200 CHAPTER 7 The Thyroid Gland

A B

C D

FIGURE 7 28 Examination of the thyroid gland. A. Observe the neck, especially as the patient swallows. B. Examine from the front, rotat-
ing the gland slightly with one thumb while palpating the other lobe with the other thumb. C. Examine from behind, using three fingers and
the same technique. D. The size of each lobe or of thyroid nodules can be measured by first drawing an outline on the skin.

HYPOTHYROIDISM
Hypothyroidism is a clinical syndrome resulting from a deficiency
of thyroid hormones, which results in widespread organ-specific
effects. Hypothyroidism in infants and children results in marked
slowing of growth and development, with serious permanent con-
sequences, including mental retardation when it occurs in infancy
and short stature, when it occurs in later childhood. Hypothyroid-
ism with onset in adulthood causes diminished calorigenesis and
oxygen consumption; impaired cardiac, pulmonary, renal, gastro-
intestinal, and neurological functions and deposition of glycos-
aminoglycans in intracellular spaces, particularly in skin and
muscle, producing in extreme cases the clinical picture of
myxedema. The symptoms and signs of hypothyroidism in adults
(described in detail later) are reversible with therapy.
Etiology and Incidence (Table 7–6)
Hypothyroidism may be classified as (1) primary which is by far
the most common, (2) secondary due to pituitary TSH deficiency,
(3) tertiary due to hypothalamic TRH deficiency, or (4) peripheral
thyroid hormone resistance.
The incidence of various causes of hypothyroidism varies
depending on geographic and environmental factors, such as
TABLE 7 6 Etiology of hypothyroidism.
Primary:
1. Hashimoto thyroiditis:
a. With goiter
b. “Idiopathic” thyroid atrophy, presumably end-stage
autoimmune thyroid disease, following either Hashimoto
thyroiditis or Graves disease
c. Neonatal hypothyroidism due to placental transmission of
TSH-R blocking antibodies
2. Radioactive iodine therapy for Graves disease
3. Subtotal thyroidectomy for Graves disease, nodular goiter, or
thyroid cancer
4. Excessive iodide intake (kelp, radiocontrast dyes)
5. Subacute thyroiditis (usually transient)
6. Iodide deficiency (rare in North America)
7. Inborn errors of thyroid hormone synthesis
8. Drugs
a. Lithium
b. Interferon-alfa
c. Amiodarone
Secondary: Hypopituitarism due to pituitary adenoma, pituitary
ablative therapy, or pituitary destruction
Tertiary: Hypothalamic dysfunction (rare)
Peripheral resistance to the action of thyroid hormone

