults.
Although 90% of thyroid nodules are benign, the pres-
ence of a thyroid nodule 1 cm diameter warrants
follow-up and further testing for function and malignancy.
An occasional nodule <1 cm diameter requires follow-up
if it has high-risk characteristics on ultrasound or if the
patient has had prior head-neck radiation therapy. Thyroid
nodules that are incidentally discovered on 18FDG-PET
scanning have a 33% risk for being malignant and defi-
nitely require biopsy.
Most patients with a thyroid nodule are euthyroid, but
there is a high incidence of hypothyroidism or hyperthy-
roidism. Goiter may be caused by numerous conditions,
including multinodular goiter, iodine deficiency, preg-
nancy (in areas of iodine deficiency), Graves disease,
Hashimoto thyroiditis, subacute thyroiditis, or infections.
About 90% of thyroid nodules are benign adenoma, col-
loid nodule, or cyst but may sometimes be a primary thy-
roid malignancy or (less frequently) a metastatic neoplasm.
Patients with multiple thyroid nodules have the same over-
all risk of thyroid cancer as patients with solitary nodules.
The risk of a thyroid nodule being malignant is higher
among patients with a history of headneck radiation, total
body radiation for bone marrow transplantation, exposure
CMDT 2013 1124
to radioactive fallout as a child or teen, a family history of
thyroid cancer or a thyroid cancer syndrome (eg, Cowden
syndrome, multiple endocrine neoplasia type 2, familial
polyposis, Carney syndrome), or a personal history of
another malignancy. The risk of malignancy is also higher
if there is hoarseness or vocal fold paralysis, and if the thy-
roid nodule is large, adherent to the trachea or strap mus-
cles, or associated with lymphadenopathy. The presence of
Hashimoto thyroiditis does not reduce the risk of malig-
nancy; a nodule of 1 cm in a gland with thyroiditis carries
an 8% chance of malignancy.
`cClinical Findings
Table 266 illustrates the approach to the evaluation
of thyroid nodules based on the index of suspicion for
malignancy.
A. Symptoms and Signs
Most small thyroid nodules cause no symptoms. They may
sometimes be detected only by having the patient swallow
during careful inspection and palpation of the thyroid.
A thyroid nodule or multinodular goiter can grow to
become visible and of concern to the patient. Particularly
large nodular goiters can become a cosmetic embarrass-
ment. Nodules can grow large enough to cause discomfort,
hoarseness, or dysphagia. Retrosternal large multinodular
goiters can cause dyspnea due to tracheal compression.
Large substernal goiters may cause superior vena cava syn-
drome, manifested by facial erythema and jugular vein
distention that progress to cyanosis and facial edema when
both arms are kept raised over the head (Pemberton sign).
Depending on their cause, goiters and thyroid nodules
may be associated with hypothyroidism (Hashimoto thy-
roiditis, endemic goiter) or hyperthyroidism (Graves dis-
ease, toxic nodular goiter, subacute thyroiditis, and thyroid
cancer with metastases).
B. Laboratory Findings
A serum TSH level (sensitive assay) should be obtained for
all patients with a thyroid nodule. Patients with a subnor-
mal serum TSH must have further assessment for hyper-
thyroidism and have a radionuclide thyroid scan (123I or
99m
Tc pertechnetate) to determine whether the nodule is
hyperfunctioning; hyperfunctioning nodules are rarely
malignant. Tests for antithyroperoxidase antibodies and
antithyroglobulin antibodies may also be helpful. Very high
antibody levels are found in Hashimoto thyroiditis.
However, thyroiditis frequently coexists with malignancy,
so suspicious nodules should always be biopsied. Serum
calcitonin is obtained if a medullary thyroid carcinoma is
suspected in a family member with a history of familial
medullary thyroid carcinoma or MEN type 2.
C. Imaging
Neck ultrasonography should be performed to measure the
size of a nodule and to determine whether a palpable nod-
ule is part of a multinodular goiter. The following ultra-
sound characteristics of thyroid nodules increase the
 1125 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
Table 266. Clinical evaluation of thyroid nodules.1
Clinical Evidence Low Index of Suspicion
History Family history of goiter; residence in area of
endemic goiter
Physical characteristics Older women; soft nodule; multinodular goiter
Serum factors High titer of antithyroid antibody; hypothyroidism; Elevated serum calcitonin
hyperthyroidism
Fine-needle aspiration biopsy Colloid nodule or adenoma
Scanning techniques
Uptake of 123I Hot nodule
Ultrasonogram Cystic lesion
Roentgenogram Shell-like calcification
Response to thyroxine Regression after 0.050.1 mg/d for 6 months
therapy or more
1
Clinically suspicious nodules should be evaluated with fine-needle aspiration biopsy.
likelihood of malignancy: irregular or indistinct margins,
heterogenous nodule echogenicity, intranodular vascular
images, microcalcifications, complex cyst, or diameter over
1 cm. Ultrasound is also useful for long-term surveillance
of thyroid nodules and multinodular goiter. Ultrasono-
graphy is generally preferred over CT and MRI because of
its accuracy, ease of use, and lower cost.
RAI (123I or 131I) scans have limited usefulness in the
evaluation of thyroid nodules. Hypofunctioning (cold)
nodules have a somewhat increased risk of being malignant
but most are benign. Hyperfunctioning (hot) nodules are
ordinarily benign but may sometimes be malignant. RAI
uptake and scanning is helpful if a patient is found to have
evidence of hyperthyroidism. (See Hyperthyroidism)
CT scanning is helpful for larger thyroid nodules and
multinodular goiter; it can determine the degree of tra-
cheal compression and the degree of extension into the
mediastinum.
D. Incidentally Discovered Thyroid Nodules
Thyroid nodules are frequently discovered as an incidental
finding, with an incidence that depends on the imaging
modality: MRI, 50%; CT, 13%; and 18FDG-PET, 2%. When
such scanning detects a thyroid nodule, an ultrasound is
performed to better determine the nodules risk for malig-
nancy and the need for FNA biopsy, and to establish a
baseline for ultrasound follow-up. The malignancy risk is
about 17% for nodules discovered incidentally on CT or
MRI, and 2550% for nodules discovered incidentally by
18
FDG-PET. For incidentally discovered thyroid nodules of
borderline concern, follow-up thyroid ultrasound in
36 months may be helpful; growing lesions may be biopsied
or resected.
CMDT 2013 1125
High Index of Suspicion
Previous therapeutic radiation of head, neck, or chest;
hoarseness
Young adults, men; solitary, firm nodule; vocal cord
paralysis; enlarged lymph nodes; distant metastatic
lesions
Papillary carcinoma, follicular lesion, medullary or
anaplastic carcinoma
Cold nodule
Solid lesion
Punctate calcification
Increase in size
E. Fine-Needle Aspiration Biopsy
Fine-needle aspiration (FNA) biopsy is the best method to
assess a thyroid nodule for malignancy. FNA biopsy can
be done while patients continue taking anticoagulants or
aspirin. For multinodular goiters, the four largest nodules
( 1 cm diameter) should be biopsied to minimize the risk
of missing a malignancy. For solitary thyroid nodules, FNA
biopsy is indicated for the following: (1) nodules > 5 mm
diameter with a suspicious appearance on ultrasound;
(2) nodules associated with abnormal cervical lymph
nodes; (3) nodules 1 cm diameter that are solid or
have microcalcifications; (4) mixed cystic-solid nodules
1.5 cm diameter with any suspicious features on ultra-
sound or 2 cm diameter with benign features on ultra-
sound; (5) spongiform nodules 2 cm diameter. Pure
cystic nodules are benign and do not require FNA biopsy.
Using ultrasound guidance for FNA biopsy improves the
diagnostic accuracy for both palpable and nonpalpable
thyroid nodules. The chance of an optimal tissue sampling
is also improved by having an experienced clinician per-
form the FNA biopsy and by having the aspirate inter-
preted by a skilled cytopathologist.
In one review of thyroid FNA biopsies, about 70% were
benign, 5% were malignant, 10% were suspicious, and
15% were nondiagnostic. Nondiagnostic, bloody, or
hypocellular FNA biopsies should be repeated under ultra-
sound guidance; nodules that continue to have nondiag-
nostic cytology should be monitored closely; those that are
solid or that grow should be resected.
