ObjectivesUpon completion of this self-assessment course,
the participant should be able to:
- Discuss the epidemiology of hypothyroidism.
- Describe the factors that regulate thyroid hormone secretion.
- Recognize the clinical presentations of hypothyroidism.
- Recommend the most appropriate diagnostic tests for detecting
- Review how to establish thyroid replacement therapy.
- Develop strategies to periodically monitor thyroid function.
- Summarize the current clinical controversies in hypothyroidism
Hypothyroidism is a relatively common disorder resulting from the inability
of the thyroid gland to secrete adequate amounts of thyroid hormone. It has a
variety of causes, from autoimmune thyroid disease to previous treatment for
hyperthyroidism. The clinical presentation depends on patients' age, gender, and
physical condition. Symptoms of the disease are often too vague to confirm the
diagnosis, and even those with overt biochemical hypothyroidism may present with
subtle clinical symptoms. The diagnosis of hypothyroidism is confirmed by
clinical laboratory assessment of thyroid function. Because of the wide-ranging
effects of thyroid hormone, hypothyroidism can have profound detrimental effects
on numerous organ systems. In most patients, a majority of these effects can be
prevented or reversed by thyroid hormone replacement. Therefore, in order to
recommend the most appropriate treatment, physicians should be knowledgeable
about the physiology and etiology of hypothyroidism and its most common clinical
Hypothyroidism is a condition resulting from insufficient production or
diminished action of thyroid hormone. It may begin in utero
or later in
life. Hypothyroidism is characterized by a generalized reduction in metabolic
function that most often manifests as a slowing of physical and mental activity.
The clinical presentation may vary from mild and asymptomatic to severe and
overt disease and may also depend on the patient's age, gender, physical
condition, and the rate at which hypothyroidism develops. In most spontaneous
cases, a decrease in thyroid function occurs gradually, with subclinical
hypothyroidism progressing over time to overt hypothyroidism.
Although clinical symptoms may suggest hypothyroidism, they usually are not
sufficiently specific to achieve a diagnosis, which can only be confirmed by
laboratory assessments of thyroid function. Hypothyroidism may be associated
with either a decrease or an increase (goiter) in thyroid size. Some patients
will present with obvious symptoms of hypothyroidism and minimal changes in
thyroid hormone levels, whereas others will have subtle symptoms despite
markedly abnormal thyroid function. A subset of patients will present with
thyroid hormone levels that suggest a complex underlying disease.
Because of the wide-ranging physiologic effects of thyroid hormone,
hypothyroidism can have profound detrimental effects on numerous organ systems.
In very young infants, hypothyroidism can result in irreversible mental
retardation and slowed physical growth unless thyroid hormone replacement
therapy is initiated within weeks after birth. This has led to the routine
testing for congenital hypothyroidism in newborn infants. In most patients over
3 years of age, the majority of the effects of the disease can be corrected by
thyroid hormone replacement. This review will provide an overview of the
physiology and etiology of hypothyroidism, its most common clinical
manifestations, and specific treatment approaches. In most patients, primary
hypothyroidism can be confirmed by appropriate laboratory tests and subsequently
treated with thyroid hormone replacement therapy. For more complicated cases,
experienced endocrinologists and thyroidologists may recommend different
diagnostic and therapeutic approaches.
Epidemiology of Hypothyroidism
In its clinically overt form, hypothyroidism is a relatively common
condition, with an approximate prevalence of 2% in adult women and 0.2% in adult
Older adults, particularly those over 60 years of age,
have a higher incidence of subclinical disease compared with younger adults --
the prevalence is approximately 6% in older women and 2% in older
In select groups of patients, the prevalence of undiagnosed
and untreated hypothyroidism may be significantly higher.
Hypothyroidism may be caused by dysfunction of the thyroid gland (primary),
pituitary (secondary), or hypothalamus (tertiary). Secondary and tertiary
syndromes are sometimes collectively referred to as central hypothyroidism.
Rarely, hypothyroidism is caused by mutations of thyroid hormone receptors,
which produce a syndrome characterized by a variable resistance to the actions
of thyroid hormone.[5, 6]
In more than 95% of patients,
hypothyroidism is caused by primary dysfunction of the thyroid gland. Table 1
lists some of the factors associated with an increased risk for developing
Table 1. Factors Associated With an Increased Risk of Hypothyroidism
|Age over 60 years|
|Thyroid nodular disease|
|History of hypothyroidism, hyperthyroidism, thyroiditis|
|Family history of thyroid disease|
|History of radiotherapy for head and neck cancer (external radiation
and iodine 131)|
|Nonthyroid autoimmune disease|
|Drugs (lithium, amiodarone)|
Thyroid hormones are the only iodine-containing substances of physiologic
significance in vertebrates. Thyroid cells actively extract and concentrate
iodide from plasma. Once in the thyroid gland, iodide is oxidized to iodine
before it is bound to tyrosyl residues on thyroglobulin. The oxidation of iodide
is catalyzed by thyroid peroxidase. Secretion of thyroid hormones depends upon
proteolysis of iodinated thyroglobulin, which yields iodotyrosines that are
eventually coupled to each other to form 3,5,3'-triiodo-L-thyronine
) and 3,5,3',5'-tetraiodo-L-thyronine (T4
coupling reaction is also catalyzed by thyroid peroxidase.
