108
CHAPTER
Jerome M. Hershman
Thyroid disorders in the elderly population are common, often chal-
lenging diagnostically, and frequently overlooked. The clinical pre-
sentations of thyroid diseases maybe subtle, with nonspecific signs
and symptoms that are attributed to other illnesses or to a normal
aging process. Thyroid function tests can be misleading in the pres-
ence of concurrent acute or chronic diseases and may be affected by
some medications. This chapter describes the most common thyroid
disorders encountered in the elderly population.
THE AGING HUMAN THYROID
Anatomy
The thyroid gland is the largest endocrine organ in the human body,
and weighs approximately 12 to 20 g in adults. The structural and
functional changes of the thyroid gland that occur with aging are
controversial. Some investigators report that there were no size or
weight changes, others found increases to twice normal size after age
70 years, whereas other reports indicated that the thyroid gland un-
dergoes atrophy, fibrosis, and decrease in weight. The thyroid gland
is also more nodular with advancing age, and there is an increase in
fibrosis and lymphocytic infiltration. Despite these changes, normal
thyroid function is maintained by the vast majority of the elderly
population. Estimation of the thyroid size and its palpation may be
difficult in elderly patients because of cervical kyphosis, obesity, or
chronic pulmonary disease.
Physiology
Iodine, an essential substrate for synthesis of thyroid hormone, is
absorbed from the diet and enters the circulation as inorganic io-
dide that is distributed in extracellular fluids as well as in salivary,
breast, and gastric secretions. The average daily iodine intake is about
Thyroid Diseases
■ Sima Hassani ■ Mary H. Samuels
250 µg/day in the United States. A 24-hour urinary iodine measure-
ment is an index of dietary iodine intake.
Iodide is actively concentrated by the thyroid gland or cleared
from the plasma by the kidney. The thyroid gland, compared with
the kidneys, is the active participant in the competition for plasma
iodide and adjusts the rate of entry of iodide into the thyroid tissue
based on the changes in thyroid hormone synthesis rather than renal
avidity for iodide ion. The active transport of iodide from plasma
to follicular cell is carried out by the sodium iodide symporter, a
transport protein on the follicular cell plasma membrane. The ex-
tracellular fluid iodide concentration is usually very low because of
the rapid clearance of iodide from extracellular fluid by the thyroidal
uptake and renal clearance.
Table 108-1 summarizes the aging effects on thyroid function.
The renal and thyroidal iodide clearance rate diminishes with ad-
vancing age. Thyroid iodide clearance, estimated by a 24-hour ra-
dioactive iodine uptake by the thyroid gland, decreases in euthyroid
subjects after age 60 years. Urinary iodine excretion also was found
to be significantly reduced in subjects older than 80 years of age.
In the thyroid cell, the iodide is oxidized by the peroxidase enzyme
and incorporated into tyrosines in thyroglobulin to form the thy-
roid hormone precursors monoiodotyrosine (MIT) and diiodoty-
rosine (DIT). The MIT and DIT within the large thyroglobulin
molecule couple to form thyroxine (T4 ) and triiodothyronine (T3 ).
In the plasma, the main binding protein is thyroid-binding globulin
(TBG), which binds about 70% of serum T4 and T3 . The other
binding proteins are transthyretin and albumin. Only 0.02% of T4
and 0.3% of T3 are free and metabolically active because only the free
hormone is rapidly transported into cells. Total serum T4 and T3 are
readily measured. Free T4 (FT4 ) and free T3 (FT3 ) concentrations
also can be measured to evaluate thyroid function.
The daily production rate of T4 is about 85 µg/day and that
of T3 is about 30 µg/day in normal adults. About 85% of T3
production is derived from T4 -to-T3 conversion by 5′ -deiodinase,
a selenoprotein (Figure 108-1), in extrathyroidal tissues such as the
1288 PART IV / Organ Systems and Diseases

Thyroid hormone regulation is through a negative feedback loop

TABLE 108-1
Age-Related Changes in Thyroid Physiology
Renal iodide clearance ↓
Thyroid iodide clearance ↓
Total T4 production ↓
T4 degradation ↓
Serum T4 concentration ↔
Serum TBG concentration ↔
T3 concentration ↓
Reverse T3 concentration ↑
TSH response to TRH ↑↔↓
Diurnal variation of TSH ↓ ↓
↓, Decreased; ↑, increased; ↔, unchanged. T3 , triiodothyronine; T4 , thyroxine; TBG,
thyroid-binding globulin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.
liver, muscles, and kidneys. The other 15% of T3 production is that
secreted directly by the thyroid gland. Selenium deficiency results in
reduced 5-deiodinase activity and serum T3 concentration. Reverse
T3 (rT3 ), inactive biologically, differs from T3 because it is missing
an iodine from the inner or tyrosyl ring of T4 rather than from the
outer ring or phenolic ring. T4 is converted to rT3 by 5-deiodinase
in peripheral tissue. Total T4 production and degradation decline
with aging, but T4 concentration and TBG concentration remain
unchanged in healthy individuals throughout adult life. In contrast,
the concentration of T3 was reported to decrease by 10% to 20%
with advancing age and the concentration of rT3 increases. These
findings suggest that 5′ -deiodinase activity decreases with increasing
age.
involving the hypothalamus, the anterior pituitary, and the thyroid
gland (Figure 108-2). Thyrotropin-releasing hormone (TRH), syn-
thesized and stored within the hypothalamus, stimulates the release
of thyroid-stimulating hormone (TSH) from the anterior pituitary
gland. TSH binds to the TSH receptor located on the outer side of
the thyroid cell plasma membrane and increases thyroid hormone
synthesis and secretion. In turn, T4 and T3 from the serum feedback
on the pituitary and the hypothalamus to inhibit TSH and TRH
production and secretion.
The secretory response of TSH to TRH stimulation in aging
men has been reported to be decreased to 38% of the values in
young men. This maybe an adaptive mechanism to the reduced need
for thyroid hormone in old age. However, other reports of TRH-
stimulated TSH secretion with aging have shown an unchanged or
even increased response.
The serum TSH concentration has been either unchanged, low-
ered, or increased with aging in various reports. The heterogeneity
of the populations studied may explain some of these discrepancies.
Studies employing sensitive TSH assays have raised the question of
whether the abnormal TSH reflects the prevalence of thyroid disor-
ders or physiologic changes related to aging. In a random selection
of the community-based population followed in the Framingham
Heart Study, euthyroid older persons were found to have the same
level of TSH as younger persons, although older euthyroid women
had a slightly lower serum TSH level than middle-aged women.
In a study of healthy centenarians (age range, 100–110 years), the
median serum TSH level was lower than that of older individuals
(age range, 65–80 years). The data of this study are consistent with
TSH being well preserved until the eighth decade of life in healthy
elderly subjects, whereas a decline in TSH may occur in those older

FIGURE 108-1. Structures of T4 and the enzymatic pathways for deiodination of T4 to its major active metabolite, T3 , and to reverse T3 in peripheral
tissues.

FIGURE 108-2. Feedback regulation for control of thyroid function that
involves the hypothalamus–pituitary–thyroid axis. Arrows represent positive
feedback; dashed lines denote the inhibitory feedback of T4 and T3 on
pituitary thyroid-stimulating hormone (TSH) and hypothalamic thyrotropin-
releasing hormone (TRH) secretion.
than 100 years of age. TSH levels rise about 50% in the late evening
before the onset of sleep. Sleep attenuates this nocturnal peak of
TSH secretion, and sleep deprivation exaggerates nocturnal TSH
secretion. The diurnal variation of TSH levels has been reported to
be absent in the elderly. The data from the healthy centenarians and
individuals older than age 65 years also showed an age-related blunt-
ing of the nocturnal TSH peak. An increased prevalence of thyroid
autoantibodies is also associated with human aging.
SCREENING FOR THYROID DISEASE
Both functional and anatomic abnormalities of the thyroid gland
occur with increasing prevalence as patients age, and may present
with nonspecific clinical findings. Therefore, the clinician should
maintain a low threshold for testing if a patient presents with symp-
toms or signs that suggest the presence of thyroid disease or with
atypical clinical findings (e.g., unexplained weight loss caused by
apathetic hyperthyroidism). Testing should also be carried out in
patients with a prior history of thyroid disease, other autoimmune
disease, unexplained depression, cognitive dysfunction, or hyper-
cholesterolemia.
Whether truly asymptomatic older subjects should be screened
for thyroid disease is more controversial. The American Thyroid As-
sociation recommends screening all adults older than age 35 years for
thyroid dysfunction and every 5 years thereafter. However, the Amer-
ican College of Physicians does not recommend routine screening
CHAPTER 108 / Thyroid Diseases 1289
of asymptomatic patients because of presumed lack of demonstrated
efficacy or proven benefit in treatment of subclinical thyroid disease.
In our opinion, the high prevalence of hypothyroidism and often
subtle or nonspecific symptoms in patients older than 65 years of
age justifies periodic screening for hypothyroidism.
In most ambulatory patients, the measurement of a serum TSH
level is sufficient to screen for thyroid dysfunction. Modern TSH
assays are sufficiently sensitive to distinguish normal from low or
high values. TSH levels become abnormal before serum T4 or T3
levels because of the exquisite sensitivity of the pituitary gland to
small increments in thyroid hormone feedback. However, there are
certain patient populations where TSH levels alone may not provide
accurate information about thyroid function. Patients with pituitary
or hypothalamic disorders may have altered thyroid function with
misleading TSH levels, and a full panel of thyroid tests is required to
characterize their thyroid function. More commonly, patients with
serious acute or chronic illnesses or receiving certain drugs may have
altered thyroid hormone and TSH levels that do not accurately reflect
their thyroid function. These common scenarios are described in the
sections below on nonthyroidal illness and drug effects on thyroid
function.
NONTHYROIDAL ILLNESS
The terms sick euthyroid syndrome or nonthyroidal illness (NTI) refer
to altered serum thyroid hormone concentrations secondary to the
physiologic stress of severe illness. By definition, patients with NTI
have no apparent intrinsic thyroid disease. The types of illnesses re-
sponsible for thyroid function abnormalities include sepsis, surgery,
trauma, burns, infections, malignancy, and chronic metabolic dis-
eases such as malnutrition, starvation, and poorly controlled diabetes
mellitus. An understanding of the effect of NTI on thyroid function
tests is important, especially in the elderly patient who has multiple
other underlying medical problems.