When FNA cytology is suspicious for papillary thy-
roid carcinoma or Hrthle cell neoplasm, the risk of malig-
nancy is 57%. When FNA cytology yields a suspicious
follicular lesion, the overall risk of the lesion being malignant
 1126 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
is about 2025%. The risk that a follicular lesion is malig-
nant increases for patients who are much younger or older
than age 50. Most patients with suspicious FNA cytology
are advised to have surgery.
Cystic nodules yielding serous fluid are usually benign,
but the aspirate should be submitted for cytologic testing.
Cystic nodules yielding bloody fluid have a higher chance
of being malignant.
False-positive thyroid FNA biopsy results occur at a rate
of about 4%. False-negative thyroid FNA biopsy results
also occur at an overall rate of about 4%, less commonly
when performed under ultrasound guidance and inter-
preted by cytopathologists. False-negative results delay
surgical excision and lead to an increased risk of vascular
and capsular invasion by the malignancy. Some false-
negative FNA biopsy results may not have actually been
inaccurate, since truly benign thyroid nodules can later
become malignant. Patients who have a negative thyroid
FNA should have observational follow-up, ideally with
both palpation and ultrasound; nodules that continue to
grow should be rebiopsied or excised.
`cTreatment
All thyroid nodules, including those that are benign, need
to be monitored by regular periodic palpation and ultra-
sound and rebiopsied if growth occurs. A toxic multi-
nodular goiter and hyperthyroidism, associated with the
ingestion or intravenous administration of large amounts
of iodine, may develop in patients with multinodular
goiters. It is therefore prudent to minimize excessive
dietary iodine intake and intravenous iodinated contrast.
Patients found to have hyperthyroidism may have a RAI
uptake and scan for additional evaluation, especially if
131
I is a therapeutic consideration. Patients with toxic mul-
tinodular goiters may also be treated with methimazole,
propranolol, or surgery (see Hyperthyroidism section).
A. Levothyroxine Suppression Therapy
Patients with elevated levels of serum TSH are treated with
levothyroxine replacement. Otherwise, for small benign
thyroid nodules, levothyroxine suppression therapy is not
recommended. For larger nodules (> 2 cm), if TSH levels
are elevated or normal, TSH suppression with levothyrox-
ine (starting doses of 50 mcg orally daily) can be consid-
ered. Thyroxine suppression therapy is most successful in
iodine-deficient areas of the world and less successful in
iodine-sufficient regions. Long-term levothyroxine sup-
pression of TSH tends to keep nodules from enlarging, but
only 20% shrink more than 50%. In one 5-year study, thy-
roid nodule size increased in 29% of patients treated with
levothyroxine, compared to growth in 56% of nodules in
patients not receiving levothyroxine. Levothyroxine sup-
pression also reduces the emergency of new nodules: 8%
with levothyroxine and 29% without levothyroxine.
Levothyroxine suppression therapy is not usually given to
patients with cardiac disease, since it increases the risk for
angina and atrial fibrillation. Levothyroxine suppression
causes a small loss of bone density, particularly in post-
menopausal women if the serum TSH is suppressed to
CMDT 2013 1126
< 0.05 mU/L. Such patients are advised to have bone den-
sity testing every 35 years. Levothyroxine should not be
administered if the baseline TSH is low, since that is an
indication of autonomous thyroid secretion, such that
levothyroxine therapy will be ineffective and liable to cause
clinical thyrotoxicosis.
Levothyroxine suppression needs to be carefully moni-
tored, since it carries a 17% risk of inducing symptoms of
hyperthyroidism. This can occur due to excessive levothy-
roxine dosing, the emergence of an autonomous or toxic
nodule or Graves disease, or a reduction in thyroid binding
globulin seen in early menopause or with discontinuing
oral estrogen therapy. Therefore, coronary insufficiency
and cardiac arrhythmias are relative contraindications to
levothyroxine suppression. All patients receiving levothy-
roxine suppression therapy should have serum TSH levels
monitored regularly, with the dose of levothyroxine
adjusted to keep the serum TSH mildly suppressed between
0.2 mU/L and 0.8 mU/L. Thyroid nodules require careful
clinical evaluation and thyroid palpation or ultrasound
examinations about every 6 months initially. After several
years of stability, yearly examinations are sufficient.
B. Potassium Iodide
Additional suppression of thyroid nodules may be obtained
by adding oral potassium iodide, 150 mcg daily, to levothy-
roxine suppression therapy (see above) for patients with
thyroid nodules 1 cm in diameter. In a German study, the
addition of potassium iodide to levothyroxine further
decreased thyroid nodule size over the course of 1 year.
However, the study excluded children; pregnant women;
non-whites; and patients with autoimmune thyroid dis-
ease, autonomous nodules, consumption of other iodine-
containing medications, dermatitis herpetiformis, or iodine
allergy. The long-term risk of administering potassium
iodide to iodine-sufficient patients is unknown.
C. Surgery
Total thyroidectomy is required for thyroid nodules that are
malignant on FNA biopsy (see Thyroid Cancer section).
More limited thyroid surgery is indicated for benign nodules
with indeterminate or suspicious cytologic test results, com-
pression symptoms, discomfort, or cosmetic embarrass-
ment. Surgery may also be used to remove hyperfunctioning
hot thyroid adenomas or toxic multinodular goiter caus-
ing hyperthyroidism (see Hyperthyroidism section).
D. Percutaneous Ethanol Injection
Thyroid cysts can be aspirated, but cystic fluid recurs in
75% of patients. Percutaneous ethanol injection has been
used to shrink pure cysts; it must often be repeated, but the
success rate is 80%. Percutaneous ethanol injection can
also be used to shrink benign (biopsy proven) thyroid nod-
ules. The complication rate is about 9%, but serious or
permanent complications are rare.
E. Radioiodine (131I) Therapy
Radioactive 131I is a treatment option for hyperthyroid
patients with toxic thyroid adenomas, multinodular goiter,
 1127 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
or Graves disease (see Hyperthyroidism section). It may also
be used to shrink benign nontoxic thyroid nodules. Thyroid
nodules shrink an average of 40% by 1 year and 59% by
2 years after 131I therapy. Nodules that shrink after 131I ther-
apy generally remain palpable and become firmer; they may
develop unusual cytologic characteristics on FNA biopsy. 131I
therapy may be used to shrink large multinodular goiter but
may rarely induce Graves disease. Hypothyroidism is a risk
and may occur years after 131I therapy, so it is advisable to
assess thyroid function every 3 months for the first year,
every 6 months thereafter, and immediately for symptoms of
hypothyroidism or hyperthyroidism.
`cPrognosis
The great majority of thyroid nodules are benign. Benign
thyroid nodules may involute but usually persist or grow
slowly. About 90% of thyroid nodules will increase their
volume by 15% over 5 years; cystic nodules are less likely
to grow. Cytologically benign nodules that grow are unlikely
to be malignant; in one series, only 1 of 78 rebiopsied nod-
ules was found to be malignant. The prognosis for patients
with thyroid nodules that prove to be malignant is deter-
mined by the histologic type and other factors (see below).
Multinodular goiters tend to persist or grow slowly, even in
iodine-deficient areas where iodine repletion usually does
not shrink established goiters. Patients with very small, inci-
dentally discovered, nonpalpable thyroid nodules do require
follow-up with thyroid ultrasound every 12 years but are at
low risk for malignancy. Nodules that are malignant have a
minor effect on morbidity and mortality.
Bahn RS et al. Approach to the patient with nontoxic multi-
nodular goiter. J Clin Endocrinol Metab. 2011 May;96(5):
120112. [PMID: 21543434]
Bastin S et al. Role of ultrasound in the assessment of nodular
thyroid disease. J Med Imaging Radiat Oncol. 2009 Apr;53(2):
17787. [PMID: 19527364]
Grussendorf M et al. Reduction of thyroid nodule volume by
levothyroxine and iodine alone and in combination: a ran-
domized, placebo-controlled trial. J Clin Endocrinol Metab.