The normal thyroid produces all of the circulating T4 and about
20% of the circulating T3. Most of the biologic
activity of thyroid hormones is due to the cellular effects of T3,
which has a greater affinity for the thyroid hormone receptor and is
approximately 4-10 times more potent than T4.[8, 9]
Because 80% of serum T3 is derived from the deiodination of
T4 in tissues such as the liver and kidney, and as the thyroid
hormone receptor preferentially recognizes T3, T4 is
considered a prohormone.
Once T4 and T3 are released into the circulation, they
are bound by 3 important plasma proteins--thyroxine-binding globulin (TBG),
transthyretin (thyroxine-binding prealbumin), and albumin. Thyroxine-binding
globulin has the highest affinity for T4 and T3 and the
lowest capacity, whereas albumin has the lowest affinity and the highest
capacity. It is generally accepted that T4 and
T3 are inactive when bound to circulating proteins and only the free
(unbound) fraction is able to bind to specific thyroid hormone receptors in
peripheral tissues and possesses biologic activity. Normally, approximately
0.03% of T4 and 0.5% of T3 is free.[12, 13]
Variations in the structure or production of the major thyroid hormone
transport proteins may be inherited or acquired. Although these conditions
affect the amount of bound T4 and T3, they do not usually
affect serum free thyroid hormone concentrations, and therefore thyroid
status. However, changes in the binding capacity of thyroid
hormone transport proteins may significantly affect the measurement of total
thyroid hormone concentration and thereby complicate the diagnosis of
hypothyroidism. For example, increased levels of total thyroid hormones are
associated with excess TBG, familial dysalbuminemic hyperthyroxinemia, and
transthyretin-associated hyperthyroxinemia, whereas diminished levels of total
thyroid hormones are found in patients with TBG deficiency.[14, 15]
Because patients with abnormal levels of thyroid hormone binding proteins
usually have no obvious symptoms of abnormal thyroid function and no palpable
thyroid abnormalities, they are often inappropriately treated for thyroid
disease. Therefore, in patients with atypical thyroid function
tests, it is important to consider abnormalities in thyroid hormone transport
proteins and to select more direct methods for analysis of free thyroid
hormones. The accurate diagnosis of thyroid disease is more difficult in
patients with multiple abnormalities in thyroid hormone-binding
proteins. Table 2 lists factors and conditions that alter thyroid
hormone binding proteins and may make the diagnosis of hypothyroidism difficult.
Table 2. Conditions Affecting Thyroid Hormone-Binding Proteins and Their
Effect on the Diagnosis of Hypothyroidism
|Decreased TBG concentration
- Inherited syndromes
- Androgens, glucocorticoids
- Nephrotic syndrome
|Increased TBG concentration
- Inherited syndromes
- Hepatitis, hepatoma
- HIV infection
|Competitive inhibition of T4 binding
- Salicylates, furosemide
- Nonthyroidal illness
|Familial dysalbuminemic hyperthyroxinemia|
||Increased transthyretin binding
- Inherited syndromes
- Pancreatic and hepatic tumors
Adapted from Ladenson et al
Central regulation of thyroid hormone secretionThe thyroid gland is
controlled by the activity of the hypothalamic-pituitary-thyroid axis (Figure
1). The anterior pituitary produces thyroid-stimulating hormone (TSH), a
glycoprotein that interacts with specific receptors on thyroid cells and
stimulates the synthesis and secretion of thyroid hormones. The synthesis and
release of TSH from the pituitary is influenced by thyroid hormones and the
hypothalamic peptide thyrotropin-releasing hormone (TRH).[18, 19] The
activity of the thyroid gland is regulated by a neuroendocrine negative feedback
loop, in which thyroid hormone interacts with specific receptors on pituicytes
to inhibit TSH secretion and at the hypothalamus to inhibit TRH
secretion.[20-22] Thyroid hormone causes a dose-related decrease in
the TSH response to TRH. There is also evidence that thyroid
function is controlled by short-loop negative feedback, in which thyroid
hormone inhibits the responsiveness of the thyroid gland to
Figure 1. The hypothalamic-pituitary-thyroid
The interactions along the hypothalamus-pituitary-thyroid axis
maintain a stable amount of thyroid hormones in the circulation. Therefore,
abnormal levels of TSH almost always indicate the presence of underlying thyroid
disease. Although there is evidence that hormones,[25-29]
neurotransmitters, [32, 33]
regulate TSH secretion, the physiologic relevance of
their actions has not been completely characterized.