dietary iodide and goitrogen intake, the genetic characteristics
of the population, and the age distribution of the population
(pediatric or adult). Iodine deficiency is is still frequently seen
in developing countries and is the most common cause of
hypothyroidism world wide. The causes of hypothyroidism,
listed in approximate order of frequency in the United States,
are presented in Table 7–6. Hashimoto thyroiditis is by far the
most common cause of hypothyroidism in the developed
world. In younger patients, it is more likely to be associated
with goiter; in older patients, the gland may be totally
destroyed by the immunologic process, and the only trace of
the disease is a persistently positive test for TPO Abs. Similarly,
the end stage of Graves disease may be hypothyroidism, occur-
ring spontaneously or following destructive therapy with radio-
active iodine or thyroidectomy. Thyroid glands afflicted with
autoimmune inflammation are particularly susceptible to exces-
sive iodide intake (eg, ingestion of kelp tablets, iodide-containing
cough preparations, or the antiarrhythmic drug amiodarone)
or intravenous administration of iodide-containing radiographic
contrast media. Large amounts of iodide block thyroid hormone
synthesis via the Wolff-Chaikoff effect (see earlier), producing
iodine-induced hypothyroidism with goiter in the patient with an
abnormal thyroid gland; the normal gland escapes from the Wolff-
Chaikoff effect or iodide block, but for unclear reasons, autoim-
munity renders the gland more sensitive to the inhibitory effects
of iodine. Hypothyroidism may occur during the late phase of
subacute thyroiditis or silent thyroiditis; this is usually transient,
but it may be permanent especially in silent thyroiditis, where
permanent hypothyroidism occurs in about 25% of patients. Cer-
tain drugs can block hormone synthesis and produce hypothy-
roidism with goiter; at present, the most common pharmacologic
causes of hypothyroidism (other than iodide) are lithium carbon-
ate, used for the treatment of bipolar disease, and amiodarone.
Chronic therapy of hyperthyroidism with the antithyroid drugs
PTU and methimazole have the same effects. Interferon alfa, used
infrequently now to treat hepatitis C and other conditions, can
cause altered immunity that can result in hypothyroidism due to
Hashimoto thyroiditis. Inborn errors of thyroid hormone synthe-
sis, called thyroid dyshormonogenesis, result from genetic defi-
ciencies in enzymes necessary for hormone biosynthesis. These
effects may be complete, resulting in a syndrome of severe con-
genital hypothyroidism (cretinism) with goiter; or partial, result-
ing in goiter with milder hypothyroidism. At least five separate
biosynthetic abnormalities have been reported: (1) impaired
transport of iodine; (2) deficient TPO with impaired oxidation of
iodide to iodine and failure to incorporate iodine into TG; (3)
impaired coupling of iodinated tyrosines to triiodothyronine or
tetraiodothyronine; (4) absence or deficiency of iodotyrosine deio-
dinase, so that iodine is not conserved within the gland; and (5)
excessive production of metabolically inactive iodoprotein by the
thyroid gland (see Figure 7–6). The latter may involve impaired or
abnormal TG synthesis.
Pituitary and hypothalamic deficiencies as causes of hypothy-
roidism are quite rare and are usually associated with other symp-
toms and signs of pituitary insufficiency (see Chapter 4).
Peripheral RTH is discussed later.
CHAPTER 7 The Thyroid Gland 201
Pathogenesis
Thyroid hormone deficiency affects virtually every tissue in the
body, so that the symptoms are multiple. Pathologically, the most
characteristic finding is the accumulation of glycosaminogly-
cans—mostly hyaluronic acid—in interstitial tissues. Accumula-
tion of this hydrophilic substance and increased capillary
permeability to albumin account for the interstitial nonpitting
edema that is particularly evident in the skin, heart muscle, and
striated muscle. The accumulation is due not to excessive synthesis
but to decreased metabolism of glycosaminoglycans.
Clinical Presentations and Findings
A. Newborn infants (cretinism) The term cretinism was
originally applied to infants born in areas of severe iodine defi-
ciency with mental retardation, short stature, a characteristic
puffy appearance of the face and hands, and (frequently) deaf
mutism and neurologic signs of pyramidal and extrapyramidal
tract abnormalities. In the United States, neonatal screening
programs have revealed that in the Caucasian population the
prevalence of sporadic neonatal hypothyroidism is 1:5000,
whereas in the African American population the prevalence is
only 1:32,000. In areas of iodine sufficiency, neonatal hypothy-
roidism typically results from failure of the thyroid to descend
during embryonic development from its origin at the base of the
tongue to its usual site in the lower anterior neck, resulting in an
absent or ectopic thyroid gland that functions poorly. Placental
transfer to the embryo of blocking anti-TSH receptor Abs from
a mother with Hashimoto thyroiditis may result in agenesis of
the thyroid gland and athyreotic cretinism, but usually it only
causes transient hypothyroidism. Inherited defects in thyroid
hormone biosynthesis may also cause neonatal hypothyroidism
and goiter. Other possible causes of neonatal hypothyroidism
include exposure during pregnancy to iodides, antithyroid drugs
given to the mother, or inadvertent administration of radioac-
tive iodine for thyrotoxicosis or thyroid cancer.
The signs of hypothyroidism in newborns include respiratory
difficulty, cyanosis, jaundice, poor feeding, hoarse cry, umbilical
hernia, and marked retardation of bone maturation. The proxi-
mal tibial epiphysis and distal femoral epiphysis are present in
almost all full-term infants with a body weight over 2500 g.
Absence of these epiphyses strongly suggests hypothyroidism.
The introduction of routine screening of newborns for TSH or
T4 in the developed world has been a major public health
achievement, because early diagnosis can prevent permanent
mental retardation. A drop of blood obtained by heel stick 24 to
48 hours after birth is placed on filter paper and sent to a central
laboratory. A serum T 4 under 6 µg/dL or a serum TSH over
25 mU/L is suggestive of neonatal hypothyroidism. The diagnosis
can then be confirmed by repeat testing and radiologic evidence
of retarded bone age. Note that euthyroid infants born to hypo-
thyroid mothers who have been inadequately treated with levo-
thyroxine during pregnancy are not hypothyroid, but may have
diminished intellectual potential later in childhood—emphasizing
the importance of maintaining the mother in a euthyroid state
throughout pregnancy.
202 CHAPTER 7 The Thyroid Gland