2011 Sept;96(9):278695. [PMID: 21715542]
Kim DW et al. Ultrasound-guided fine-needle aspiration biopsy
of thyroid nodules: comparison in efficacy according to nod-
ule size. Thyroid. 2009 Jan;19(1):2731. [PMID: 19021460]
Mihai R et al. One in four patients with follicular thyroid
cytology (THY3) has a thyroid carcinoma. Thyroid. 2009
Jan;19(1):337. [PMID: 18976164]
THYROID CANCER
`c ccc
EssEntials of diagnosis
Painless swelling in region of thyroid.
`c ccc
`c ccc thyroid function tests usually normal.
`c ccc Past history of irradiation to head and neck region
may be present.
`c cccPositive thyroid needle aspiration.
CMDT 2013 1127
`cGeneral Considerations
The incidence of papillary and follicular (differentiated)
thyroid carcinomas increases with age. The overall
female:male ratio is 3:1. The yearly incidence of thyroid
cancer has been increasing in the United States, with the
number of cases diagnosed annually reaching 37,200,
probably as a result of the wider use of CT, MRI, PET, and
ultrasound that incidentally find small thyroid malignan-
cies. Thyroid cancer mortality has been stable, accounting
for about 1500 deaths in the United States annually.
Thyroid microcarcinoma ( 10 mm diameter) is found
with the surprising frequency of 35%. Clearly, most thy-
roid cancers remain microscopic and indolent. However,
larger thyroid cancers (palpable or 1 cm in diameter) are
more malignant and require treatment.
Papillary thyroid carcinoma is the most common thy-
roid malignancy (Table 267).
Pure papillary and mixed papillary-follicular carcinoma
represent about 80% of all thyroid cancers. It usually pres-
ents as a single thyroid nodule, but it can arise out of a
multinodular goiter. Papillary thyroid carcinoma is com-
monly multifocal within the gland, with other foci usually
arising de novo rather than representing intraglandular
metastases. About 10% of cases present with palpable cer-
vical lymph node metastases from a small thyroid cancer.
Papillary thyroid carcinomas tend to grow slowly and often
remain confined to the thyroid and regional lymph nodes
for years. However, they may become more aggressive,
especially in patients over age 45 years, and most particu-
larly in the elderly. The cancer may invade the trachea and
local muscles and may spread to the lungs.
Papillary thyroid carcinoma is caused by genetic muta-
tions or translocations. Activating mutations of the ras
oncogene can cause benign thyroid adenomas or nodular
goiter. Additional activating mutations in BRAF or TRK
genes can lead to papillary carcinoma. About 45% of papil-
lary thyroid carcinomas are caused by over expression of
the ret oncogene by the translocation of certain gene pro-
moters to it, producing retPTC-1, retPTC-2, or retPTC-3.
Radiation treatments to the head and neck region tend to
cause retPTC-1. Nuclear fallout exposure tends to cause
retPTC-3, resulting in more aggressive papillary thyroid
carcinomas. Additional loss of the p53 tumor suppressor
gene can cause progression of papillary thyroid carcinoma
to anaplastic thyroid carcinoma.
Exposure to head and neck radiation therapy poses a
particular threat to children who then have an increased
lifetime risk of developing thyroid pathology, including
papillary thyroid carcinoma; thyroid malignancy may
emerge between 10 and 40 years after exposure, with a peak
occurrence 2025 years later. After an explosion at the
Chernobyl Nuclear Plant in the Ukraine in 1986, the risk of
developing papillary thyroid carcinoma was highest among
children who were under age 5 at the time of exposure to
radiation; emergence of more aggressive papillary thyroid
carcinoma occurred within 67 years after exposure.
Papillary thyroid carcinoma can occur in familial syn-
dromes as an autosomal dominant trait, caused by loss of
various tumor suppressor genes. Such syndromes (with
associated features) include familial papillary carcinoma
 1128 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
Table 267. some characteristics of thyroid cancer.
Papillary Follicular
Incidence Most common Common
Average age 42 50
Females 70% 72%
Invasion
Juxtanodal +++++ + ++++++
Blood vessels + +++
Distant sites + +++
123I uptake + ++++
Mortality + + + to + + +
(with papillary renal carcinoma); familial nonmedullary
thyroid carcinoma; familial polyposis (with large intestine
polyps and gastrointestinal tumors); Gardner syndrome
(with small and large intestine polyps, fibromas, lipomas,
osteomas); and Turcot syndrome (with large intestine
polyps and brain tumors). Older patients with multinodu-
lar goiter may rarely develop a papillary thyroid carcinoma.
Papillary carcinoma can sometimes undergo a late anaplas-
tic transformation into an aggressive carcinoma.
Generally speaking, papillary carcinoma is the least
aggressive thyroid malignancy. However, the tumor spreads
via lymphatics within the thyroid, appearing to be multifo-
cal in 60% of patients and involving both lobes in 30% of
patients. About 80% of patients have microscopic metasta-
ses to cervical lymph nodes. Unlike other forms of cancer,
patients with papillary thyroid carcinoma who have pal-
pable lymph node metastases do not have a particularly
increased mortality rate; however, their risk of local recur-
rence is increased.
Occult metastases to the lung occur in 1015% of papil-
lary thyroid cancer. About 70% of small lung metastases
resolve following 131I therapy; however, larger pulmonary
metastases have only a 10% remission rate.
Microscopic micropapillary carcinoma ( 1 mm and
invisible even on thyroid ultrasound) is a variant of nor-
mal, being found in 24% of thyroidectomies performed for
benign thyroid disease when 2-mm sections were carefully
examined. It thus appears that the overwhelming majority
of these microscopic foci never become clinically signifi-
cant. The surgical pathology report of such a tiny papillary
carcinoma that is otherwise benign does not justify aggres-
sive follow-up or treatment because a cancer diagnosis is
unwarranted and harmful. All that may be required is
yearly follow-up with palpation of the neck and mild TSH
suppression by thyroxine.
Follicular thyroid carcinoma and its variants (eg,
Hrthle cell carcinoma) account for about 14% of thyroid
malignancies; follicular thyroid carcinoma is generally
more aggressive than papillary carcinoma. Rarely, some fol-
licular carcinomas secrete enough T4 to cause thyrotoxicosis
if the tumor load becomes significant. Metastases commonly
CMDT 2013 1128
Medullary Undifferentiated
Uncommon Uncommon
50 57
56% 56%
+++
+++ + + ++ +
++ ++++
0 0
+ to + + + + ++++++++
are found in neck nodes, bones, and lungs. Most follicular
thyroid carcinomas avidly absorb iodine, making possible
diagnostic scanning and treatment with 131I after total
thyroidectomy. The follicular histopathologic features that
are associated with a high risk of metastasis and recurrence
are poorly differentiated and Hrthle cell (oncocytic) vari-
ants. The latter variants do not take up RAI.
Follicular carcinoma results from certain gene muta-
tions or translocations. Aberrant DNA methylation, activa-
tion of the ras oncogene, and mutations of the MEN1 gene
can result in benign follicular adenomas. Loss of function
of PPAR or the 3P tumor suppressor gene can lead to fol-
licular carcinoma, and additional loss of the p53 tumor
suppressor gene can produce anaplastic carcinoma.
Follicular thyroid carcinoma and adenomas develop in
patients with Cowden disease, a rare autosomal dominant
familial syndrome caused by loss of a tumor suppressor
gene; such patients tend to have macrocephaly, multiple
hamartomas, early-onset breast cancer, intestinal polyps,
facial papules, and other skin and mucosal lesions.
Medullary thyroid carcinoma represents about 3% of
thyroid cancers. About one-third of cases are sporadic,
one-third are familial, and one-third are associated with
MEN type 2. Medullary thyroid carcinoma is often caused
by an activating mutation of the ret oncogene on chromo-
some 10. Mutation analysis of the ret oncogene exons 10,
11, 13, and 14 detects 95% of the mutations causing MEN
2A and 90% of the mutations causing familial medullary
thyroid carcinoma. Patients with MEN 2B have activating
mutations in exon 16 of the ret oncogene. These germline
mutations can be detected by DNA analysis of peripheral
WBCs. Therefore, discovery of a medullary thyroid carci-
noma makes genetic analysis mandatory. If a gene defect is
discovered, related family members must have genetic
screening for that specific gene defect. When a family
member with MEN 2A or familial medullary thyroid carci-
noma does not have an identifiable ret oncogene mutation,
gene carriers may still be identified using family linkage
analysis. Even when no gene defect is detectable, family
members should have thyroid surveillance every 6 months.