The effects of NTI on thyroid function have been described as the
low T3 and low T4 states. The low T3 state is associated with a de-
crease in extrathyroidal T3 production, resulting in a low serum total
T3 level and usually low free T3 level with a normal serum TSH con-
centration. With more severe illness, the serum T4 level decreases. In
severe NTI, the decreases in T4 and T3 maybe an adaptation to spare
the patient from the catabolic effect of thyroid hormone during the
periods of extreme stress. A reduction in serum T3 concentration
is the most common change of thyroid function tests in NTI with
a frequency of 25% to 50%. The severity of the underlying illness
correlates with the degree of the fall in serum T3 concentration. The
mechanisms responsible for low T3 concentration are (1) a decrease
in the peripheral conversion of T4 to T3 either because of inhibi-
tion of the 5′ -deiodinase that is responsible for this conversion or
because of a deficiency of a cofactor, such as glutathione, which is
necessary for the activity of 5′ -deiodinase; (2) a decrease in T3 secre-
tion from the thyroid gland; and (3) a decrease in tissue uptake of T4
that limits the conversion of T4 to T3 in the extrathyroidal tissues.
The serum rT3 is increased in NTI because of the impaired rT3
clearance as a consequence of the decreased activity of 5′ -deiodinase
with illness. The central question is how does the body maintain a
euthyroid state when serum T3 is reduced? The basis for an appar-
ent euthyroid status in NTI is still unclear. There are several possi-
ble explanations: (1) T3 concentrations may remain normal in the
1290 PART IV / Organ Systems and Diseases
intracellular compartment even though serum T3 level is decreased;
(2) T3 maybe converted to triiodothyroacetic acid (Triac), which is
metabolically active; and (3) studies of patients with various acute
illnesses showed an increase in T3 -receptor messenger ribonucleic
acids (mRNAs) and T3 -receptor protein that results in an increase
in production of proteins that express the action of thyroid hormone,
hence maintaining a euthyroid state in NTI.
The patients with the low T4 state, also known as a low T3 /T4
state, exhibit a low serum thyroxine level as well as low T3 with a nor-
mal serum TSH concentration. Low serum total T4 correlates with
a poor prognosis. The mortality of critically ill patients with NTI is
inversely related to serum T4 concentration and has been reported to
be as high as 84% in patients with serum T4 concentration less than
3 µg/dL. There is no clear mechanism to fully explain the low T4
state; however, possibilities include (1) reduced TBG concentration
as a consequence of reduced hepatic protein synthesis; (2) inhibition
of serum T4 binding to TBG, probably by a substance released by in-
jured tissue, or an acquired structural alteration of TBG that reduces
its affinity for T4 ; (3) alterations in hepatic uptake and metabolism
of T4 ; and (4) reduced secretion of T4 caused by alteration in the
structure of TSH, resulting in decreased biologic activity. Proinflam-
matory cytokines produced by the mononuclear cells (macrophages,
lymphocytes, and monocytes) of the immune system in patients with
NTI are probably responsible for the changes in thyroid function
tests. Administration of proinflammatory cytokines such as tumor
necrosis factor (TNF)-α and interleukin (IL)-1 to experimental an-
imals made the animals sick and reduced serum T4 , T3 , and TSH
concentrations. These cytokines inhibit thyroid iodide uptake by
reducing the activity and transcription of the sodium iodide sym-
porter, and they inhibit T3 production by reducing the activity and
transcription of 5′ -deiodinase.
Recovery from the underlying illness results in improvement of
the low T3 and T4 states. Serum T4 level returns to normal faster than
FIGURE 108-3. The relative changes in serum thy-
rotropin and thyroid hormone concentrations with
increasing severity of nonthyroidal illness and with
recovery. Serum T4 and free T4 falls with more se-
vere illness, whereas serum T3 is subnormal in mild
illness. The recovery is generally a reverse of the
illness pattern with a slight elevation of serum TSH
in many instances.
serum T3 level. Serum TSH concentration usually remains normal
except in those patients receiving pharmacologic doses of dopamine
or glucocorticoids, which reduce serum TSH levels. During the re-
covery stage, serum TSH usually remains in the normal range, but
it may transiently increase above the normal range. Figure 108-3.
diagrams the changes in thyroid hormone and serum TSH levels in
NTI.
The effects of thyroid hormone replacement in NTI have been
studied. Treatment of the low T3 state with replacement doses of T3
was found to be detrimental in a fasting model of NTI, resulting in
an increase in protein catabolism and possibly muscle breakdown.
T3 given intravenously to cardiac patients undergoing open-heart
surgery improved cardiac performance, but this was not confirmed
in randomized trials. T4 therapy in severe NTI had no beneficial
effects and did not improve survival.
DRUGS AND THYROID FUNCTION
Altered sensitivity to drugs is particularly relevant in elderly patients
with thyroid diseases. The metabolism and secretion of many drugs
are attenuated in hypothyroidism and accelerated in thyrotoxicosis.
Hypothyroidism results in increases in the plasma half-life of digoxin,
insulin, glucocorticoids and morphine; consequently, sensitivity to
the toxic effects of these drugs increases and doses should be de-
creased until the patient is euthyroid. Opposite metabolic changes
in hyperthyroidism result in increased maintenance doses of these
drugs while the patient is hyperthyroid. Resistance to the antico-
agulant effect of warfarin in hypothyroidism is a result of slower-
than-normal clearance of vitamin K-dependent coagulation factors;
an augmented response is seen in hyperthyroidism.
Medications can affect many aspects of thyroid hormone secre-
tion, absorption, transport, or metabolism, as listed in Table 108-2.
 CHAPTER 108 / Thyroid Diseases 1291

A few drugs have been shown to suppress TSH secretion, most com-
TABLE 108-2
monly seen in patients with critical illnesses receiving glucocorticoids
Drugs That Affect Thyroid Function and/or dopamine who can have low or undetectable TSH levels as
Decrease TSH secretion a result. Low TSH levels are also seen during octreotide therapy for
Dopamine acromegaly or other rare endocrine diseases, and during administra-
Glucocorticoids tion of the retinoid X receptor ligand bexarotene for malignancies.
Octreotide Some of these patients develop central hypothyroidism and require
Bexarotene thyroxine therapy.
Increase thyroid hormone secretion A second major category of drugs that affect thyroid function in-
Iodine and iodine-containing compounds clude agents that directly increase thyroid hormone secretion. This
Amiodarone may occur as a result of stimulation of a thyroid gland with un-
Lithium
derlying autonomous function, such as latent Graves’ disease or a
Interferon alpha and IL-2
multinodular goiter. Iodine, iodine-containing radiocontrast agents,
Decrease thyroid hormone secretion
and amiodarone all act in this way to increase thyroid hormone
Thionamides (proplythiouracil, methimazole)
synthesis and precipitate hyperthyroidism. A second mechanism
Lithium
Iodine and iodine containing compounds
is induction of destructive thyroiditis, leading to release of pre-
Amiodarone
formed thyroid hormone and transient thyrotoxicosis, as can occur
Aminoglutethimide with admiodarone, lithium, or the cytokines interferon alpha and
Interferon alpha and interleukin 2 IL-2.
Sunitinib Another class of drugs decreases thyroid hormone secretion. The
Decrease T4 absorption thionamides proplythiouracil and methimazole are potent inhibitors
Calcium of thyroid hormone synthesis and are used to treat hyperthyroidism.
Proton pump inhibitors This class also includes iodine and iodine-containing agents, which
Cholestyramine, Colestipol can suppress thyroid hormone secretion in patients with underlying
Aluminum hydroxide, sevelamer defective thyroid glands (e.g., Hashimoto’s disease). It also includes
Ferrous sulfate some of the same drugs that cause thyroiditis, including amiodarone,
Sucralfate
lithium, and interferon alpha and IL-2. During drug-induced thy-
Raloxifene (?)
roiditis, the initial thyrotoxic phase is followed by a phase of reduced
Increase serum TBG
thyroid hormone secretion until the injured gland can recover syn-
Estrogen
thetic function. The tyrosine kinase inhibitor, sunitinib, used to
Tamoxifen and raloxifene
Clofibrate
treat renal cancer and gastrointestinal stromal tumor, and aminog-
Fluorouracil and capecitabine lutethamide, used to treat adrenal cancer, have also been reported to
Mitotane decrease thyroid hormone secretion.
Heroin A number of agents decrease thyroid hormone absorption from
Methadone the gastrointestinal tract, including drugs commonly prescribed for
Decrease serum TBG elderly patients like calcium, ferrous sulfate, and proton pump in-
Androgen hibitors. These drugs do not affect thyroid hormone levels in eu-
Anabolic steroids (danazol) thyroid subjects, but they can lead to thyroxine malabsorption in
Glucocorticoid patients taking exogenous thyroxine. Thyroxine should be given
Inhibit thyroid hormone binding to transport proteins separately from these drugs, and the dose may have to be increased
Phenytoin and carbamazepine as well.
Furosemide Drugs that cause increased serum TBG levels lead to increases
Salicylates and salsalate
in serum total T4 and total T3. Free T4, free T3, and TSH levels
Fenclofenac and meclofenamate
remain normal, attesting to the patient’s euthyroid state. The most
Heparin
Sulfonylureas
common cause of increased serum TBG and T4 concentrations in
postmenopausal women is estrogen replacement therapy. The serum
Decrease T4 5′ -deiodinase activity
Propylthiouracil
TBG concentration is increased by 30% to 50% in women receiving
Amiodarone 0.625 mg of conjugated estrogen daily. Less common are drugs that
Glucocorticoids lower serum TBG (and therefore total T4 and total T3) levels.
Increase hepatic T4 and T3 metabolism Other drugs inhibit thyroid hormone binding to TBG and other
Phenobarbital transport proteins. Like agents that decrease TBG levels, this in-
Rifampin hibition causes low total T4 levels, with normal free T4 and TSH
Phenytoin levels, with the patient remaining euthyroid. The most frequently
Carbamazepine prescribed drugs in this category include high-dose aspirin or sal-
Sertraline salate, high-dose furosemide, and heparin.
Drugs that inhibit 5′ deiodinase activity include propylthiouracil,
amiodarone, propronolol, and glucocorticoids. These agents block
T4 to T3 conversion, but do not lead to clinical thyroid disease in
euthyroid subjects.
1292 PART IV / Organ Systems and Diseases
The activity of the hepatic microsomal enzymes that metabo-
lize T4 and T3 is increased by phenobarbital, rifampin, phenytoin,
and carbamazepine. Hypothyroid patients treated with levothyrox-
ine may become hypothyroid again when these agents are admin-
istered, and some patients require substantial increases of thyroxine
dose.