B. Children and adolescents Hypothyroidism in children
and adolescents is characterized by retarded growth and short
stature, the typical signs and symptoms of hypothyroidism seen
in adults (see later), and variable but usually declining school
performance. Precocious puberty may occur, and there may be
enlargement of the sella turcica due to pituitary thyrotrope
hyperplasia associated with augmented TSH production.
C. Adults In adults, the common features of moderate to
severe hypothyroidism include easy fatigability; cold sensitivity;
weight gain (generally <10-20 lb); constipation; menstrual
abnormalities, especially menorrhagia; and muscle cramps.
Physical findings may include a cool, rough, dry skin; puffy face
and hands; a hoarse, husky voice; and slow reflexes. Reduced
conversion of carotene to vitamin A and increased blood levels
of carotene may give the skin a yellowish color. However, many
or all of the symptoms and signs are diminished or absent in
patients with milder degrees of thyroid failure.
1. Cardiovascular signs—Hypothyroidism is manifested by
impaired ventricular contraction, bradycardia, and increased
peripheral resistance, resulting in diminished cardiac output.
The electrocardiogram (ECG) may reveal low voltage of QRS
complexes and P and T waves, with improvement in response
to therapy. Cardiac enlargement may occur, due in part to
interstitial edema, nonspecific myofibrillary swelling, and left
ventricular dilation, as well as nonhemodynamically significant
pericardial effusion (Figure 7–29). The degree of pericardial

A B

C D

FIGURE 7 29 Top. Chest radiograph studies of patient with hypothyroid cardiomyopathy. A. Before therapy, showing pronounced cardio-
megaly. B. Six months after institution of thyroxine therapy, the heart size has returned to normal. (Reproduced with permission from Reza MJ,
Abbasi AS. Congestive cardiomyopathy in hypothyroidism. West J Med. 1975 Sep;123(3):228-230.)
Bottom. Echocardiogram of a 29-year-old woman with hypothyroidism C. before and D. after 2 months of therapy with levothyroxine sodium.
Note disappearance of pericardial effusion following levothyroxine therapy. (CW, chest wall; RVW, right ventricular wall; RVC, right ventricular
cavity; IVS, inter-ventricular septum; LVC, left ventricular cavity; PWLV, posterior wall left ventricle.) (Reproduced with permission from Sokolow M,
McIlroy MB. Clinical Cardiology, 4th ed. New York; McGraw-Hill Education; 1986.)