Somatic mutations of the ret oncogene can be identified in
 1129 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
the tumors of 30% of patients with sporadic (nonfamilial)
medullary thyroid carcinoma. (See Multiple Endocrine
Neoplasia.)
Medullary thyroid carcinoma arises from parafollicular
thyroid cells that can secrete calcitonin, prostaglandins,
serotonin, ACTH, corticotropin-releasing hormone (CRH),
and other peptides. These peptides can cause symptoms
and can be used as tumor markers. Early local metastases
are usually present, usually to adjacent muscle and trachea
as well as to local and mediastinal lymph nodes. Eventually,
late metastases may appear in the bones, lungs, adrenals, or
liver. Medullary thyroid carcinoma does not concentrate
iodine.
Anaplastic thyroid carcinoma represents about 2% of
thyroid cancers. It usually presents in an older patient as a
rapidly enlarging mass in a multinodular goiter. It is the
most aggressive thyroid carcinoma and metastasizes early
to surrounding nodes and distant sites. Local pressure
symptoms include dysphagia or vocal cord paralysis. This
tumor does not concentrate iodine.
Anaplastic thyroid carcinoma is caused by certain gene
mutations, including inactivating mutations of the p53
tumor suppressor gene, as described above for papillary
and follicular thyroid carcinomas.
Other thyroid malignancies together represent about
3% of thyroid cancers. Lymphoma of the thyroid is more
common in older women. Thyroid lymphomas are most
commonly B cell lymphomas (50%) or mucosa-associated
lymphoid tissue (MALT; 23%); other types include
follicular, small lymphocytic, and Burkitt lymphoma and
Hodgkin disease. Thyroidectomy is rarely required. Other
cancers may sometimes metastasize to the thyroid, partic-
ularly bronchogenic, breast, and renal carcinomas and
malignant melanoma.
`cClinical Findings
A. Symptoms and Signs
Thyroid carcinoma usually presents as a palpable, firm,
nontender nodule in the thyroid. Most thyroid carcinomas
are asymptomatic, but large thyroid cancers can cause neck
discomfort, dysphagia, or hoarseness (due to pressure on
the recurrent laryngeal nerve). About 3% of thyroid malig-
nancies present with a metastasis, usually to local lymph
nodes but sometimes to distant sites such as bone or lung.
Palpable lymph node involvement is present in 15% of
adults and 60% of youths. Metastatic functioning differen-
tiated thyroid carcinoma can sometimes secrete enough
thyroid hormone to produce thyrotoxicosis. Anaplastic
thyroid carcinoma is more apt to be advanced at the time
of diagnosis, presenting with dysphagia, hoarseness, dysp-
nea, and metastases to the lungs. Occasionally, such carci-
nomas may be discovered while they are still relatively
small and localized.
Medullary thyroid carcinoma frequently causes flush-
ing and persistent diarrhea (30%), which may be the initial
clinical feature. Patients with metastases often experience
fatigue as well as other symptoms. Cushing syndrome
develops in about 5% of patients from secretion of ACTH
or CRH. Signs of pressure or invasion of surrounding tissues
CMDT 2013 1129
are present in anaplastic or large tumors; recurrent laryn-
geal nerve palsy can occur.
Lymphoma usually presents as a rapidly enlarging,
painful mass arising out of a multinodular or diffuse goiter
affected by autoimmune thyroiditis, with which it may be
confused microscopically. About 20% of cases have con-
comitant hypothyroidism.
B. Laboratory Findings
(FNA biopsy is discussed above in the section on Thyroid
Nodules.) Thyroid function tests are generally normal
unless there is concomitant thyroiditis. Follicular carci-
noma may secrete enough T4 to suppress TSH and cause
clinical hyperthyroidism.
Serum thyroglobulin is high in most metastatic papillary
and follicular tumors, making this a useful marker for
recurrent or metastatic disease. Caution must be exercised
for the following reasons: (1) Circulating antithyroglobulin
antibodies can cause erroneous thyroglobulin determina-
tions. (2) Thyroglobulin levels may be misleadingly ele-
vated in thyroiditis, which often coexists with carcinoma. (3)
Certain thyroglobulin assays falsely report the continued
presence of thyroglobulin after total thyroidectomy and
tumor resection, causing undue concern about possible
metastases. Therefore, unexpected thyroglobulin levels
should prompt a repeat assay in another reference laboratory.
Serum calcitonin levels are usually elevated in medul-
lary thyroid carcinoma, making this a marker for meta-
static disease. However, serum calcitonin may be elevated
in many other conditions, such as thyroiditis; pregnancy;
azotemia; hypercalcemia; and other malignancies, includ-
ing pheochromocytomas, carcinoid tumors, and carcino-
mas of the lung, pancreas, breast, and colon.
In patients with medullary thyroid carcinoma, serum
calcitonin and carcinoembryonic antigen (CEA) determi-
nations should be obtained before surgery, then regularly
in postoperative follow-up: every 4 months for 5 years,
then every 6 months for life. In patients with extensive
metastases, serum calcitonin should be measured in the
laboratory with serial dilutions. Calcitonin levels remain
elevated in patients with persistent tumor but also in some
patients with apparent cure or indolent disease. Therefore,
rising levels of calcitonin (or CEA) are the best indication
for recurrence. Serum calcitonin levels > 250 pg/mL are
also an indication for recurrent or metastatic medullary
thyroid carcinoma. Serum CEA levels are usually elevated
with medullary carcinoma, making this a useful second
marker; however, it is not specific for this carcinoma.
C. Imaging
1. Ultrasound of the neckUltrasound of the neck
should be performed routinely on all patients with thyroid
cancer for the initial diagnosis and for follow-up.
Ultrasound is useful in determining the size and location
of the malignancy as well as the location of any neck
metastases.
2. Radioactive iodine scanningRAI (131I or 123I) thy-
roid and whole-body scanning is used after thyroidectomy
for surveillance as described below, supplanting its previous
 1130 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
use to determine whether a nodule was cold as a sign of
malignancy.
3. CT and MRI scanningCT scanning may demonstrate
metastases and is particularly useful for localizing and
monitoring lung metastases. However, CT scanning is less
sensitive than ultrasound for detecting metastases within
the neck. Iodinated contrast should never be given prior to
RAI scanning or RAI therapy, since the large amounts of
iodine in contrast media competitively inhibit the uptake
of RAI by the thyroid, greatly reducing the effectiveness of
subsequent RAI scanning and therapy. Medullary carci-
noma in the thyroid, nodes, and liver may calcify, but lung
metastases rarely do so. MRI is particularly useful for imag-
ing bone metastases.
4. PET scanningPET scanning is particularly useful for
detecting thyroid cancer metastases that do not have suffi-
cient iodine uptake to be visible on RAI scans. Metastases
are best detected using 18FDG-PET whole-body scanning.
The sensitivity of 18FDG-PET scanning for differentiated
thyroid cancer is enhanced if the patient is hypothyroid or
receiving thyrotropin, which increases the metabolic activ-
ity of differentiated thyroid cancer. Disadvantages of PET
scanning include its lack of specificity for thyroid cancer as
well as its expense and lack of availability in some loca-
tions. 18FDG-PET scanning has prognostic implications,
since differentiated thyroid cancer metastases with low
standard uptake value (SUV) scores are associated with a
better prognosis.
`cDifferential Diagnosis
Neuroendocrine carcinomas may metastasize to the thy-
roid and be confused with medullary thyroid carcinoma.
False-positive 131I scans are common with normal
residual thyroid tissue and have been reported with Zenker
diverticulum, struma ovarii, pleuropericardial cyst, gastric
pull-up, and 131I-contaminated bodily secretions. False-
negative 131I scans are common in early metastatic differen-
tiated thyroid carcinoma but occur also in more advanced
disease, including 14% of bone metastases.