HYPOTHYROIDISM
Definition
Hypothyroidism is a general term that refers to a state of decreased
thyroid hormone availability to peripheral tissues. Overt hypothy-
roidism occurs when serum FT4 levels are below the normal range
and usually is associated with some symptoms of hypothyroidism.
Mild thyroid failure with an elevated serum TSH level and normal
FT4 concentration is referred to as subclinical (biochemical) hypothy-
roidism. Subclinical hypothyroidism is discussed in depth at the end
of this section.
Prevalence
The prevalence of hypothyroidism varies based on the population
under study (i.e., geriatric inpatient vs. primary care setting), age
range, ethnicity, iodine content of the diet, and prevalence of an-
tithyroid antibodies. In patients older than 60 years of age in the
general population, the incidence of overt hypothyroidism is 2.3%
to 10.3%. As dietary iodine intake increases, these rates also increase
as a result of iodine effects to suppress the thyroid gland. In a com-
parative study of healthy elderly female patients, the prevalence of
hypothyroidism in Regio Emilia, Italy, where there is low dietary
iodine intake, was 0.9%, whereas a prevalence of 14% was found in
Worcester, Massachusetts, where the dietary iodine is much higher.
Etiology and Pathogenesis
Table 108-3 lists the main causes of hypothyroidism. Primary hy-
pothyroidism accounts for the vast majority of cases of thyroid fail-
ure. Less than 1% of cases are caused by central hypothyroidism.
In the areas of adequate iodine intake, chronic autoimmune
(Hashimoto’s) thyroiditis is the most common cause of primary
hypothyroidism in elderly people, and is more common in women.
Chronic autoimmune thyroiditis is characterized pathologically by a
focal or diffuse lymphocytic infiltration of thyroid parenchyma and
damaged or atrophic follicles. The thyroid maybe enlarged or at-
rophic. Thyroid atrophy has been attributed to blocking antibodies
that bind to the TSH receptor and inhibit the action of TSH.
Autopsy reports from the United Kingdom and the United States
reveal the presence of focal thyroiditis in 40% to 50% of women and
in 20% of men with no prior history of thyroid diseases. The inci-
dence of chronic autoimmune thyroiditis was significantly higher in
Caucasians than in African-Americans in the same study. Antithy-
roid peroxidase (antimicrosomal) or antithyroglobulin antibodies are
present in the serum of greater than 90% of patients with chronic
autoimmune thyroiditis. The prevalence of positive thyroid antibod-
ies increases with age, with frequencies as high as 33% in women
TABLE 108-3
Causes of Hypothyroidism in the Elderly Population
Primary hypothyroidism
Chronic autoimmune thyroiditis (Hashimoto’s thyroiditis)
Radiation
131
I therapy for hyperthyroidism
Radiation therapy for head and neck cancer
Surgical thyroidectomy
Drugs
Iodine-containing drugs: amiodarone, radiocontrast agents
containing iodine
Antithyroid drugs (propythiouracil, methimazole)
Other drugs that decrease TSH or thyroid hormone secretion
(see Table 108-2)
Central hypothyroidism
Hypothalamic tumors or infiltrative lesions
Pituitary tumors or infiltrative lesions
Pituitary surgery
Radiation
older than 70 years of age. The presence of antithyroid antibodies
increases the risk of developing subclinical or overt hypothyroidism,
and also increases the risk of progression from subclinical to overt
hypothyroidism.
The second most common cause of hypothyroidism is iatrogenic,
caused by radiation treatment to the thyroid gland or thyroid surgery.
Radiation-induced hypothyroidism is caused by either radioactive
iodine treatment of hyperthyroidism or by external radiation therapy
of head and neck cancers. Hypothyroidism has been reported in 76%
of hyperthyroid patients treated with radioiodine and 20% to 47% of
patients receiving radiotherapy for treatment of various malignancies
of the head and neck region. This may take many years to develop,
so patients having received radiation treatment at a young or middle
age may develop hypothyroidism in old age.
Hypothyroidism in the elderly person maybe precipitated by cer-
tain drugs listed in Table 108-2. Patients with underlying autoim-
mune thyroid disease are more susceptible to developing iodine-
induced hypothyroidism. This effect is a result of iodine-induced
inhibition of thyroid hormone synthesis. Exposure of an elderly
patient to iodine can occur as a result of administration of iodine-
containing radiocontrast agents used during computed tomography
(CT) scanning. Another source of exposure is the use of amiodarone,
an iodine-containing drug used for treatment of arrhythmias.
The incidence of amiodarone-induced hypothyroidism varies with
the environmental iodine intake, with frequency of 10% to 30% in
the United States. Overtreatment of hyperthyroidism with thion-
amide drugs (propythiouracil, methimazole) can lead to hypothy-
roidism. A number of other drugs that suppress TSH or T4 secretion
(listed in Table 108-2) can precipitate hypothyroidism in elderly
patients. Finally, there are drugs that interfere with exogenous thy-
roid hormone absorption, also listed in Table 108-2. These drugs
do not cause hypothyroidism in euthyroid subjects, but they can
lead to inadequate thyroid hormone dosing and hypothyroidism in
thyroxine-treated patients who previously had normal TSH levels.
Common culprits include calcium, ferrous sulfate, and proton pump
inhibitors, all frequently prescribed in the elderly population.
 CHAPTER 108 / Thyroid Diseases 1293

Central hypothyroidism, resulting from an anatomic or func-

TABLE 108-5
tional disorder of the pituitary gland or the hypothalamus or both,
is relatively rare. Thyroid hormone secretion is reduced secondary Comparison of Clinical Features of Overt Hypothyroidism in
to deficient stimulation of the normal thyroid gland by TSH. Elderly versus Young Patients
The impairment of TSH secretion is caused by either primary or Symptoms Elderly, ≥70 Young, ≤55
metastatic pituitary tumors, infiltrative lesions, external radiother- and Signs Years (%) Years (%)
apy, or surgery. Bradycardia 12 19
Fatigue 68 83
Weight gain 24 59
Cold intolerance 35 65
Clinical Manifestations
Depression 28 52
The classic signs and symptoms of hypothyroidism include fatigue, Disorientation 9 0
weight gain, cold intolerance, dry skin, and constipation. Many el- Hypoactive reflexes 24 31
derly hypothyroid patients exhibit these classic findings, but they Weakness 53 67
are often attributed to other comorbid conditions or to the aging Paresthesia 18 61
Dry skin 35 45
process itself. This is because they are nonspecific and because hy-
Hair loss 12 28
pothyroidism usually has an insidious onset and slow progression
Reduced hearing 32 25
over months to years. Hypothyroidism may also present in a less Muscle cramps 20 55
typical fashion in elderly patients. Table 108-4 lists the common Snoring 18 22
clinical features of symptomatic hypothyroidism in older patients, Constipation 33 41
including findings that tend to occur at all ages, as well as neuro-
From Hassani S, Hershman JM. Thyroid diseases. In: Hazzard WR et al., eds.
logic, psychiatric, and cardiac features that particularly affect older Principles of Geriatric Medicine & Gerontology. 5th ed. New York, New York:
patients. Table 108-5 compares signs and symptoms of overt hy- McGraw-Hill; 2003:843.
pothyroidism between elderly and younger patients. In the study
summarized in this table, the mean serum TSH and FT4 levels and
duration of disease were similar between the two groups of patients. reviews some of the clinical aspects of hypothyroidism that are most
This study showed that the classic signs of overt hypothyroidism such relevant to the elderly population.
as cold intolerance, paresthesias, weight gain, and muscle cramps The neuropsychiatric features of hypothyroidism in the elderly
were less frequent in older patients. The remainder of this section population are initially nonspecific. Patients may report slowing of
thought processes. As the patient becomes less motivated and re-
sponsive to others, disoriented, and less interested in usual activities,
the diagnosis maybe confused with that of depressive mood disorder.
TABLE 108-4 Older people who present with deterioration in personality, retarda-
Clinical Features of Hypothyroidism in Elderly Patients tion of thought or action, apathy, or global loss of intellectual func-
tion should be evaluated for hypothyroidism. As hypothyroidism
Dry skin
Hair loss
becomes more severe, paranoia, delusions, hallucinations, and psy-
Edema of face and eyelids chosis may develop. Because of these symptoms, hypothyroidism can
Cold intolerance be a cause of “pseudodementia” in some elderly people. However,
Neurologic hypothyroidism as a major contributing cause of dementia is rare;
Paresthesia (carpal tunnel syndrome) in one study of patients with dementia, the incidence of hypothy-
Ataxia roidism was the same as in the general population. In another study
Dementia of demented patients, 2.3% were found to have hypothyroidism, of
Psychiatric and behavioral whom only 25% improved with treatment.
Depression
Abnormalities in plasma lipids are among the most important
Apathy or withdrawal
metabolic changes that occur in hypothyroidism. Both hyperc-
Psychosis
holesterolemia and hypertriglyceridemia can occur, and may exac-
Cognitive dysfunction
Metabolism
erbate primary hyperlipidemia in older patients. In the majority of
Weight gain overt hypothyroid patients, hypercholesterolemia (plasma choles-
Hypercholesterolemia terol level >250 mg/dL) is present. A reduction in cholesterol up-
Hypertriglyceridemia take because of reduced number of low-density lipoprotein (LDL)
Peripheral edema receptors results in an increase in low-density cholesterol-carrying
Musculoskeletal apolipoprotein concentration. The synthesis rate of free fatty acids
Myopathy and triglycerides is normal in hypothyroidism; the hypertriglyc-
Arthritis/arthralgia eridemia is caused by a decreased fractional removal rate of trigly-
Cardiovascular cerides.
Bradycardia
Thyroid hormone deficiency causes several cardiac abnormali-
Pericardial effusion
ties. Cardiomegaly is secondary to hypothyroid-induced pericardial
Congestive heart failure
effusion, bradycardia, diastolic hypertension, and/or atherosclerosis.
1294 PART IV / Organ Systems and Diseases
Pericardial effusion is found in approximately 30% to 50% of pa-
tients with overt hypothyroidism. The volume of the effusion cor-
relates with the severity of the disease. The electrocardiogram may
show ST and T wave changes, QT prolongation, and more often
low-amplitude QRS complexes or a low voltage that is a result of peri-
cardial effusion rather than a myocardial conduction defect. Cardiac
tamponade and hemodynamic compromise are very rare. Bradycar-
dia results from the effects of thyroid hormone deficiency on the
cardiac conducting system. The slowing of the heart rate is moderate
and its role in the development of fatigue in hypothyroid patients
is unclear. Hypothyroidism may mask typical symptoms of coro-
nary artery disease by causing depressed myocardial contractility and
bradycardia, resulting in reduced myocardial oxygen consumption.