effusion can easily be determined by echocardiography.
Although cardiac output is reduced, congestive heart failure
and pulmonary edema are rarely noted. There is controversy
about whether hypothyroidism induces coronary artery dis-
ease, but coronary artery disease is more common in patients
with hypothyroidism, likely related to increased levels of total
cholesterol, LDL cholesterol, and possibly other nontraditional
atherogenic factors such as lipoprotein A and homocysteine. In
patients with angina pectoris, hypothyroidism may protect the
heart from ischemic stress, and replacement therapy may aggra-
vate the angina by increasing myocardial oxygen consumption.
2. Pulmonary function—In the adult, hypothyroidism is
characterized by shallow, slow respirations and impaired
ventilatory responses to hypercapnia or hypoxia. Respiratory
failure is a major problem in patients with myxedema coma
(see later).
3. Intestinal peristalsis—Peristalsis is markedly slowed, resulting
in chronic constipation and occasionally severe fecal impaction
or ileus.
4. Renal function—Renal function is impaired, with decreased
glomerular filtration rate and impaired ability to excrete a
water load. This predisposes the hypothyroid patient to hypo-
natremia from water intoxication if excessive free water is
administered.
5. Anemia—There are at least four mechanisms that may contrib-
ute to anemia in patients with hypothyroidism: (1) impaired
hemoglobin synthesis as a result of T4 deficiency; (2) iron defi-
ciency from increased iron loss with menorrhagia, as well as
impaired intestinal absorption of iron; (3) folate deficiency
from impaired intestinal absorption of folic acid; and (4) perni-
cious anemia, with vitamin B12-deficient megaloblastic anemia.
Pernicious anemia is often part of a cluster of autoimmune
diseases, including hypothyroidism due to Hashimoto or auto-
immune thyroiditis associated with thyroid autoantibodies,
pernicious anemia associated with parietal cell autoantibodies,
diabetes mellitus associated with islet cell autoantibodies, and
adrenal insufficiency associated with adrenal autoantibodies
(Schmidt syndrome; see Chapter 2). These conditions are part
of what has been termed the polyendocrine failure syndrome.
6. Neuromuscular system—Many patients complain of symp-
toms referable to the neuromuscular system, including severe
muscle cramps, paresthesias, and muscle weakness.
7. Central nervous system—Symptoms may include chronic
fatigue, lethargy, and inability to concentrate. Patients with
hypothyroidism are usually quite placid but can be severely
depressed or even extremely agitated (myxedema madness).
Patient takes Patient takes no
thyroid hormone thyroid hormone
Stop medication Serum FT4 and
6 weeks serum TSH
FT4 normal FT4 low,
TSH normal TSH high
EUTHYROID PRIMARY
HYPOTHYROIDISM
FIGURE 7 30 Diagnosis of hypothyroidism.
CHAPTER 7 The Thyroid Gland 203
8. Reproductive system—Hypothyroidism impairs the conver-
sion of estrogen precursors to estrogens resulting in altered
FSH and LH secretion and in anovulatory cycles and infertil-
ity. This may be associated with menorrhagia, which may also
be due, in part, to altered platelet function. Men may have
decreased libido and erectile dysfunction.
Diagnosis
The combination of a low serum FT4 and an elevated serum TSH
is diagnostic of primary hypothyroidism (Figure 7–30). Serum T3
levels are variable and may be within the normal range. Com-
monly, the serum FT4 is normal or low-normal, and the serum
TSH is elevated slightly, a situation termed subclinical hypothy-
roidism. This represents the mildest form of hypothyroidism and
is a consequence of the very sensitive feedback relationship
between the thyroid and the pituitary gland. In this situation, a
small decrement in thyroid hormone output by the thyroid
gland, in which serum T4 levels are still within the normal range,
results in a serum TSH level that is elevated, albeit usually less
than 10 mU/L. Subclinical hypothyroidism is usually due to
underlying Hashimoto thyroiditis, which can be confirmed by
assessing anti-TPO Ab titers. In patients with secondary or cen-
tral hypothyroidism, the serum FT4 will be low and serum TSH
will be low or normal, rather than elevated. Since serum TSH
rises with advancing age, some healthy elderly persons may have
mildly elevated serum TSH (eg, 5-7 mU/L), that can mimic sub-
clinical hypothyroidism.
The patient may be taking thyroid hormone when first seen.
A palpable or enlarged thyroid gland and a positive test for thy-
roid autoantibodies would suggest underlying Hashimoto thy-
roiditis, in which case the medication should be continued. If
antithyroid Abs are absent and the indication for therapy uncer-
tain, the medication could be withdrawn for 6 weeks and deter-
mination made for FT4 and TSH. The 6-week period of
withdrawal is necessary because of the long half-life of T4 (7 days)
and to allow the pituitary gland to recover after a long period of
suppression. The pattern of recovery of thyroid function after
withdrawal of T4 is noted in Figure 7–31. In hypothyroid indi-
viduals, serum TSH becomes elevated at 5 to 6 weeks and FT4
remains subnormal, whereas both are normal after 6 weeks in
euthyroid individuals.
The clinical picture of fully developed myxedema is usually
quite clear, but the symptoms and signs of mild or subclinical
FT4 low,
TSH normal or low
SECONDARY
HYPOTHYROIDISM
204 CHAPTER 7 The Thyroid Gland