`cComplications
The complications vary with the type of carcinoma.
Differentiated thyroid carcinomas may have local or distant
metastases. One-third of medullary carcinomas may secrete
serotonin and prostaglandins, producing flushing and diar-
rhea, and may be complicated by the coexistence of pheo-
chromocytomas or hyperparathyroidism. The risks of
radical neck surgery include permanent hypoparathyroid-
ism and vocal cord palsy due to recurrent laryngeal nerve
damage; permanent hypothyroidism is expected after thy-
roidectomy and should always be treated adequately.
`cTreatment of Differentiated
Thyroid Carcinoma
A. Surgical Treatment
Surgical removal is the treatment of choice for thyroid carci-
nomas. Neck ultrasound is obtained preoperatively, since
CMDT 2013 1130
suspicious cervical lymphadenoapathy is detected in about
25%. Intraoperative thyroid ultrasound by the surgeon also
helps assess the extent of the tumor and lymph node
involvement, altering surgical treatment in many cases. For
differentiated papillary and follicular carcinoma > 1 cm
diameter, total thyroidectomy is performed with limited
removal of cervical lymph nodes. For medullary thyroid
carcinoma, repeated neck dissections are often required.
For indeterminate nodules, surgery consists of a thy-
roid lobectomy for an indeterminate follicular lesion that
is 4 cm diameter. If malignancy is diagnosed on pathol-
ogy, a completion thyroidectomy is performed. For inde-
terminate follicular lesions > 4 cm diameter that are at
higher risk for being malignant, a bilateral thyroidectomy
is performed as the initial surgery. Higher risk lesions
include those with a FNA biopsy that shows marked atypia
or that are suspicious for papillary carcinoma and those
that occur in patients with a history of radiation exposure
or a family history of thyroid carcinoma.
For biopsies that are diagnostic of malignancy, sur-
gery involves lobectomy alone for papillary thyroid carci-
nomas < 1 cm diameter in patients under age 45 years who
have no history of head and neck irradiation and no evi-
dence of lymph node metastasis on ultrasonography. Other
patients should have a total or near total thyroidectomy.
The advantage of near-total thyroidectomy for differenti-
ated thyroid carcinoma is that multicentric foci of carci-
noma are more apt to be resected. Also, there is less normal
thyroid tissue to compete with cancer for 131I administered
later for scans or treatment. A central neck lymph node
dissection is performed at the time of thyroidectomy for
patients with nodal metastases that are clinically evident. A
lateral neck dissection is performed for patients with
biopsy-proven lateral cervical lymphadenopathy. Neck
muscle resections are usually avoided for differentiated
thyroid carcinoma. However, patients with the Hrthle cell
variant of follicular carcinoma may benefit from a
modified radical neck dissection. Metastases to the brain
are best treated surgically, since treatment with radiation or
RAI is ineffective. Levothyroxine is prescribed in doses of
0.050.1 mg orally daily immediately postoperatively (see
Thyroxine Suppression and Chemotherapy, below). About
24 months after surgery, patients require reevaluation and
often require therapy with 131I (see below).
Permanent injury to one recurrent laryngeal nerve
occurs in between 12% and 7% of patients, depending
on the experience of the surgeon. Bilateral nerve palsies
are rare. Temporary recurrent laryngeal nerve palsies
occur in another 5% but often resolve within 6 months.
After total thyroidectomy, temporary hypoparathyroid-
ism occurs in 20% and becomes permanent in about 2%.
The incidence of hypoparathyroidism may be reduced
if accidentally resected parathyroids are immediately
autotransplanted into the neck muscles. Thyroide-
ctomy requires at least an overnight hospital admission,
since late bleeding, airway problems, and tetany can
occur. Ambulatory thyroidectomy is potentially danger-
ous and should not be done. Following surgery, staging
(Table 268) should be done to help determine prognosis
and to plan therapy and follow-up.
 1131 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
Table 268. Pathologic tumor-node-metastasis (ptnM) staging and tumor-related approximate survival rates
for adults with appropriately treated differentiated (papillary) thyroid carcinoma based upon patient age,
primary tumor size and invasiveness (t), lymph node involvement (n), and distant metastases (M).1
Stage Description
I Under 45: any T, any N, no M
Over 45: T 1 cm, no N, no M
II Under 45: any T, any N, any M
Over 45: T > 1 cm limited to thyroid, no N, no M
III Over 45: T > 4 cm limited to thyroid, no N, no M; or any T
limited to thyroid, regional N, no M
IV Over 45: T local invasion, any N, any M; or T extensive
invasion, any N, no M; or any T, any N, distant M
1Patients having a relatively worse prognosis include those with familial differentiated thyroid carcinoma.
In pregnant women with thyroid cancer, surgery is usu-
ally delayed until after delivery, except for fast-growing
tumors that may be resected after 24 weeks gestation; there
has been no difference in survival or tumor recurrence
rates in women who underwent surgery during or after
their pregnancy. Differentiated thyroid carcinoma does not
behave more aggressively during pregnancy. But there is a
higher risk of complications in pregnant women undergo-
ing thyroid surgery, compared to nonpregnant women.
B. Thyroxine Suppression and Chemotherapy
Patients who have had a thyroidectomy for differentiated
thyroid cancer must take thyroxine replacement for life.
Oral thyroxine should be given in doses that suppress serum
TSH without causing clinical thyrotoxicosis. An ultrasensi-
tive TSH assay should be used; serum TSH should be sup-
pressed below 0.1 mU/L for patients with stage II disease
and below 0.05 mU/L for patients with stage IIIIV disease.
(See Table 268.) Although patients receiving thyroxine
suppression therapy (TSH < 0.05 mU/L) are at risk for a
lower bone density than age-matched controls, the adverse
effect upon bone density and fracture risk is relatively
minor for patients who remain clinically euthyroid.
Nevertheless, patients receiving thyroxine suppression ther-
apy are advised to have periodic bone densitometry.
Zoledronic acid, an intravenous bisphosphonate, has
proven useful for osteolytic metastases from other solid
tumors and has been used for patients with thyroid bone
metastases, but its effectiveness is unknown.
Thyroid carcinomas are extraordinarily resistant to
chemotherapy. Sorafenib and sunitinib are tyrosine
kinase inhibitors that have shown some activity against
metastatic differentiated thyroid carcinomas that are
radioiodine-resistant, with partial responses in 20% and
stable disease in 60%.
C. Radioactive Iodine (131I) Therapy
Differentiated thyroid cancers variably retain the normal
thyroids ability to respond to TSH, secrete thyroglobulin,
and concentrate iodine. There are two reasons to treat
CMDT 2013 1131
Five-Year Survival Ten-Year Survival
99% 98%
99% 90%
95% 75%
85% 65%
patients with 131I after thyroidectomy: (1) thyroid remnant
ablation and (2) treatment of known or suspected thyroid
cancer. 131I is usually administered 24 months after
surgery. Treatment with 131I is repeated 912 months later
if surveillance RAI scanning shows evidence of metastatic
disease. (See Surveillance, below.)
Before starting 131I therapy, patients follow a low iodine
diet for at least 2 weeks. The low iodine diet consists of
avoiding the following: iodized table salt, sea salt, fish,
shellfish, seaweed, commercial bread, dairy products, pro-
cessed meats, canned or dried fruit, canned fruit juices,
highly salted soups and snack foods, black tea, instant
coffee, food coloring with Red Dye #3, egg yolks, multivita-
mins with iodine, or topical iodine. Patients must not be
given amiodarone or intravenous radiologic contrast dyes
containing iodine.
1. Thyroid remnant ablationA small dose of 30 mCi
(1110 MBq) 131I is given for remnant ablation of residual
normal thyroid tissues after surgery for differentiated thy-
roid cancer. This small dose of 131I is given to patients with
no lymph node involvement who are at low risk for metas-
tases. There are several advantages for giving thyroid rem-
nant ablation: (1) There is usually remnant normal tissue
that can produce thyroglobulin (a useful tumor marker);
(2) Remnant ablation using 131I may destroy microscopic
deposits of cancer; (3) The post-therapy scan may visualize
metastatic cancer that would otherwise have been invisible.