Exertional dyspnea and reduced exercise tolerance are present
in 50% of elderly patients with overt hypothyroidism and maybe
related to skeletal muscle dysfunction rather than impaired cardiac
function. Anginal chest pain was reported in 25% of patients with
overt hypothyroidism, suggesting an increased prevalence of coro-
nary heart disease in these patients. Patients with a long-standing
history of hypothyroidism are especially at risk of developing
atherosclerotic vascular disease that may have been induced by
diastolic hypertension and hypercholesterolemia. Hypothyroidism
predisposes to diastolic hypertension by impairment of the diastolic
relaxation phase. Approximately 1% of patients with diastolic hyper-
tension may have hypothyroidism as the cause. Blood pressure nor-
malizes with thyroid hormone replacement therapy in such patients.
Given the prevalence of hypothyroidism in the elderly popula-
tion and the comorbidities listed above, it is not uncommon to be
faced with an untreated elderly hypothyroid patient who requires
surgery. A few small, retrospective studies suggest that surgery is
relatively safe in hypothyroid subjects, and urgent surgery does not
need to be postponed while therapy is started. However, particular
attention must be given to anesthetic and drug administration since
hypothyroid patients clear medications more slowly than euthyroid
patients.
Diagnosis
The diagnosis of primary hypothyroidism is relatively straightfor-
ward since all cases are associated with elevated serum TSH levels.
The serum-free T4 level will be low in overt hypothyroidism and
will be normal in subclinical hypothyroidism. Serum T3 concentra-
tions are not helpful in diagnosing hypothyroidism since they are
normal in about one-third of overtly hypothyroid patients and since
they do not decrease below normal until the free T4 is already low.
Therefore, TSH and free T4 levels are sufficient diagnostic tests for
hypothyroidism.
There is some controversy regarding what TSH level indicates hy-
pothyroidism. Most laboratories currently report upper limits of the
TSH normal range to be approximately 4.5 to 5.0 mU/L. However,
the upper normal range is lowered to 3.5 to 4.0 mU/L if subjects
with antithyroid peroxidase antibodies are excluded, suggesting that
the reported normal range includes subjects with incipient thyroid
disease. This has led some experts to recommend a narrower TSH
normal range, with TSH levels above 3.5 mU/L consistent with mild
thyroid disease. If adopted, this would reclassify millions of patients
as being hypothyroid or undertreated with thyroid hormone. There
is almost no information on putative clinical effects in patients with
TSH levels of 3.5 to 5.0 mU/L, and therefore at this time it is
premature to adopt this recommendation.
There are a few other caveats to the biochemical diagnosis of hy-
pothyroidism. An elevated serum TSH level also may be seen during
the recovery period from NTI or after withdrawal of certain drugs
that suppress TSH levels. Therefore, the serum TSH measurement
must be interpreted in the context of the clinical situation. Central
hypothyroidism results in low serum T4 and T3 levels with a low
or normal serum TSH concentration, rather than an elevated TSH
level.
Treatment
The purpose of treatment of hypothyroidism, regardless of its cause,
is to achieve a euthyroid state that is reflected by normal thyroid
function tests. Synthetic levothyroxine is the preferred preparation
for treatment of hypothyroidism because of its long half-life (approx-
imately 7 days), reliable absorption, and relatively constant serum T4
concentration after single daily doses. The replacement therapy dose
of levothyroxine depends on the weight and age of the patient. Thy-
roxine requirements are decreased in the elderly because of a decline
in the degradation of thyroid hormone. The average requirement of
T4 in elderly patients is 25% less than in young adults.
In elderly patients with coexisting cardiovascular disease, starting
treatment with full replacement doses can result in exacerbation of
angina and worsening of the underlying heart disease. Therefore, it
is crucial that the starting dose of thyroxine should be small, such as
12.5 to 25 µg/day. The replacement dose titration needs to be done
cautiously with close monitoring of the patient’s symptoms and thy-
roid function tests. The dose should be adjusted at 6-week intervals
by an increment of 12.5 to 25 µg until the patient is euthyroid and
the serum TSH is in the mid-normal range. Once the serum TSH
level is within the normal range, its measurement may be done every
6 to 12 months to monitor the dose and compliance. Patients with
primary hypothyroidism can be monitored with a TSH alone, while
patients with central hypothyroidism should be monitored by free
T4 measurement.
Levothyroxine absorption is decreased by food, a high-fiber diet,
conditions associated with impaired gastric acid production, and a
number of medications (see Table 108-2). Drugs that block its ab-
sorption include calcium carbonate, ferrous sulfate, proton pump
inhibitors, cholestyramine, colestipol, sucralfate, and aluminum hy-
droxide. This malabsorption of thyroxine can be avoided to a large
extent by instructing the patient to allow a time interval of at least
4 hours between the ingestion of the two drugs, but in some cases,
an increase in thyroxine dose maybe required (such as during pro-
ton pump inhibitor therapy). Other medications accelerate thyrox-
ine clearance, including rifampin, carbamazepine, phenytoin, and
sertraline. Therefore, a higher levothyroxine replacement dose is re-
quired. Finally, estrogen therapy increases TBG levels, leading to a
greater amount of administered thyroxine being bound to TBG and
an increased thyroxine dose requirement.
Subclinical Hypothyroidism
Subclinical hypothyroidism is the term applied to the state in which
serum TSH concentration is raised while free T4 and T3 concentra-
tions are normal in a patient with no clinical features of hypothy-
roidism. Serum TSH concentrations bear a logarithmic relation to

free T4 levels; small decrements in free T4 concentration (even within
the population normal range) result in large increases in serum TSH
concentration.
The prevalence of subclinical hypothyrodism is age dependent.
The classic Whickham survey in Great Britain reported increasing
prevalence of elevated TSH levels with age, up to 18% in women
older than 74 years of age. The more recent Colorado Health Fair
study reported a prevalence of elevated TSH levels of 9.5% in the
entire study population, rising to 19% in those older than 74 years
of age. Finally, the most recent National Health and Nutrition Ex-
amination Survey in the United States found that 12% to 14% of
the population older than age 70 years had high serum TSH, as
compared with approximately 2% of the population younger than
age 40 years.
Most studies show that older women are at greatest risk for sub-
clinical hypothyroidism. In the Whickham survey, the prevalence
of subclinical hypothyroidism was more than threefold increased in
older women compared to older men. In a survey in the United
States, the prevalence of serum TSH elevation was 8.5% in women
and 4.4% in men older than age 55 years. However, rates of sub-
clinical hypothyroidism among older men in the Colorado Health
Fair study approached those of older women.
The common causes of subclinical hypothyroidism are the same
as the causes of overt hypothyroidism (see Table 108-3). The ma-
jority of patients have chronic autoimmune thyroiditis with positive
antithyroid peroxidase antibodies. Those patients with high titers
of antithyroid antibodies and more than twice the upper limit of
serum TSH are most likely to develop overt hypothyroidism. In the
20-year follow-up study of patients with subclinical hypothyroidism
in the Whickham Survey, the annual rate of thyroid failure was 4.3%
in those with positive thyroid antibodies, as compared to 0.3% in
thyroid-antibody-negative patients.
The clinical manifestations of subclinical hypothyroidism are de-
bated; some studies have suggested adverse effects on serum lipids,
cardiac function, or neuropsychiatric function. Cardiac and lipid
effects have received particular attention since a large-scale survey
of elderly women in Rotterdam showed that subclinical hypothy-
roidism increased the risk for myocardial infarction two- to three-
fold. Lipid abnormalities associated with subclinical hypothyroidism
have primarily included cholesterol or LDL levels slightly higher
than euthyroid control groups. Cardiovascular abnormalities associ-
ated with mild thyroid failure include left ventricular diastolic and
endothelial dysfunction. The cardiac structure and function remain
normal at rest, but ventricular function and cardiovascular and res-
piratory adaptation are impaired during exercise. Left ventricular
ejection fraction is similar to the euthyroid state at rest, but reduced
with exercise. In terms of neuropsychiatric function, previous cross-
sectional studies have suggested increased rates of anxiety, depression,
or cognitive impairment in subclinical hypothyroidism. However, a
recent large cross-sectional study failed to find any association be-
tween subclinical hypothyroidism and numerous measures of mood
and cognition.
Further studies have assessed the effects of thyroxine treatment
on serum lipid concentrations, cardiac function, cognitive function,
and psychiatric status in subclinical hypothyroidism. Results have
been mixed, with some studies showing decreased cholesterol and
LDL levels, improved cardiac function, or improved cognitive and af-
fective symptoms. However, not all studies have demonstrated these
effects, which are often of small magnitude and unclear clinical rel-
CHAPTER 108 / Thyroid Diseases 1295
evance. An expert consensus panel reviewed the efficacy of treating
subclinical hypothyroidism. The panel concluded that treatment
was reasonable in patients with TSH levels greater than 10 mU/L,
those with symptoms, or those with elevated cholesterol levels. If
implemented, the goal of therapy is to normalize the serum TSH
concentration. In older people, 12.5 to 25 µg levothyroxine is rec-
ommended as the initial dose. With minimal TSH elevations and
absence of clinical features, treatment is not necessary, but patients
should be followed at intervals of 6 months.
Myxedema Coma
Myxedema coma is a rare syndrome that represents the result of se-
vere untreated hypothyroidism. Most patients are older than 60 years
of age. It is characterized by lethargy, progressive weakness, stupor,
hypothermia, hyponatremia, cardiovascular shock, and coma. The
mortality rate is very high in older patients, approximately 80% in
untreated cases. Myxedema coma maybe precipitated by exposure to
cold weather; drugs such as narcotics, sedatives, analgesics, anesthet-
ics, or tranquilizers; pulmonary or urinary tract infections; and other
coexisting medical conditions such as cerebrovascular accidents or
congestive heart failure.
The patient may have a history of a previous thyroid disease, ra-
dioiodine therapy, or thyroidectomy. The medical history is of grad-
ual onset of progressive weakness and impaired cognitive function,
depression, and stupor. Physical findings include marked hypother-
mia, bradycardia, hoarseness, delayed reflexes, dry skin, and peri-
orbital edema. Laboratory evaluation may indicate hyponatremia,
elevated creatine phosphokinase level, neutropenia with a left shift,
elevated serum cholesterol level, increased cerebrospinal fluid pro-
tein, carbon dioxide retention, and hypoxia. Serum tests reveal a
low FT4 level and a markedly elevated TSH concentration, except
in central hypothyroidism, in which case an increased serum TSH
is not found.