12 Euthyroid (n = 6) reproductive function, including infertility, delayed or precocious

Hypothyroid puberty, or menorrhagia; idiopathic edema or pleuropericardial
T4 (µg/dL)

8 effusions; retarded growth; obstipation; chronic rhinitis or

SEM hoarseness due to edema of nasal mucosa or vocal cords; and
LLN
4 severe depression progressing to emotional instability or even
frank paranoid psychosis. In the elderly, hypothyroidism may
0 present with apathy and withdrawal, often attributed to senility.
In such cases, assessing thyroid function with serum FT4 and
TSH measurements confirms or rules out hypothyroidism as a
150
contributing factor.
T3 (ng/dL)

90 LLN
Complications
30 A. Myxedema coma Myxedema coma, an extremely rare
0
condition, is the end stage of untreated hypothyroidism (see also
Chapter 24). It is characterized by progressive weakness, stupor,
Basal TSH (µU/mL)

40
hypothermia, hypoventilation, hypoglycemia, and hyponatre-
20
mia, and it may ultimately result in shock and death. It occurs
most frequently in the winter in older female patients with
10
ULN underlying pulmonary and vascular disease, and the mortality
0
rate may be greater than 50%.
The patient (or a family member if the patient is comatose)
240 may recall previous thyroid disease, radioiodine or radiation
therapy to the neck area, or thyroidectomy. The medical history is
∆ TSH (µU/mL) after TRH

160 one of gradual onset of lethargy progressing to stupor or coma.

40
20
10
0
0 1 2 3 4 5
Weeks
FIGURE 7 31 Changes in T4, T3, TSH, and TRH response follow-
ing abrupt withdrawal of suppressive thyroxine therapy. Note that in
euthyroid individuals, the T 4 may not return to normal until 6 weeks
after withdrawal of therapy and that serum TSH is never elevated. In
hypothyroid patients, TSH may be elevated as early as 2 weeks after
withdrawal of therapy, and TRH response is exaggerated. (LLN, lower
limit of normal; ULN, upper limit of normal.) (Adapted with permis-
sion from Vagenakis AG, Braverman LE, Azizi F, et al. Recovery of
pituitary thyrotropic function after withdrawal of prolonged thyroid
suppression therapy. N Engl J Med. 1975 Oct 2;293(14):681-684.)
hypothyroidism may be very subtle or absent. This has led to
the recommendation by some professional organizations that
screening for hypothyroidism be undertaken, especially in
high-risk groups, such as older women where the prevalence is
high (up to 20% in women age >65), and in pregnant women,
where untreated hypothyroidism may cause adverse outcomes
in the child.
At times, patients with hypothyroidism present with unusual
features: neurasthenia with symptoms of muscle cramps, pares-
thesias, and weakness; refractory anemia; disturbances in
Examination reveals bradycardia and marked hypothermia, with
body temperature as low as 24°C (75°F). The patient is usually an
obese elderly woman with yellowish skin, a hoarse voice, a large
tongue, thin hair, puffy eyes, ileus, and slow reflexes. There may
be signs of other illnesses such as pneumonia, myocardial infarc-
tion, cerebral thrombosis, or gastrointestinal bleeding. Seizures,
6 bleeding episodes, hypocalcemia, or hypercalcemia may occur.
Laboratory clues to the diagnosis of myxedema coma include lac-
tescent serum, high serum carotene, hyponatremia, elevated BUN
and creatinine, elevated serum cholesterol, and increased cerebro-
spinal fluid protein. Pleural, pericardial, or abdominal effusions
with high protein content may be present. Serum tests reveal a low
FT4 and a markedly elevated TSH. Thyroid autoantibodies are
usually strongly positive, indicating underlying Hashimoto thy-
roiditis. The ECG shows sinus bradycardia and low voltage. If
laboratory studies are not immediately available, which is fre-
quently the case, the diagnosis must be made clinically.
The pathophysiology of myxedema coma involves three major
features: (1) CO2 retention and hypoxia, (2) fluid and electrolyte
imbalance, and (3) hypothermia. CO2 retention and hypoxia are
probably due in large part to a marked depression in the ventila-
tory responses to hypoxia and hypercapnia, although factors such
as obesity, heart failure, ileus, immobilization, pneumonia, pleural
or peritoneal effusions, central nervous system depression, and
weak chest muscles may also contribute. Impairment of ventila-
tory drive is often severe, and assisted respiration is almost always
necessary in patients with myxedema coma. Thyroid hormone
therapy in patients with myxedema corrects the hypothermia and
improves the ventilatory response to hypoxia. Water intoxication,
due to reduced renal perfusion and impaired free water clearance,
is the major fluid and electrolyte disturbance. This causes