However, 131I remnant ablation has not been useful for
patients with stage I papillary thyroid carcinomas < 1 cm
diameter that are unifocal or multifocal. Such very low-risk
patients may have close surveillance without receiving
remnant ablation.
2. Treatment of metastasesRAI therapy improves
survival and reduces recurrence rates for patients with
stage III-IV cancer and those with stage II cancer having
gross extrathyroidal extension. RAI therapy is also given
to patients with stage II cancer who have distant metasta-
ses, a primary tumor > 4 cm diameter, or primary tumors
14 cm diameter with lymph node metastases or other
high-risk features. Brain metastases do not usually respond
 1132 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
to 131I and are best resected or treated with gamma knife
radiosurgery (Table 268). A post-therapy whole-body
scan is performed 210 days after 131I therapy.
Staging with RAI scanning or 18FDG-PET/CT scanning
assists dosing decisions for 131I therapy. Radioiodine doses
of 50100 mCi are given to patients with large primary
tumors or tumors at the surgical margin. Patients with
local lymph node involvement typically receive 100 mCi of
131
I; patients with more extensive neck node involvement,
regional or distant metastases receive 131I at a dose of
125200 mCi (46257400 MBq). Unfortunately, about
35% of patients with differentiated thyroid carcinoma have
poor uptake of 131I into metastases. Patients with asymp-
tomatic, stable, radioiodine-resistant metastases may be
carefully monitored for tumor progression.
Some patients have elevated serum thyroglobulin levels
but a negative whole-body radioiodine scan and a negative
neck ultrasound. In such patients, an 18F-FDG PET/CT
scan is obtained. If all scans are negative, empiric therapy
with 131I is not useful.
Doses of 131I over 100 mCi (3800 MBq) can cause gas-
tritis, temporary oligospermia, sialadenitis, and xerosto-
mia. RAI therapy can cause neurologic decompensation in
patients with brain metastases; it is advisable to treat such
patients with prednisone 3040 mg orally daily for several
days before and after 131I therapy. Cumulative doses of 131I
over 500 mCi can cause infertility, pancytopenia (4%), and
leukemia (0.3%). Pulmonary fibrosis can occur in patients
with diffuse lung metastases after receiving cumulative 131I
activities of > 600 mCi (22 GBq). The kidneys excrete RAI,
so patients receiving dialysis for kidney disease require a
dosage reduction to only 20% of the usual dose of 131I.
3. rhTSH-stimulated 131I therapy, thyroglobulin, and
scanRecombinant human thyroid stimulating hormone
(rhTSH, Thyrogen) is given to increase the sensitivity of
serum thyroglobulin for residual cancer and to increase the
uptake of 131I into residual thyroid tissue (thyroid remnant
ablation) or cancer. Thyrogen must be kept refrigerated
and is administered according to the following protocol:
Thyroxine replacement is held for 2 days before rhTSH and
for 3 days afterward. rhTSH 0.9 mg is administered intra-
gluteally (not intravenously) daily for 2 consecutive days.
On the third day, blood is drawn: serum TSH is assayed to
confirm that it is > 30 mcU/mL; serum hCG is measured in
reproductive-age women to screen for pregnancy; and
serum thyroglobulin is measured as a tumor marker. RAI is
then administered at the prescribed dose (see above).
Thyrogen should not be administered to patients with
an intact thyroid gland because it can cause severe thyroid
swelling and hyperthyroidism. Hyperthyroidism can also
occur in patients with significant metastases or residual
normal thyroid. Other side effects include nausea (11%)
and headache (7%). Thyrotropin has caused neurologic
deterioration in 7% of patients with central nervous sys-
tem metastases.
4. Thyroxine-withdrawal stimulated 131I therapy,
thyroglobulin, and scanThyroxine withdrawal is some-
times used because of its lower cost, despite the discomforts
of becoming hypothyroid. Thyroxine is withdrawn for
CMDT 2013 1132
14 days and the patient is allowed to become hypothyroid;
high levels of endogenous TSH stimulate the uptake of RAI
and production of thyroglobulin by thyroid cancer or
residual thyroid. Just prior to 131I therapy, the following
blood tests are obtained: serum TSH to confirm it is > 30
mcU/mL, serum hCG in reproductive-age women to screen
for pregnancy, serum thyroglobulin as a tumor marker.
Three days after 131I therapy, thyroxine therapy may be
resumed at full replacement dose.
5. Side effects and contraindicationsNational Cancer
Institute surveillance data for thousands of patients with
thyroid cancer indicate that patients with differentiated
thyroid cancer, treated with only surgery, have a 5%
increased risk of developing a second non-thyroid malig-
nancy (especially breast cancer). Patients with thyroid
cancer who received 131I therapy have a 20% increased risk
of developing a second non-thyroid malignancy (especially
leukemia and lymphoma). The greatest risk of second
cancers appeared within 5 years of 131I therapy and was
most significant for younger patients.
Pregnant women may not receive RAI therapy. Women
are advised to avoid pregnancy for at least 4 months fol-
lowing 131I therapy. Men have been found to have abnor-
mal spermatozoa for up to 6 months following 131I therapy
and are advised to use contraceptive methods during
that time.
`cTreatment of Other Thyroid
Malignancies
Patients with anaplastic thyroid carcinoma are treated with
local resection and radiation. Lovastatin has been demon-
strated to cause differentiation and apoptosis of anaplastic
thyroid carcinoma cells in vitro; however, clinical studies
have not been performed. Anaplastic thyroid carcinoma
does not respond to 131I therapy and is resistant to
chemotherapy.
Patients with thyroid MALT lymphomas have a low risk
of recurrence after simple thyroidectomy. Patients with
other thyroid lymphomas are best treated with external
radiation therapy; chemotherapy is added for extensive
lymphoma. Patients with systemic lymphomas involving
the thyroid are usually treated with chemotherapy.
Patients with a ret protooncogene mutation should
have a prophylactic total thyroidectomy, ideally by age
6 years (MEN 2A) or at age 6 months (MEN 2B). Medullary
thyroid carcinoma is best treated with surgery for the pri-
mary tumor and metastases. It does not respond to 131I
therapy and is generally resistant to chemotherapy. In one
study, vandetanib (100 mg orally once daily) produced a
partial remission in 16% and stable disease in 53% of
patients with locally advanced or metastatic medullary
thyroid carcinoma.
A. External Radiation Therapy
External radiation may be delivered to bone metastases,
especially those without radioiodine uptake. Local neck
radiation therapy may also be given to patients with ana-
plastic thyroid carcinoma. Brain metastases can be treated
with gamma knife radiosurgery.
 1133 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
`cSurveillance
Patients with differentiated thyroid carcinoma must be
observed long-term for recurrent or metastatic disease.
Patients with differentiated thyroid carcinoma have tradi-
tionally required at least two annual consecutively negative
stimulated serum thyroglobulin determinations < 1 ng/mL
and normal RAI scans (if done) and neck ultrasound
before they are considered to be in remission. The first
surveillance occurs with stimulated postoperative serum
thyroglobulin, 131I therapy, and post-therapy scanning
about 24 months after surgery. (See Treatment, above.) At
912 months postoperatively, patients usually receive
another stimulated serum thyroglobulin and radioiodine
scan. Patients with persistent RAI uptake restricted to
the thyroid bed need not have repeated 131I therapies if the
neck ultrasound appears normal and stimulated serum
thyroglobulin is < 2 ng/mL. Further radioiodine or other
scans may be required for patients with more aggressive
differentiated thyroid cancer, prior metastases, rising serum
thyroglobulin levels, or other evidence of metastases.
1. Serum TSH suppressionPatients with differentiated
thyroid cancer are treated with thyroxine doses that are
sufficient to suppress the serum TSH below the normal
range. For intermediate- or high-risk patients, the serum
TSH should be suppressed below 0.1 mU/L, while the
target TSH for low-risk patients is 0.10.5 mU/mL. Patients
who are considered cured should nevertheless be treated
with sufficient thyroxine to keep the serum TSH < 2 mU/L.