Myxedema coma is an acute medical emergency and treatment
should be initiated immediately; 500-µg levothyroxine should be
given by intravenous bolus because such patients absorb drugs poorly
through the gastrointestinal tract. This is followed by daily adminis-
tration of 50-µg thyroxine intravenously. Because the possibility of
concomitant adrenal insufficiency (because of autoimmune adrenal
or pituitary insufficiency) may exist, hydrocortisone hemisuccinate
100 mg intravenously should be administered followed by 50 mg
every 6 hours. A serum cortisol level should be obtained prior to hy-
drocortisone infusion. If the serum cortisol level is greater than 20
µg/dL, then the corticosteroid can be discontinued. The patient’s
renal function, fluid status, and cardiopulmonary status must be
monitored closely.
HYPERTHYROIDISM
Definition
Hyperthyroidism refers to a state of excessive thyroid hormone avail-
ability to peripheral tissues. Overt hyperthyroidism occurs when
serum FT4 and/or T3 levels are above the normal range and usually
is associated with symptoms of hyperthyroidism. Mild thyroid over-
activity with a suppressed serum TSH level and normal FT4 and
1296 PART IV / Organ Systems and Diseases
T3 concentrations is referred to as subclinical (biochemical) hyper-
thyroidism. Subclinical hyperthyroidism is discussed in depth at the
end of this section.
Prevalence
There is a considerable variation reported in the prevalence of
hyperthyroidism in older subjects. Based on different ethnic and
geographic regions and the criteria used for diagnosis, the preva-
lence varies from 0.5% to 2.3% in the elderly population. Approxi-
mately 10% to 17% of all hyperthyroid patients are older than age
60 years.
Etiology and Pathogenesis
By far the most common cause of hyperthyroidism in the general
population is Graves’ disease, or diffuse toxic goiter. In older patients,
Graves’ disease remains a common cause of hyperthyroidism, but
other etiologies become more frequent. Graves’ disease is an autoim-
mune disorder that results from the action of a thyroid-stimulating
antibody on TSH receptors. TSH receptor antibodies are detectable
in the serum of approximately 80% to 100% of untreated patients
with Graves’ disease. The cause of the extrathyroidal manifestations
of Graves’ disease, such as ophthalmopathy and dermopathy, is un-
known. The proposed mechanism for the ophthalmopathy is the de-
velopment of retrobulbar autoimmune inflammation caused by the
release of cytokines, thickening of extraocular muscles, and swelling
of orbital contents.
Toxic multinodular goiter is more common in the elderly popu-
lation and has been reported in about one half of older patients with
hyperthyroidism, especially in regions of relative iodine deficiency. It
occurs most often in patients with a long-standing history of multin-
odular goiter. In most cases, the etiologic factor causing the transition
from nontoxic to toxic multinodular goiter is unclear. However, there
is generation of new follicles within the gland with functional auton-
omy independent from TSH stimulation. Autonomously function-
ing thyroid nodules synthesize and secrete thyroid hormones despite
suppression of TSH secretion. Thyrotoxicosis can be precipitated in
patients with nontoxic multinodular goiter by administration of a
large iodine load such as radiocontrast agent or amiodarone.
Thyroiditis, either acute or subacute, occurs with less frequency in
the aged as compared with younger patients with hyperthyroidism.
Thyrotoxicosis results from extensive destruction of follicular cells
by either an inflammatory or infectious process and release of T4
and T3 into the circulation. Certain drugs, including amiodarone,
lithium, and cytokines such as interferon alpha and IL-2, may cause
destructive thyroiditis and thyrotoxicosis.
Amiodarone-induced hyperthyroidism is particularly complex
and difficult since the drug is prescribed to elderly patients with
underlying cardiac disease or arrhythmias, which increases the risks
of the superimposed hyperthyroidism. Amiodarone-induced thyro-
toxicosis (AIT) in association with iodine excess is termed type 1 AIT,
while destructive thyroiditis is called type 2 AIT. A combination of
type 1 and type 2 AIT can also occur. Treatment can be difficult, and
recommendations vary depending on whether the patient has type 1
or type 2 AIT. Unfortunately, distinguishing between the two types
of AIT is sometimes impossible, especially in the acute situation,
and patients are often treated simultaneously for both.
Hyperthyroidism resulting from a TSH-secreting pituitary ade-
noma or pituitary resistance to thyroid hormone is very rare. Clinical
manifestations are similar to those of Graves’ disease except that the
patient does not have a suppressed TSH level.
Clinical Manifestations
The classic signs and symptoms of hyperthyroidism include weight
loss with increased appetite, heat intolerance, excessive sweating,
diarrhea or loose stools, tremor, tachycardia, and palpitations. Al-
though they can be present, these classic findings are less common in
older patients with hyperthyroidism. Absence of the typical manifes-
tations of hyperthyroidism in the elderly patient was first described
in 1931 by Lahey as “apathetic hyperthyroidism,” in which there was
only slight evidence of hypermetabolism. Instead, the dominant clin-
ical findings maybe weight loss or cardiac or gastrointestinal mani-
festations, and the diagnosis of hyperthyroidism maybe overlooked.
Table 108-6 lists the signs and symptoms of hyperthyroidism in the
elderly patient. Recognition of these important clues will facilitate
detection of the disease at an earlier stage.
Table 108-7 compares clinical findings of hyperthyroidism in
elderly and young patients independent of etiology. In this study,
thyroid hormone levels were similar in both groups, and there was
no correlation between serum TSH and FT4 levels and the preva-
lence of signs and symptoms of hyperthyroidism. The results of
this study confirm that the presentation of hyperthyroidism in older
patients is associated with fewer classic signs or symptoms and in-
creased frequency of anorexia, atrial fibrillation, and a lack of goiter.
Interestingly, palpable goiter is absent in approximately 50% of the
older patients with hyperthyroidism, whereas 80% of the younger
patients have thyroid enlargement on physical examination.
The cardiovascular manifestations of thyrotoxicosis may pre-
dominate in elderly patients, especially atrial fibrillation or supraven-
tricular tachycardia. Occult hyperthyroidism should be ruled out in
any elderly patient with a new onset of tachyarrhythmias. Elderly
hyperthyroid patients with atrial fibrillation are at risk for systemic
embolization and stroke, especially those with coexisting cardiac
disease.
TABLE 108-6
Clinical Features of Hyperthyroidism in Elderly Patients
Cardiovascular
Palpitations
Chronic or intermittent atrial fibrillation
Congestive heart failure
Psychiatric and behavioral
Depression
Apathy
Lethargy
Irritability
Gastrointestinal
Decreased appetite
Weight loss
Nausea
Constipation
Musculoskeletal
Proximal muscle weakness
Muscle atrophy
 CHAPTER 108 / Thyroid Diseases 1297

prevalence of somatic complaints, anxiety, and fewer complaints

TABLE 108-7
of sadness or guilt) later in life should be evaluated for hyper-
Comparison of Clinical Features of Hyperthyroidism in thyroidism.
Elderly versus Young Patients

Symptoms Elderly, >70 Young, <50

and Signs Years (%) Years (%) Diagnosis
Tachycardia 71 96 The preferred approach to diagnosis of hyperthyroidism is the com-
Fatigue 56 84
bination of free thyroxine or free thyroxine index level (either of
Weight loss 50 51
which will be elevated) and a sensitive TSH assay (which will be
Tremor 44 84
Dyspnea 41 56
suppressed). Although serum TSH level is suppressed in hyperthy-
Apathy 41 25 roidism, there are other reasons for a suppressed TSH, so this test
Anorexia 32 4 alone in a geriatric patient is not diagnostic of hyperthyroidism. In
Nervousness 31 84 fact, most elderly subjects with low serum TSH levels are not hy-
Hyperactive reflexes 28 96 perthyroid (see “Subclinical Hyperthyroidism” later in this chapter).
Weakness 27 61 Medications such as dopamine or glucocorticoids and conditions
Depression 24 22 such as hypothalamic or pituitary disorders may cause suppression
Increased sweating 24 95 of the serum TSH level.
Diarrhea 18 43 An elevation of serum T3 level in addition to an elevated serum
Muscular atrophy 16 10
T4 level is a strong confirmation of hyperthyroidism. However, the
Confusion 16 0
serum T3 level is not increased in every elderly patient with hyperthy-
Heat intolerance 15 92
Constipation 15 0
roidism and was found to be elevated in only 50% of such patients
between 75 and 95 years of age. The relative absence of T3 elevation
maybe a reflection of less conversion of T4 to T3 peripherally in the
aged population.
Patients with a low serum TSH and normal FT4 levels should
The excessive amounts of thyroid hormones in hyperthyroidism
have the T3 level measured to identify T3 thyrotoxicosis, a con-
increase myocardial oxygen demand and may unmask coronary
dition seen in 1% or 2% of hyperthyroid patients in the United
artery disease or exacerbate underlying cardiac conditions such as
States. T3 thyrotoxicosis is more common in elderly patients with
angina pectoris or congestive heart failure. Elderly patients with thy-
a solitary adenoma or with early toxic multinodular goiter. Its
rotoxicosis and evidence of cardiac contractile dysfunction caused
causes and treatment are the same as for hyperthyroidism in
by hypertension, coronary artery disease, valvular heart disease, or
general.
atrial fibrillation are at higher risk of developing congestive heart
Once hyperthyroidism is detected, a 24-hour radioactive iodine
failure.
uptake should be done to exclude conditions causing thyrotoxicosis
Dyspnea on exertion and exercise intolerance are also common
with low thyroid uptake: thyroiditis, exogenous intake of thyroid
complaints of thyrotoxic patients. These symptoms can be caused by
hormone, or iodine-containing drugs. If there is concern for a toxic
weakness of the skeletal and respiratory muscles rather than compro-
nodule or toxic multinodular goiter, a 24-hour radioactive iodine
mised cardiac function. Marked weakness and atrophy of muscles
scan can be added to the uptake measurement.