hyponatremia and is best managed by free water restriction.
Hypothermia may not be recognized if the ordinary clinical ther-
mometer only goes down to about 34°C (93°F); and a thermom-
eter that registers a broader scale must be used to obtain accurate
body temperature readings. Active rewarming of the body is con-
traindicated, because it may induce vasodilation and vascular col-
lapse. A rise in body temperature is a useful indication of
therapeutic effectiveness of T4 therapy.
Disorders that may precipitate myxedema coma include heart
failure, pneumonia, or administration of sedative or narcotic drugs
to a patient with severe hypothyroidism. Adrenal insufficiency may
occur occasionally in association with myxedema coma, either due
to functional pituitary impairment or concurrent autoimmune
adrenal insufficiency (Schmidt syndrome). Concomitant glucocor-
ticoid therapy is recommended until normal adrenal function can
be documented by laboratory testing. It is important to differenti-
ate myxedema coma due to primary thyroid gland failure from that
due to pituitary failure (central hypothyroidism). In the latter situ-
ation, glucocorticoid replacement is essential. Clinical clues to the
presence of pituitary disease include the following: a history of
amenorrhea or impotence, scanty pubic or axillary hair, and nor-
mal serum cholesterol and normal or low serum TSH levels. CT or
MRI may reveal an enlarged sella turcica. The treatment of myx-
edema coma is discussed later.
B. Hypothyroidism and heart disease In the past, treat-
ment of patients with severe hypothyroidism and heart disease,
particularly coronary artery disease, was very difficult, because
levothyroxine replacement was sometimes associated with exac-
erbation of angina, heart failure, or myocardial infarction. Now
that β-adrenergic–blocking agents, coronary stenting, and coro-
nary artery bypass surgery are available, hypothyroid patients
with coronary artery disease can be treated medically or surgi-
cally first, and T4 replacement therapy is then better tolerated.
C. Hypothyroidism and neuropsychiatric disease
Hypothyroidism is often associated with depression, which may
be quite severe. More rarely, severely hypothyroid patients may
become confused, paranoid, or even manic (myxedema mad-
ness). Screening of psychiatric admissions with serum FT4 and
TSH is an efficient way to identify these patients, who fre-
quently respond to T4 therapy alone or in combination with
psychopharmacologic agents. The effectiveness of T4 therapy in
depressed hypothyroid patients has given rise to the hypothesis
that the addition of T3 or T4 to psychotherapeutic regimens for
depression may be helpful in patients without demonstrable
thyroid disease, but this concept has been difficult to prove.
Treatment
A. Treatment of hypothyroidism Hypothyroidism is
treated with T4, which is available in pure form and is stable and
inexpensive. Because T4 is converted to T3 in peripheral tissues,
both hormones become available, even though only one is admin-
istered. Desiccated thyroid is now considered obsolete because it
CHAPTER 7 The Thyroid Gland 205
contains both T4 and T3, and triiodothyronine (as liothyronine)
is unsatisfactory because of its rapid absorption, short half-
life, and transient effects. The half-life of T4 is about 7 days,
so it needs to be given only once daily. It is well absorbed,
and blood levels are easily monitored by following FT4 and
serum TSH levels. T4 and T 3 levels are stable throughout the
day, although there is a slight increase in free T 4 levels several
hours after the medication is taken; this is not clinically
significant.
B. Dosage of levothyroxine Replacement doses of T4 in
adults range from 0.05 to 0.2 mg/d, with a mean of about 0.125
mg/d. The dose of T4 varies according to the patient’s age and
body weight (Table 7–7). Because of more rapid T4 metabolism,
infants and young children require a surprisingly high dose of T4
compared with adults. In adults, the mean replacement dose of