Follow-up must include physical examinations and labora-
tory testing to ensure that patients remain clinically euthy-
roid with serum TSH levels in the target range. To achieve
suppression of serum TSH, the required dose of thyroxine
may be such that serum FT levels may be slightly elevated;
4
in that case, measurement of serum T3 or free T3 can be
useful to ensure the patient is not fr y hype yroid.
ankl rth
Thyrotoxicosis can be caused by overreplacement with
thyroxine or by the growth of functioning metastases.
2. Serum thyroglobulinThyroglobulin is produced by
normal thyroid tissue and by most differentiated thyroid
carcinomas. It is only after a total or near-total thyroidec-
tomy and 131I remnant ablation that thyroglobulin becomes
a useful tumor marker for patients with differentiated pap-
illary or follicular thyroid cancer, particularly for patients
who do not have serum antithyroglobulin antibodies.
Detectable thyroglobulin levels do not necessarily indi-
cate the presence of residual or metastatic thyroid cancer.
Conversely, baseline serum thyroglobulin levels are insensi-
tive markers for disease recurrence. However, baseline or
stimulated serum thyroglobulin levels 2 ng/mL indicate
the need for a repeat neck ultrasound and further scanning
with RAI or 18FDG-PET. If serum thyroglobulin levels
remain 2 ng/mL in the presence of normal scanning, it is
prudent to repeat the serum thyroglobulin in a national
reference laboratory. In one series of patients with differen-
tiated thyroid cancer following thyroidectomy, there was a
21% incidence of metastases in patients with serum thyro-
globulin < 1 ng/mL (while receiving thyroxine for TSH
suppression). Therefore, baseline serum thyroglobulin
CMDT 2013 1133
levels are inadequately sensitive and stimulated serum thy-
roglobulin measurements should be used and always with
neck ultrasound. The usefulness of routinely doing a radio-
iodine scan (see below) in low-risk patients is controversial
but continues to be done in many centers during stimula-
tion following either rhTSH or thyroid hormone with-
drawal, according to described protocols.
3. Neck ultrasoundNeck ultrasound should be used in
all patients with thyroid carcinoma to supplement neck
palpation; it should be performed preoperatively, 3 months
postoperatively, and regularly thereafter. Ultrasound is more
sensitive for lymph node metastases than either CT or MRI
scanning. Small inflammatory nodes may be detected post-
operatively and do not necessarily indicate metastatic dis-
ease, but follow-up is necessary. Ultrasound-guided FNA
biopsy should be performed on suspicious lesions.
4. Radioactive iodine (RAI: I or
131 123
I) neck and
whole-body scanning Despite its limitations, RAI scan-
ning has traditionally been used to detect metastatic dif-
ferentiated thyroid cancer and to determine whether the
cancer is amenable to treatment with 131I. RAI scanning is
particularly useful for high-risk patients and those with
persistent antithyroglobulin antibodies that make serum
thyroglobulin determinations unreliable.
The 131I isotope may be used in scanning doses, given
< 2 weeks before scheduled 131I treatment to avoid stunning
metastases such that they take up less of the RAI therapy
dose. The radioisotope 123I may also be used and does not
stun tumors; it allows single-photon emission computed
tomography (SPECT) to better localize metastases. Initial
RAI scanning is typically performed about 24 months
following surgery for differentiated thyroid carcinoma.
Whole-body scanning should be performed for at least
30 minutes for at least 140,000 counts and spot views of
the neck should be obtained for at least 35,000 counts.
About 65% of metastases are detectable by RAI scan-
ning, but only after optimal preparation: Patients should
ideally have a total or near-total thyroidectomy, since any
residual normal thyroid competes for RAI with metastases,
which are less avid for iodine. It is reasonable to perform a
rhTSH-stimulated scan and thyroglobulin level 23 months
after the initial neck surgery; if the scan is negative and the
serum thyroglobulin is < 2 ng/mL, low-risk patients may
not require further scanning but should continue to be
monitored with neck ultrasound and serum thyroglobulin
levels every 612 months. For higher-risk patients, the
rhTSH-stimulated thyroglobulin and RAI scan may be
repeated about 1 year after surgery and then again if war-
ranted. Serum thyroglobulin and radioiodine scanning are
stimulated by either rhTSH or thyroid hormone with-
drawal according to the protocols described above for 131I
treatment.
The combination of rhTSH-stimulated scanning and
thyroglobulin levels detects a thyroid remnant or cancer
with a sensitivity of 84%. However, the presence of antithy-
roglobulin antibodies renders the serum thyroglobulin
determination uninterpretable. In about 21% of low-risk
patients, rhTSH stimulates serum thyroglobulin to
above 2 ng/mL; such patients have a 23% risk of local neck
 1134 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
metastases and a 13% risk of distant metastases. The
rhTSH-stimulated radioiodine neck and whole-body scan
detects only about half of these metastases because they are
small or not avid for iodine. Some patients have persistent
radioiodine uptake in the neck on diagnostic scanning but
have no visible tumor on neck ultrasound; such patients do
not require additional radioiodine therapy, especially if the
serum thyroglobulin level is very low.
5. Positron emission tomography scanning18FDG-
PET scanning is particularly useful for detecting thyroid
cancer metastases in patients with a detectable serum thyro-
globulin (especially serum thyroglobulin levels >10 ng/mL
and rising) who have a normal whole-body RAI scan and an
unrevealing neck ultrasound. The patient should be fasting
at least 6 hours prior to 18FDG-PET scanning; water is
allowed, but no sweetened beverages. Diabetic patients with
blood sugars < 200 mg/dL may be scanned. 18FDG-PET
scanning can be combined with a CT scan; the resultant
18
FDG-PET/CT fusion scan is 60% sensitive for detecting
metastases that are not visible by other methods. This scan is
less sensitive for small brain metastases. 18FDG-PET scan-
ning detects the metabolic activity of tumor tissue; for dif-
ferentiated thyroid carcinoma, this scan is more sensitive
when the patients thyroid cancer is stimulated with rhTSH
(Thyrogen) as described above. One problem with 18FDG-
PET scanning is its lack of specificity. False-positives can
occur with benign hepatic tumors, sarcoidosis, radiation
therapy, suture granulomas, reactive lymph nodes, or inflam-
mation at surgical sites that can persist for months. False-
positive uptake can also occur in muscles and brown fat.
18
FDG-PET scanning predicts survival better than stan-
dard staging; the number, location, and SUVmax of metas-
tases are all significant prognostic factors. (See Prognosis.)
18
FDG-PET scanning is particularly sensitive for detecting
medullary thyroid carcinoma metastases, and prescan thy-
rotropin does not improve the PET scan sensitivity for
medullary thyroid carcinoma.
6. Other scanningThallium-201 (201Tl) scans may be use-
ful for detecting metastatic differentiated thyroid carcinoma
when the 131I scan is normal but serum thyroglobulin is ele-
vated. MRI scanning is particularly useful for imaging metas-
tases in the brain, mediastinum, or bones. CT scanning is
useful for imaging and monitoring pulmonary metastases.
`cPrognosis
Papillary thyroid cancer staging and survival data are
shown on Table 268. 18FDG-PET scanning independently
predicts survival, with patients having few PET-avid metas-
tases and low SUVmax (highest image-pixel standardized
uptake value) having a better prognosis. There is generally
a good prognosis, particularly for adults under age
45 years, despite the fact that up to 40% of these patients
are found to harbor lymph node metastases when extensive
lymph node dissections are performed. The following
characteristics imply a worse prognosis: age over 45 years,
male sex, bone or brain metastases, macronodular (> 1 cm)
pulmonary metastases, and lack of 131I uptake into metas-
tases. Younger patients with pulmonary metastases tend to
CMDT 2013 1134
respond better to 131I therapy than do older adults. Certain
papillary histologic types are associated with a higher risk
of recurrence and reduced survival: tall cell, columnar cell,
and diffuse sclerosing types. Brain metastases are detected
in 1%; they reduce median survival to 12 months, but the
patients prognosis is improved by surgical resection.
Patients with a follicular variant of papillary carcinoma
have a prognosis somewhere between that of papillary and
follicular thyroid carcinoma.