may have an insidious onset and slow progression in some elderly
patients with thyrotoxicosis that has been long-standing as a result of
delayed diagnosis because of its atypical presentation. Weakness in-
Treatment
volves mostly the proximal muscles, especially those of the shoulder
girdle and the pelvis. The preferred mode of therapy for hyperthyroidism in the elderly is
The classic gastrointestinal signs and symptoms of hyperthy- radioactive iodine-131. To avoid postradiation release of preformed
roidism are increased appetite, rapid intestinal transit, resulting in thyroid hormone from glandular stores and subsequent exacerbation
more frequent defecation, and weight loss. However, some elderly of hyperthyroidism, severely affected patients should be treated with
patients with apathetic hyperthyroidism present with weight loss, antithyroid drugs for at least 3 months to achieve a normal or near-
anorexia, nausea, vomiting, and constipation. In a group of 880 pa- normal serum free T4 level prior to use of 131 I. The usual doses are
tients with Graves’ disease, weight loss became a major diagnostic 5 to 15 mCi of radioactive 131 I for Graves’ disease and 15 to 50
finding in 80% of patients older than age 70 years. This weight loss mCi for large multinodular glands. The antithyroid drugs should be
is secondary to increased metabolic demands and reduced appetite. discontinued 7 days before administration of the radioiodine dose
Thus, hyperthyroidism should be ruled out as a cause of weight loss and restarted 7 days after 131 I treatment. Beta-blockers are often used
in elderly patients before proceeding with an extensive evaluation as an adjuvant, especially in cases of symptomatic tachycardia, and
for occult malignancy or gastrointestinal disease. should be continued until the patient is euthyroid. The incidence
The neurobehavioral and psychiatric changes associated with hy- of hypothyroidism in the first year after radioiodine treatment is
perthyroidism in young adults include anxiety, emotional lability, dose-dependent, ranging up to 90%, and hypothyroidism continues
insomnia, lack of concentration, restlessness, and tremulousness. In to develop in subsequent years. Therefore, the patient should be
contrast to these features, apathy, lethargy, pseudodementia, and monitored regularly for the development of hypothyroidism, and
depressed mood frequently are present in older people with hy- thyroxine therapy should be started promptly after the diagnosis of
perthyroidism. Patients with an atypical depression (an increased hypothyroidism is established.
1298 PART IV / Organ Systems and Diseases
Therapy with thionamide antithyroid drugs is also appropriate
for otherwise healthy elderly patients with Graves’ disease or toxic
nodular goiters. Propylthiouracil and methimazole are the antithy-
roid drugs available in the United States. Methimazole is preferred
over propylthiouracil since it can be given once a day and has a better
side effect profile. When used for Graves’ disease, thionamides are
usually given for 12 to 18 months and then discontinued to see if
a sustained remission has been achieved. Beta-blockers can be used
temporarily until euthyroidism is achieved. Retrospective analysis of
the therapeutic response to antithyroid drugs in patients with hyper-
thyroid Graves’ disease has shown that euthyroidism was achieved
in 2 to 3 months in patients older than age 60 years after treatment
with methimazole. In long-term follow-up after thionamides are dis-
continued, recurrence rates are up to 50%. They were found to be
the highest in patients younger than age 30 years and were signifi-
cantly less with advanced age. If a relapse occurs after discontinuing
a thionamide, the drug can be restarted, or radioactive iodine can
be used. When used for toxic nodular goiters, thionamides have to
be given indefinitely since these conditions do not remit.
Patients should be warned about the side effects of antithyroid
drugs, which include rash, hepatic injury, and agranulocytosis. The
latter two side effects are rare but potentially life-threatening. Rou-
tine monitoring of blood counts and liver function tests is not rec-
ommended, since these side effects can occur abruptly. If the patient
develops sore throat, chills, fever, or signs of liver damage, the an-
tithyroid drug should be stopped until the patient is assessed clin-
ically. Fortunately, these side effects are reversible with supportive
care.
Surgery for hyperthyroidism is only advised if there are obstruc-
tive symptoms from a large goiter or the presence of a nodule that is
suspicious for malignancy. Preparation for thyroidectomy includes
using a beta-adrenergic antagonist drug for several weeks before
surgery in doses sufficient to lower the resting pulse rate to less
than 90 beats per minute. If surgery must be done urgently, then
sodium iopanoate has been reported to be safe and effective when
given for 5 days together with a β-adrenergic antagonist. Although
the mortality from subtotal thyroidectomy is very low, the complica-
tions of recurrent laryngeal nerve damage and hypoparathyroidism
can result in lifelong disability. Because of the complications, surgery
is rarely advisable in the elderly patient.
Atrial fibrillation in the context of hyperthyroidism is more com-
mon in elderly patients and is treated with standard agents while
the hyperthyroidism is being treated. Atrial fibrillation may resolve
once euthyroidism is achieved. Approximately 8% of hyperthyroid
patients with atrial fibrillation may develop embolic stroke, with
increasing rates in older patients with underlying structural heart
disease; therefore, such patients should be given anticoagulation un-
less there is a contraindication. Anticoagulant doses must be carefully
monitored, since hyperthyroidism affects clotting factor levels and
drug metabolism.
Subclinical Hyperthyroidism
Subclinical hyperthyroidism is defined as a state of suppression of
serum TSH with normal free thyroxine (FT4 ) and triiodothyronine
(T3 ) levels in a patient who lacks clinical features of thyrotoxicosis.
The most common cause of subclinical hyperthyroidism is iatrogenic
because of the use of TSH-suppressive doses of thyroxine. This is
done purposely in patients with thyroid cancer and inadvertently
in patients with hypothyroidism. Other endogenous causes of sub-
clinical hyperthyroidism are the same as for overt hyperthyroidism,
including Graves’ disease, toxic nodules or toxic multinodular goi-
ters, and iodine or amiodarone administration.
In addition to subclinical hyperthyroidism, there are other rea-
sons a patient might have a low or suppressed TSH. These include
acute or chronic illness (the NTI syndrome described earlier in this
chapter), drugs that suppress TSH levels, and transient thyroiditis.
In fact, depending on the population, most patients with a low TSH
level will have one of these other conditions, and not subclinical hy-
perthyroidism. For this reason, a thorough evaluation must be done
before a patient receives a diagnosis of subclinical hyperthyroidism.
The prevalence of subclinical hyperthyroidism in older patients
varies according to whether patients receiving exogenous thyroid
hormone are included. If these patients are excluded, the prevalence
is less than 2% of older subjects. The progression of subclinical hy-
perthyroidism to overt thyrotoxicosis is variable, with some patients
eventually becoming hyperthyroid, while others remain stable or
revert to a normal TSH level.
Most of the available data on pathophysiologic effects of TSH
suppression have been derived from patients with either thyroid
carcinoma or nontoxic nodular goiter on levothyroxine suppressive
therapy. These effects have been studied in three main areas: symp-
toms and neuropsychiatric effects, bone loss, and cardiac effects. It
should be noted that many of these studies included few if any older
patients, so their generalizability to elderly people is unclear.
There are relatively few studies regarding symptoms and neu-
ropsychiatric effects in patients with a suppressed TSH level, but
some do suggest that these patients may have increased rates of hy-
perthyroid symptoms and decrements in mood or cognition. How-
ever, most of these studies suffer from bias, since patients were aware
of their diagnoses and often treated with thyroxine. The largest and
most recent cross-sectional study failed to find any associations be-
tween subclinical hyperthyroidism and a number of measures of
mood and cognition.
Mild thyroid hormone excess is associated with increased bone
turnover rate; the bone resorption rate exceeds the formation rate
and bone loss results. However, there is extensive and conflicting
information on whether this is clinically significant. Many studies
in postmenopausal women with suppressed TSH have shown an
accelerated bone loss in the hip, lumbar spine, and distal radius,
whereas other studies have failed to demonstrate this. Two meta-
analysis studies found a significant 10% loss of bone density in post-
menopausal women with suppressed serum TSH. However, many
women in these studies were treated with doses of thyroxine that
would clearly be considered supraphysiologic today. The only large-
scale study of fracture rates in women (the Study of Osteoporotic
Fractures [SOF]), concluded that subclinical hyperthyroidism in-
creased fracture rates at both the hip and the vertebrae. In sum, sub-
clinical hyperthyroidism probably causes clinically relevant bone loss
in postmenopausal women (not in men or premenopausal women),
which can be attenuated with antiresorptive therapy.
Atrial fibrillation is probably the best documented and most seri-
ous consequence of subclinical hyperthyroidism. In the Framingham
Heart Study of patients older than 60 years of age with subclinical
hyperthyroidism, 28% of patients developed atrial fibrillation in a
10-year follow-up, as compared to 11% of the elderly population
with normal TSH levels. This finding has since been replicated in
other studies. In terms of cardiac structure and function, a number

of studies have shown subtle but statistically significant increases in
left ventricular mass and decreases in left ventricular diastolic func-
tion. Again, it should be noted that most of these subjects were
young, and were receiving thyroxine in suppressive doses for thyroid
cancer. Very little is known about cardiac structure and function in
subclinical hyperthyroidism in elderly patients, but one could rea-
sonably assume that the subtle decrements seen in young subjects
may contribute to clinically relevant deterioration in cardiac func-
tion in older patients. In terms of mortality, one recent longitudinal
study suggested an increase in cardiovascular mortality in older pa-
tients with subclinical hyperthyroidism, while a similar recent study
failed to find such an association.
Therapy for subclinical hyperthyroidism should be considered
in any patient with neuropsychiatric symptoms, osteoporosis, atrial
fibrillation, or cardiac disease. A trial of antithyroid drugs to normal-
ize the serum TSH level is warranted. In patients with more severe
features, such as atrial fibrillation, ablation of the hyperfunctioning
thyroid with radioactive 131 I can be considered.
THYROID NODULES
Prevalence
Thyroid nodules, either solitary or multiple, increase in frequency
with advancing age. The lifetime risk of developing a palpable thy-
roid nodule was estimated to be 5% to 10% in the United States
based on a prospective follow-up of more than 5000 patients in the
Framingham, Massachusetts, population study. The prevalence of
thyroid nodules was found to be higher in women than in men,
approximately 5:1, in the same study. An ultrasound survey of 704
people in Sicily without a history of thyroid disease detected nod-
ules in approximately 40% of those older than 60 years and 25%
of those younger than 60 years. Three-fourths of the nodules were
less than 10 mm in size, only 7% were 20 mm or larger, and the
ratio of women to men with nodules was 1.4. Autopsy examination
commonly has revealed thyroid nodules. A large autopsy series in the
United States indicated that 50% of the population with no known
history of thyroid disease had discrete nodules, 35% of whom had
nodules greater than 2 cm in diameter.