T4 is about 1.7 µg/kg/d, or about 0.8 µg/lb/d. In older adults,
the replacement dose is usually lower, about 1.6 µg/kg/d, or
about 0.7 µg/lb/d. For TSH suppression in patients post-
thyroidectomy for thyroid cancer, the average dose of T4 is
about 2.2 µg/kg/d (1 µg/lb/d). In most patients with hypothy-
roidism, one can begin treatment with the full estimated dose
requirement. After 4 to 6 weeks, the final dose is adjusted based
on the serum TSH level. The goal is to normalize the serum
TSH, which is typically between 0.5 and 4 mU/L. In older
patients or patients with underlying heart disease, it is best to
start with a low dose of T4 (eg, 0.025 mg/d) and increase the
dose at 4- to 6-week intervals based on serum TSH measure-
ments. Malabsorptive states or concurrent administration of soy
products, aluminum hydroxide antacids, bile acid–binding res-
ins such as cholestyramine and colestipol, calcium supplements,
sucralfate, or iron compounds decrease T4 absorption. In these
patients, T4 should be given before breakfast, when the stomach
is empty, and the other compounds taken 4 hours later. Other
drugs, such as the antiseizure medication carbamazepine, may
increase thyroid hormone requirements by increasing T4 metab-
olism. Proton pump inhibitors such as omeprazole may also
impair T4 absorption, possibly because gastric acid is needed for
dissolution of the tablets. Estrogen replacement may increase T4
requirements by increased binding of free T4 to TBG. T4 has a
sufficiently long half-life (7 days), so that if the patient is unable
TABLE 7 7 Replacement doses of levothyroxine.
Age Dose of Levothyroxine (μg/kg/d)
0-6 mo 10-15
7-11 mo 6-8
1-5 y 5-6
6-10 y 4-5
11-20 y 1-3
Adult 1-2
Data from Braverman LE, Utiger RD. Werner and Ingbar’s The Thyroid, 7th ed. Philadelphia:
Lippincott; 1996.
206 CHAPTER 7 The Thyroid Gland
to take medications by mouth for a few days, omitting T4 ther-
apy will not be detrimental. If a hospitalized patient is being
managed by sustained parenteral therapy, the parenteral dose of
T4 is about 75% to 80% of the usual oral dose.
C. Treatment of myxedema coma Myxedema coma is an
acute medical emergency and should be treated in the intensive
care unit. Blood gases must be monitored regularly, and the
patient usually requires intubation and mechanical ventilation.
Associated illnesses such as infections or heart failure must be
sought and appropriately treated. Intravenous fluids should
be administered with caution, and excessive free water intake
must be avoided. Because patients with myxedema coma may
absorb drugs poorly, it is imperative to give T4 intravenously.
These patients have marked total body depletion, and they
should receive an initial loading dose of 300 to 400 µg of T4
intravenously followed by 80% of the calculated full replace-
ment dose intravenously daily. Management of patients with
known or suspected heart disease is described later. If, after a few
days, the clinical response has been suboptimal, some experts
recommend adding intravenous T3 to the regimen at a dose of
5 µg every 6 hours. The clinical guides to improvement are a rise
in body temperature and the return of normal cerebral and
respiratory function. The possibility of concomitant adrenal
insufficiency (due to autoimmune adrenal disease or pituitary
insufficiency) needs to be considered and ruled out with a
cosyntropin stimulation test (see Chapter 9). Full adrenal sup-
port should then be administered (eg, hydrocortisone hemisuc-
cinate) 100 mg intravenously, followed by 50 mg intravenously
every 6 hours, tapering the dose over 7 days. Adrenal support
can be withdrawn if the pretreatment plasma cortisol is 20 µg/dL
or greater or if results of a cosyntropin stimulation test are
within normal limits. When giving T4 intravenously in large
doses, there is an inherent risk of precipitating angina, heart
failure, or arrhythmias in older patients with underlying coro-
nary artery disease.
At one time, the mortality rate of myxedema coma was about