Patients with follicular carcinoma have a cancer mor-
tality rate that is 3.4 times higher than patients with papil-
lary carcinoma. The Hrthle cell variant of follicular
carcinoma is even more aggressive. Both follicular carci-
noma and its Hrthle cell variant tend to present at a more
advanced stage than papillary carcinoma. However, at a
given stage, the different types of differentiated thyroid
carcinoma have a similar prognosis. Patients with primary
tumors > 1 cm in diameter who undergo limited thyroid
surgery (subtotal thyroidectomy or lobectomy) have a
2.2-fold increased mortality over those having total or
near-total thyroidectomies. Patients who have not received
131
I ablation have mortality rates that are increased twofold
by 10 years and threefold by 25 years (over those who have
received ablation). The risk of cancer recurrence is twofold
higher in men than in women and 1.7-fold higher in mul-
tifocal than in unifocal tumors.
Patients with a normal 18FDG-PET scan have a 98%
5-year survival, while those having > 10 metastases have a
20% 5-year survival. Those with a SUVmax of 0.1-4.6 have a
5-year survival of 85%, while those with a SUVmax > 13.3
have a 5-year survival of 20%. Patients with only local
metastases have a 5-year survival of 95%, while those with
regional (supraclavicular, mediastinal) metastases have a
5-year survival of 70%, and those with distant metastases
have a 5-year survival of 35%.
Medullary thyroid carcinoma is more aggressive than
differentiated thyroid cancer but is typically fairly indolent.
The overall 10-year survival rate is 90% when the tumor is
confined to the thyroid, 70% for those with metastases to
cervical lymph nodes, and 20% for those with distant
metastases. Patients with sporadic disease usually have
lymph node involvement noted at the time of diagnosis,
whereas distal metastases may not be noted for years. For
patients with medullary thyroid carcinoma who have
metastases to lymph nodes, modified radical neck dissec-
tion is recommended. Familial cases or those associated
with MEN 2A tend to be less aggressive; the 10-year sur-
vival rate is higher, in part due to earlier detection.
Medullary thyroid carcinoma that is seen in MEN 2B is
more aggressive, arises earlier in life, and carries a worse
overall prognosis, especially when associated with a germline
M918T mutation. The elderly tend to have more aggressive
medullary thyroid carcinomas. Women with medullary
thyroid carcinoma who are under age 40 years have a better
prognosis. A better prognosis is also obtained in patients
undergoing total thyroidectomy and neck dissection;
radiation therapy reduces recurrence in patients with
metastases to neck nodes. The mortality rate is increased
4.5-fold when primary or metastatic tumor tissue stains
heavily for myelomonocytic antigen M-1. Conversely,
 1135 CMDT 2013 ENDOCRINE
CHAPTER 26 DISORDERS
tumors with heavy immunoperoxidase staining for calci-
tonin are associated with prolonged survival even in the
presence of significant metastases.
Anaplastic thyroid carcinoma carries a 1-year survival
rate of about 10% and a 5-year survival rate of about 5%.
Patients with fully localized tumors on MRI have a better
prognosis.
Localized lymphoma carries a 5-year survival of nearly
100%. Those with disease outside the thyroid have a 63%
5-year survival. However, the prognosis is better for those with
the MALT type. Patients presenting with stridor, pain, laryn-
geal nerve palsy, or mediastinal extension tend to fare worse.
Bible KC et al. Efficacy of pazopanib in progressive, radioiodine-
refractory, metastatic differentiated thyroid cancers: results of
a phase 2 consortium study. Lancet Oncol. 2010 Oct 11;11(10):
96272. [PMID: 20851682]
Brierley JD. Update on external beam radiation therapy in
thyroid cancer. J Clin Endocrinol Metab. 2011 Aug;96(8):
228995. [PMID: 21816795]
Cabanillas ME et al. Challenges associated with tyrosine kinase
inhibitor therapy for metastatic thyroid cancer. J Thyroid Res.
2011;2011:985780. [PMID: 22007339]
Cox AE et al. Diagnosis and treatment of differentiated thyroid
carcinoma. Radiol Clin North Am. 2011 May;49(3):45362.
[PMID: 21569904]
Jasim S et al. Multiple endocrine neoplasia type 2B with RET proto-
oncogene A883F mutation displays a more indolent form of
medullary thyroid carcinoma compared with a RET M918T
mutation. Thyroid. 2011 Feb;21(2):18992. [PMID: 21186952]
Johnson NA et al. Imaging surveillance of differentiated thyroid
cancer. Radiol Clin North Am. 2011 May;49(3):47387.
[PMID: 21569906]
Kim WG et al. Empiric high-dose 131-iodine therapy lacks effi-
cacy for treated papillary thyroid cancer patients with detect-
able serum thyroglobulin, but negative cervical sonography
and 18F-flurodeoxyglucose positron emission tomography
scan. J Clin Endocrinol Metab. 2010 Mar;95(3):116973.
[PMID: 20080852]
Kojic SL et al. Anaplastic thyroid cancer: a comprehensive review
of novel therapy. Expert Rev Anticancer Ther. 2011 Mar;11(3):
387402. [PMID: 21417853]
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2010 Aug;22(6):41929. [PMID: 20605708]
IODINE DEFICIENCY DISORDER
& ENDEMIC GOITER
`c ccc
EssEntials of diagnosis
`c ccc Common in regions with low-iodine diets.
High rate of congenital hypothyroidism and
`c cccc
cretinism.
`c cccgoiters may become multinodular and enlarge.
`c cccc Most adults with endemic goiter are found to be
euthyroid; however, some are hypothyroid or
hyperthyroid.
CMDT 2013 1135
`cGeneral Considerations
About 1 billion people are iodine deficient, having no access
to iodized salt and living in areas with iodine-depleted soil.
Severe iodine deficiency increases the risk of miscarriage and
stillbirth. About 0.5% of live births in iodine-deficient areas
have full-blown cretinism. Moderate iodine deficiency dur-
ing gestation and infancy cause other manifestations of
congenital hypothyroidism, such as deafness and short stat-
ure and permanently lowers a childs IQ by 1015 points.
Populations in areas of iodine deficiency have a high
incidence of goiter. One such area is Pescopagano, Italy,
where 60% of adults have goiters. Hyperthyroidism (pres-
ent or past) occurred in 2.9%; hypothyroidism was overt in
0.2% and subclinical in 3.8%.
Although iodine deficiency is the most common cause of
endemic goiter, certain foods (eg, sorghum, millet, maize,
cassava), mineral deficiencies (selenium, iron), and water
pollutants can themselves cause goiter or aggravate a goiter
proclivity caused by iodine deficiency. In iodine-deficient
patients, smoking can induce goiter growth. Pregnancy
aggravates iodine deficiency and is associated with an increase
in size of thyroid nodules and the emergence of new nodules.
Some individuals are particularly susceptible to goiter owing
to congenital partial defects in thyroid enzyme activity.
`cClinical Findings
A. Symptoms and Signs
Endemic goiters may become multinodular and very large.
Growth often occurs during pregnancy and may cause
compressive symptoms.
Substernal goiters are usually asymptomatic but can
cause tracheal compression, respiratory distress and fail-
ure, dysphagia, superior vena cava syndrome, gastrointesti-
nal bleeding from esophageal varices, palsies of the phrenic
or recurrent laryngeal nerves, or Horner syndrome.
Cerebral ischemia and stroke can result from arterial com-
pression or thyrocervical steal syndrome. Substernal goi-
ters can rarely cause pleural or pericardial effusions. The
incidence of significant malignancy is < 1%.
Some patients with endemic goiter may become hypo-
thyroid. Others may become thyrotoxic as the goiter grows
and becomes more autonomous, especially if iodine is
added to the diet.
B. Laboratory Findings
The serum T4 and TSH are generally normal. TSH falls in the
presence of hyperthyroidism if a multinodular goiter has
become autonomous in the presence of sufficient amounts of
iodine for thyroid hormone synthesis. TSH rises with hypo-
thyroidism. Thyroid RAI uptake is usually elevated, but it may
be normal if iodine intake has improved. Serum levels of anti-
thyroid antibodies are usually either undetectable or in low
titers. Serum thyroglobulin is often elevated.
`cDifferential Diagnosis
Endemic goiter must be distinguished from all other forms
of nodular goiter that may coexist in an endemic region
(see above).