Clinical Evaluation
In formulating an effective management of a patient with a thyroid
nodule, a careful history and physical examination should be done
to assess the risk of malignancy. The patient’s age and gender are
important risk factors for malignancy. Although thyroid nodules
are found more frequently in women, the likelihood of a thyroid
nodule being malignant is higher in men than in women. The cancer
risk in a cold nodule was about sixfold higher in male patients older
than 70 years according to a 10-year follow-up study of more than
5000 patients.
The history of radiation exposure during childhood is important
because thyroid nodule or thyroid carcinoma can develop years later.
Most patients received radiation therapy for treatment of benign
conditions such as tonsillitis, acne, tinea capitis, impetigo, sinusitis,
or an enlarged thymus. The earlier the age of exposure, the higher
was the likelihood of cancer development. However, the latency
CHAPTER 108 / Thyroid Diseases 1299
period probably does not exceed 50 years, so the chance of radiation
induction from childhood exposure is very low in the elderly person.
A family history of thyroid cancer suggests familial papillary thy-
roid cancer or familial medullary thyroid cancer as a component of
multiple endocrine neoplasia (MEN) type 2. However, patients with
MEN usually present in childhood or early adulthood rather than
in the geriatric age group. Familial papillary thyroid cancer is much
more common than familial medullary thyroid cancer. A history of
goiter in the family maybe reassuring of a benign disorder.
Most thyroid nodules do not cause symptoms. Currently a large
majority of nodules are found incidentally during a procedure such
as carotid ultrasonography or CT scan or magnetic resonance imag-
ing (MRI) of the neck in the elderly person, giving rise to the term
incidentaloma. Pain may occur with a hemorrhage into a preexisting
colloid nodule or a benign adenoma. Symptoms of rapid nodular
growth over a period of weeks or months are suspicious of ma-
lignancy. Other symptoms that suggest malignancy are persistent
hoarseness or change in voice consistent with recurrent laryngeal
nerve dysfunction.
The physical examination of the patient with a thyroid nodule
should include careful palpation of the neck with attention to the
size and consistency of the nodule and the presence of adenopa-
thy. The location of the nodule within the thyroid gland and the
anatomy of the patient’s neck maybe the limiting factors in palpa-
tory examination of the neck. In general, most nodules larger than
3 cm in diameter are easily recognized on palpation. A hard and
fixed nodule is more likely to be malignant, but many papillary car-
cinomas or follicular tumors are soft or cystic. Lymphadenopathy is
strongly suggestive of malignancy in older patients; therefore, after
finding a thyroid nodule, the neck should be examined carefully for
the central and deep cervical lymph nodes.
A distinction between solitary and multiple nodules by neck ex-
amination maybe limited. In approximately 50% of patients with
a clinically solitary nodule on palpation, the lesion subsequently
was found to be a dominant nodule in a multinodular goiter on
ultrasound or histologic examination. The relative risk of cancer in
solitary versus multinodular thyroid glands is controversial. Older
studies reported lower rates of thyroid carcinoma in palpable multin-
odular glands (5% to 13%) as compared with solitary nodules (9%
to 25%), but recent studies have found similar incidences of cancer
in multinodular and single nodule glands.
Diagnostic Tests
Laboratory and radiographic evaluation of thyroid function is useful
to assist in determining whether a nodule is benign or malignant.
Figure 108-4 illustrates a recommended approach to diagnostic eval-
uation. Nearly all patients with either thyroid carcinoma or a benign
nodule are euthyroid. An abnormal thyroid function test in a pa-
tient with a thyroid nodule does not rule out thyroid cancer but
may make thyroid carcinoma a less likely possibility. Low serum
TSH concentration in the setting of a nodular goiter suggests the
presence of either an autonomously functioning adenoma or a toxic
multinodular goiter. Elevated antiperoxidase and antithyroglobulin
antibody titers indicate lymphocytic thyroiditis, which may present
as a nodule. The serum thyroglobulin level is not a useful test to
distinguish benign from malignant nodules because it is increased
with any goitrous process.
1300 PART IV / Organ Systems and Diseases
Thyroid ultrasound is a noninvasive test that discriminates cys-
tic from solid lesions. It is useful for differentiating thyroid from
nonthyroid neck masses and for localizing nodules deep within the
gland. It is routinely used to guide fine-needle aspiration (FNA)
biopsy. Thyroid ultrsonography is capable of identifying impalpa-
ble solid and cystic nodules as small as 0.2 mm in diameter. The
clinical significance of nodules smaller than 8 mm detected by ultra-
sonography remains uncertain. The ultrasonographic features that
suggest the diagnosis of malignancy are fine stippled calcifications
and intranodular vascularity.
FNA biopsy is the most important diagnostic technique. It re-
liably identifies thyroid nodule cytology and is the most effective
method to diagnose malignancy. In experienced hands, it is safe, with
accuracy, sensitivity, and specificity of 98% to 99%. Use of FNA has
been reported to result in reduction in thyroid nodule management
costs by 25%, and the number of patients requiring surgery de-
clined by more than 40%. FNA biopsy should be performed on
solid nodules larger than 1.5 cm, on nodules with both a solid
and cystic component larger than 2.0 cm, on the solid component
of large cystic nodules, and on nodules with evidence of recent
growth.
Results of FNA biopsies are divided into four basic categories:
(1) benign, (2) suspicious (includes aspirates with some features
of thyroid carcinoma but not conclusive), (3) malignant, and (4)
insufficient. In a large series of patients with FNA biopsy of the
thyroid, benign cytology was found in 69% (mainly colloid goiter),
malignant cytology in 3.5%, and suspicious cytology in 10%. The
suspicious category consists of variants of follicular neoplasm, but
follicular adenomas are about 10-fold more common than follicu-
lar carcinomas. The presence of nuclear atypia in a follicular lesion
gives a 44% prevalence of malignancy, and absence of nuclear atypia
denotes a benign lesion. The insufficient or nondiagnostic cytology
was reported as an average of 17% in the same report and has been
FIGURE 108-4. Algorithm for evalua-
tion and management of patients present-
ing with nodular thyroid disease.
attributed to lack of operator experience, nodular vascularity, or a
small or posteriorly located nodule. Those patients with a nondi-
agnostic or “insufficient” cytologic diagnosis should have a repeat
biopsy. An adequate specimen is obtained in a majority of repeat
FNA of nodules.
By thyroid scans with radioiodine, nodules are classified into hy-
perfunctional or “hot” nodules, nonfunctional or “cold” nodules, or
normal functioning or “warm” nodules. This classification is based
on the extent of radioiodine incorporation into a nodule compared
with the rest of the gland. In a study of more than 5000 patients with
thyroid nodules undergoing preoperative scanning, approximately
85% of the nodules were cold, 10% were normal, and 5% were
hot. These patients underwent thyroidectomy regardless of the scan
result. Thyroid cancer was found in 16% of patients with cold nod-
ules, in 9% with warm nodules, and in 4% with hot nodules. The
last figure is higher than expected because most other studies show
that a hot nodule is rarely malignant. The finding of a cold nodule
has relatively low specificity because the majority of both benign and
malignant solitary thyroid nodules appear hypofunctional relative to
adjacent normal thyroid tissue. Because the thyroid scan generally is
not useful for diagnosis of malignancy, it is not recommended in the
initial evaluation of a thyroid nodule. In patients with nodules that
are follicular lesions by FNA, radioiodine scan should be performed.
Hot or functional nodules are rarely malignant.
Positron emission tomography (PET) has been used to localize
recurrent thyroid cancers, but more quantitative studies of the uptake
of the glucose analog [18 F]2-deoxy-2-fluoro-d-glucose are needed to
determine its utility for diagnosis of a malignant thyroid nodule.
Management
The treatment of the thyroid nodule depends on the functional
state of the nodule and cytologic diagnosis with FNA biopsy (see

Figure 108-4). The hyperfunctioning “hot” nodule is treated with
radioiodine ablation or surgery. Older patients who refuse definitive
therapy or who are poor candidates can be treated with thionamides,
but these must be continued indefinitely, since hyperfunctioning
nodules rarely remit. Patients treated with 131 I ablation become eu-
thyroid in a few months, and hypothyroidism develops in only a
small proportion of such patients.
The vast majority of thyroid nodules are benign and should be fol-
lowed with observation alone or with thyroxine suppression therapy
in selected patients. Spontaneous regression of thyroid nodules may
occur. Thyroid hormone suppressive therapy is based on the assump-
tion that growth of the nodule depends on TSH. The aim of therapy
is to reduce serum TSH to the low-normal range. l-Thyroxine sup-
pressive therapy is useful for nodules that do not decrease in size
over several months of initial observation. Suppressive therapy in
the treatment of benign thyroid nodules has been challenged in the
past few years by failure of some studies to show a significant decrease
in nodule size and concern about reducing mineral bone density or
triggering atrial fibrillation, especially in the elderly. Several con-
trolled studies showed greater than 50% reduction in nodular size in
one fourth of patients with a single nodule. Generally, patients are
followed by palpation at intervals of 4 months. Ultrasonographic
examination can be performed to assess growth or shrinkage of a
nodule if more objective documentation is required on an annual
basis.
If the cytologic diagnosis indicates malignancy or is strongly sus-
picious for malignancy, the nodule should be removed surgically. In
the 10% to 20% of “suspicious” cytologic findings for malignancy
by FNA, approximately one-fourth of patients who undergo surgery
are found to have a malignant lesion. Altogether, only approximately
5% to 10% of thyroid nodules are malignant.
THYROID CANCER
Thyroid cancer accounts for 2.2% of all new cancers in the United
States. Mortality from thyroid cancer is 0.3% of all cancer deaths.
Epidemiologic studies during the last two decades report an increased
incidence of thyroid carcinoma in the United States because of im-
proved diagnosis; however, the mortality has decreased because of
earlier detection and improved treatment, in addition to a decline
in incidence of anaplastic thyroid carcinoma.
Thyroid carcinoma is classified into five major types: papillary,
follicular, medullary, anaplastic, and thyroid lymphoma. Most thy-
roid cancers are indolent and grow slowly over years, whereas a few
grow aggressively and cause death in a year. Thyroid carcinomas
tend to be more aggressive clinically and more poorly differentiated
in elderly patients compared with younger individuals.