80%. The prognosis has been vastly improved as a result of recog-
nition of the importance of mechanically assisted ventilation and
the use of intravenous T4. At present, the outcome probably
depends on how well the underlying comorbidities and conse-
quences of severe hypothyroidism can be managed.
D. Severe hypothyroidism with heart disease In
older patients—particularly those with known cardiovascular
disease—it is wise to start treatment slowly. T4 is given in a
dosage of 0.025 mg/d for 2 to 4 weeks, increasing by 0.025 mg
every 2 to 4 weeks until a daily dose of 0.075 mg is reached.
This dose is continued for about 6 weeks. Serum TSH is then
measured and the dosage adjusted accordingly. It typically
takes 2 to 4 months for a patient to come into equilibrium on
full dosage. In some patients, the heart is very sensitive to the
level of circulating T4, and if angina pectoris or cardiac
arrhythmia develops, it is essential to reduce the dose of T 4
immediately.
Adverse Effects of T4 Therapy
There are no reported instances of allergy to pure T4, although it
is possible that a patient may develop an allergy to the coloring
dye or some component of the tablet. The major toxic effects of
T4 overdosage are symptoms and signs of hyperthyroidism. Palpi-
tations are the most common thyrotoxic cardiac symptom, and
arrhythmias, particularly paroxysmal atrial tachycardia or atrial
fibrillation, may occur. Insomnia, tremor, restlessness, and exces-
sive warmth may also be troublesome. Simply omitting the daily
dose of T4 for 3 days and then reducing the dosage will correct the
problem.
Increased bone resorption and osteoporosis have been associ-
ated with longstanding hyperthyroidism and will also develop in
postmenopausal women chronically overtreated with T4. This can
be prevented by regular monitoring and by maintaining normal
serum TSH levels in patients receiving long-term replacement
therapy. In patients receiving TSH-suppressive therapy for thyroid
cancer, if serum FT4 levels are kept in the upper range of nor-
mal—even if TSH is suppressed—the adverse effects of T4 therapy
on bone will be minimal. In addition, concomitant administration
of estrogen or bisphosphonates to postmenopausal women receiv-
ing high-dose T 4 therapy minimizes bone resorption.
Course and Prognosis
The course of untreated hypothyroidism is one of slow deteriora-
tion, potentially leading eventually to myxedema coma and death.
With appropriate treatment, however, the long-term prognosis is
excellent. Because of the long half-life (7 days) of T4, it takes time
to establish equilibrium on a fixed dose. Therefore, it is important
to monitor the serum FT4 and TSH every 4 to 6 weeks until equi-
librium is reached. Thereafter, FT4 and TSH can be monitored
once in every 6 to 12 months. The dose of T 4 is increased by about
50% in most women during pregnancy with the greatest dosage
increases in those women with the least thyroid reserve (ie, in
women who have had a thyroidectomy or who have received
radioactive iodine therapy). Older patients metabolize T4 more
slowly, and the dose likely gradually decreases with age. A small
proportion of patients with hypothyroidism treated with levothy-
roxine monotherapy continue to have symptoms consistent with
thyroid hormone deficiency, despite having normal serum FT4
and TSH levels. The cause of this phenomenon is not known, but
some experts have recommended a trial of combination T4 and T3
therapy in selected patients, despite the fact that controlled trials
that have compared T4 monotherapy to T4 plus T3 combination
therapy showed no apparent benefit.
HYPERTHYROIDISM AND
THYROTOXICOSIS
Thyrotoxicosis is the clinical syndrome that results when tissues are
exposed to high levels of circulating thyroid hormones. It results in
a generalized acceleration of metabolic processes. In most instances,
thyrotoxicosis is due to hyperactivity of the thyroid gland, or
hyperthyroidism. Occasionally, thyrotoxicosis may be due to other