Papillary Thyroid Carcinoma
Papillary carcinoma, the most common type of thyroid cancer, ac-
counts for more than 80% of all thyroid tumors. In autopsy studies,
the prevalence of occult papillary carcinoma (<1 cm) was found to
be 7% in patients older than 80 years of age. Papillary carcinoma
arises from follicular thyroid cells and is often indolent and slow
growing. The tumor tends to invade lymphatics and metastasize to
the regional lymph nodes and the lungs. Hoarseness and vocal cord
paralysis secondary to locally invasive thyroid cancer were found to
CHAPTER 108 / Thyroid Diseases 1301
predict death from papillary carcinoma. Hematogenous spread also
can occur to the bone and the central nervous system. The disease
is more aggressive in the older patients. The prognosis of papillary
thyroid carcinoma depends on the age of the patient at the time of
initial diagnosis, the size of the primary lesion, local invasion, and
the degree of metastases. Death rates are greater in adults older than
45 years of age. The 10-year survival was only 47% for patients older
than 70 years of age.
In a 12-year follow-up of patients older than 47 years of age
with papillary thyroid carcinoma, the death rate was 70% in pa-
tients with distant metastases versus 0.8% in patients with intrathy-
roidal disease. Thyroid tumors smaller than 1.5 cm in diameter rarely
metastasize to distant sites, whereas larger tumors are associated with
higher mortality rates. Extension of the tumor through the thyroid
capsule and into the surrounding structures is associated with poorer
prognosis. Cervical lymph node metastases occur in about 50% of
patients and carry only a slightly higher rate of recurrence and mor-
tality.
Surgery, either near-total or total thyroidectomy, is the initial
treatment of choice for patients with papillary carcinoma. Near-
total thyroidectomy is performed for extensive unilateral tumors
with local metastases. Total thyroidectomy is performed for pa-
tients with extensive multifocal disease with metastases to the cer-
vical lymph nodes, contiguous neck structures, or distant sites. The
main disadvantage of total thyroidectomy is the higher incidence of
hypoparathyroidism.
The prophylactic use of radioactive iodine-131 after surgery re-
duces the mortality rate and increases survival by destroying any
residual thyroid tumor. It is used in nearly all older patients because
of their worse prognosis based on age alone. Radioiodine therapy is
also used to treat patients with residual or recurrent papillary cancer
in the neck.
In order to scan and treat patients with 131 I, thyroxine therapy
must be withheld for 4 to 6 weeks to allow serum TSH levels to
rise. Alternatively, patients can be placed on 25-µg triiodothyronine
(liothyronine) twice daily for 1 month instead of thyroxine; then
the triiodothyronine is stopped for 2 weeks before administration of
131
I. This alternative procedure shortens the period of symptomatic
hypothyroidism. Thyroid hormone in a suppressive dose is given
after thyroidectomy to reduce thyroid cancer recurrence rates. TSH
stimulates thyroid tumors that contain TSH receptors. The dose of
thyroxine should be adjusted to keep the TSH suppressed without
causing clinical thyrotoxicosis. The degree of suppression should be
based on the staging of the patient. In patients with a good progno-
sis, TSH should be suppressed to the slightly subnormal range. In
patients with worse prognosis, which includes many elderly patients,
TSH should be suppressed to less than 0.1 mU/L without causing
clinical thyrotoxicosis, if this can be done safely.
Recombinant human TSH (rhTSH) may be used to stimulate
radioiodide uptake in scanning patients with well-differentiated thy-
roid cancer while they continue to take levothyroxine. This avoids
the symptoms of hypothyroidism that occur after withdrawal of
levothyroxine. rhTSH stimulates radioiodine uptake and thyroglob-
ulin secretion in normal and abnormal thyroid tissue. A clinical
trial comparing 48-hour 131 I whole-body scan results showed 89%
concordance in patients receiving rhTSH, as compared to the with-
drawal of levothyroxine therapy. Of the discordant results, 8% of
scans were superior after levothyroxine withdrawal, while 3% were
superior after stimulation with rhTSH (no significant difference).
1302 PART IV / Organ Systems and Diseases
Because stimulated serum thyroglobulin is a more sensitive assess-
ment of recurrence, this has replaced radioiodine scans for follow-up
of patients with differentiated thyroid cancer. The use of recently
developed very sensitive assays of thyroglobulin may replace the
need for stimulating thyroglobulin with rhTSH or thyroid hormone
withdrawal because an undetectable sensitve serum thyroglobulin
correlates well with a negative (low) stimulated serum thyroglobulin
measurement.
Ultrasonography of the neck is also used for following patients
after surgery because most recurrences are in the central neck region
or in cervical lymph nodes.
Follicular Thyroid Carcinoma
Follicular thyroid carcinoma accounts for about 10% of all thy-
roid cancers in the United States and is relatively more common
in regions of iodine deficiency. It occurs more frequently in elderly
people. Approximately 80% of follicular cell neoplasms are benign.
Larger follicular cell neoplasms are more likely to be malignant, espe-
cially in men and patients older than age 50 years. Follicular thyroid
carcinoma is slightly more aggressive than papillary carcinoma. Cer-
vical lymph node involvement is less common compared to papillary
thyroid cancer, but distant metastasis is more frequent.
With minimally invasive follicular carcinoma, there is usually in-
vasion of small vessels, whereas with more invasive tumors there is
vascular and capsular invasion and penetration into the surrounding
tissue, causing a poorer prognosis. Hürthle cell carcinoma is con-
sidered a variant of follicular thyroid carcinoma and carries an even
worse prognosis. Follicular carcinoma also metastasizes to the lung,
bone, central nervous system, and other soft tissues with higher fre-
quency than papillary carcinoma. Tumor recurrence in distant sites
is seen more frequently with follicular than with papillary carcinoma
and occurs with higher prevalence in highly invasive tumors.
Treatment includes total thyroidectomy and 131 I therapy to ablate
residual tumor. Radioiodine is the principal treatment of metastatic
tumors. If the tumor does not concentrate the isotope, external radi-
ation maybe effective. As with papillary carcinoma, thyroxine ther-
apy should be given to suppress serum TSH levels to the subnormal
range.
Medullary Thyroid Carcinoma
Medullary carcinoma accounts for 2% to 4% of thyroid cancers and
is derived from the calcitonin-secreting cells or parafollicular cells.
Elevated serum calcitonin levels establish the diagnosis and correlate
with tumor mass. Approximately 20% are familial tumors and are as-
sociated with other endocrine neoplasias (MEN type 2A or 2B). The
recognition of point mutations in the ret protooncogene on chro-
mosome 10 has enhanced the ability to detect these neoplasms at an
early and potentially curable stage in suspected family members. Ap-
proximately 80% of medullary carcinoma is sporadic and diagnosed
later in life, mostly after age 50 years. Three fourths of patients with
sporadic medullary carcinoma present with a thyroid mass and 15%
have local symptoms of dysphagia, dyspnea, or hoarseness.
Immunohistochemical studies demonstrate the presence of cal-
citonin in the tumor that is also able to synthesize calcitonin gene-
related peptide, ACTH, serotonin, prostaglandin, histamine, and
carcinoembryonic antigen. Diarrhea occurs in 30% of patients with
advanced disease and correlates directly with the tumor mass. Re-
currence rate increases in frequency with age. About two thirds of
patients older than age 70 years have persistent disease or a higher
recurrence rate after surgery.
Anaplastic Thyroid Carcinoma
Anaplastic carcinoma of the thyroid, the most aggressive and lethal
neoplasm, accounts for 2% of all thyroid carcinomas. It is often
derived from a well-differentiated thyroid carcinoma. The peak oc-
currence of this tumor is in the seventh decade of life; three quarters
of patients are 60 years of age or older and it is more common
in women. Examination of the neck usually reveals a fixed, large,
firm mass that often makes it difficult to detect neck nodes clini-
cally. Hemorrhage and necrosis within the tumor may result in soft,
fluctuant masses. Large axillary nodes are sometimes seen.
Treatment includes surgery, followed by external radiation and
chemotherapy, which may result in disease-free intervals of 1 to 5
years. The mortality exceeds 80% at 12 months. Long-term survivors
usually have only a small focus of anaplastic cells.
Thyroid Lymphoma
Thyroid lymphoma accounts for about 1% of thyroid malignancies.
It is often engrafted on a background of chronic lymphocytic thy-
roiditis. At the time of presentation with lymphoma, the patient is
usually older than 60 years of age. There is a female preponderance.
This tumor arises from B-cell lymphocytes. It usually invades the
walls of blood vessels and extends outside the thyroid gland. The
usual clinical presentation is a rapidly enlarging thyroid mass in a
patient with long history of a goiter or diagnosis of Hashimoto’s
thyroiditis that was treated with thyroid hormone. The patient may
complain of neck pressure, local swelling of the thyroid gland, hoarse-
ness, and dysphagia. FNA may suggest the diagnosis, but definitive
diagnosis usually requires an open biopsy. Surgical removal of the
lymphoma by total thyroidectomy is unwise. Treatment with ex-
ternal radiation and four to six courses of chemotherapy usually
produces a permanent remission.
FURTHER READING
Bagchi N, et al. Thyroid dysfunction in adults over age 55 years. Arch Intern Med.
1990;150:785.
Bartolotta TV, et al. Incidentally discovered thyroid nodules: incidence, and greyscale
and colour Doppler pattern in an adult population screened by real-time com-
pound spatial sonography. Radiol Med (Torino). 2006;111:989.
Belfiore A, et al. Cancer risk in patients with cold thyroid nodules: relevance of iodine
intake, sex, age, and multinodularity. Am J Med. 1992;363:363.
Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and
mortality in older adults. JAMA. 2006;295:1033.
Cooper DS. Subclinical hypothyroidism. N Engl J Med. 2001;345:260.
Cooper DS, et al. Management guidelines for patients with thyroid nodules and
differentiated thyroid cancer. Thyroid. 2006;16:109.
Frates MC, et al. Management of thyroid nodules detected at US: Society of Radiol-
ogists in Ultrasound consensus conference statement. Radiology. 2005;237:794.
Frates MC, et al. Prevalence and distribution of carcinoma in patients with solitary and
multiple thyroid nodules on sonography. J Clin Endocrinol Metab. 2006;91:3411.
Gussekloo J, van Exel E, De Craen AJ, Meinders AE, Frolich M, Westendorp RG.
Thyroid status, disability and cognitive function, and survival in old age. JAMA.
2004;292:2591.
Hershman JM, et al. Serum thyrotropin and thyroid hormone levels in elderly and
middle-aged euthyroid persons. J Am Geriatr Soc. 1993;41:823.
Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical hypothyroidism.
Thyroid. 2000;10:665.
Ladenson PW, et al. American thyroid association guidelines for detection of thyroid
dysfunction. Arch Intern Med. 2000;160:1573.