The effects of TSH on the thyroid gland are numerous and complex. It
increases carbohydrate, protein, and lipid metabolism, and stimulates cell
proliferation.[35-37] In addition, TSH increases the synthesis of
thyroperoxidase[38, 39] and of thyroglobulin and the
uptake of iodine into follicular cells and its incorporation into
Thyroid cells extract and concentrate iodide from plasma by an
energy-dependent, saturable process that produces a 20- to 40-fold higher level
of iodine in the intrathyroidal space compared with plasma. A
high glandular content of organic iodine diminishes iodide transport in response
to TSH. The ability of the thyroid to concentrate iodine is
controlled by the activity of the recently identified sodium/iodide symporter
(NIS),[44, 45] a protein located on the basolateral membrane of the
thyrocyte. Thyroid-stimulating hormone regulates iodide transport by increasing
the expression of NIS mRNA and protein. The role of NIS in
various disease and physiologic states associated with altered thyroid function
is presently being investigated. Mutations of the NIS gene that
impair the ability of NIS to transport iodide can manifest as
hypothyroidism and goiter. However, genetic
mutations of the NIS often have a clinical presentation that is variable and in
part dependent on iodine status of the patient.[50, 51] Increased NIS
expression occurs in patients with Graves' disease,[52, 53] and
antibodies to NIS have been detected in the sera of patients with autoimmune
thyroiditis.[54, 55] In patients with thyroid carcinoma, the
expression of the NIS gene may vary, but it is usually decreased.
A majority of the actions of thyroid hormone are mediated by the interaction
of T3 with specific nuclear receptors.[57-59] Thyroid
hormone receptors belong to a family of hormone-responsive nuclear transcription
factors that are similar in structure and mechanism of action to steroid
hormones. After thyroid hormone binds to its nuclear receptor, the
hormone-receptor complex binds to regulatory regions of genes (thyroid
hormone-response elements) and initiates a series of events that lead to
increased DNA transcription, mRNA translation, and protein synthesis.[58,
60] For example, the activity of malic enzyme, which is involved in
lipogenesis, is increased by thyroid hormone.
Two thyroid hormone receptor genes, designated alpha and beta, have been
identified, and although both receptors are highly homologous, they are encoded
by genes on separate chromosomes and have different affinity for
T3.[58, 62-64] Two mRNA splice variants have been
identified for each gene: T3 receptor alpha 1 and alpha 2 (the latter
ironically does not bind T3) and T3 beta 1 and
T3 beta 2. Whereas pituitary, liver, and kidney
express high concentrations of thyroid hormone nuclear receptors, spleen and
gonads exhibit low levels, thus accounting for the diverse actions of thyroid
hormone. There is disagreement about whether thyroid hormone has nongenomic
actions, although support for this hypothesis has been growing.
The number of thyroid hormone receptors appears to be altered in different
physiologic and pathologic states. Occasionally, a gene mutation alters the
ability of the receptor to bind T3, variably blocking the action of
thyroid hormone at the cell. Such mutations usually run in families and produce
a clinical syndrome of generalized thyroid hormone resistance.[5, 66,
67] The abnormal receptor is usually present in both pituitary and
peripheral tissues, although there are specific instances where the site of
resistance is primarily at either the pituitary or the periphery.[5,
66] Generalized resistance to thyroid hormone is usually associated with
either a detectable, normal, or elevated TSH level in the setting of high levels
of free thyroid hormones. This syndrome should not be confused with either
hyperthyroidism or hypothyroidism, and the treatment is difficult and complex.
The differentiation between generalized thyroid hormone resistance and authentic
hyperthyroidism depends upon a thorough personal and family history and physical
examination. In resistance syndromes, serum T4, T3 and TSH
levels often do not agree with findings from the clinical examination.
Classification of Hypothyroidism
Primary hypothyroidism is caused by a decreased
production of thyroid hormones by the thyroid gland. It is a relatively common
disease in both iodine-deficient and iodine-sufficient populations. Almost all
cases of adult hypothyroidism result from primary thyroid failure. The most
common cause of hypothyroidism is destruction of the thyroid gland by autoimmune
disease or by ablative therapies (iodine 131 therapy or external radiation to
the head and neck). Hypothyroidism may also be caused by factors that negatively
affect the synthesis of thyroid hormones, such as iodine deficiency or excess,
and inherited defects in thyroid hormone biosynthesis. Pharmacologic agents such
as lithium and amiodarone may inhibit thyroid hormone synthesis.
Much rarer causes of hypothyroidism are hemochromatosis
Secondary and tertiary syndromes are often
classified as hypothyroidism of central origin resulting from pituitary or
hypothalamic disease. They are rare causes of hypothyroidism. In contrast to
primary hypothyroidism, secondary hypothyroidism is caused by pituitary gland
dysfunction that results in a diminished secretion of biologically active
Causes of secondary hypothyroidism include pituitary
insufficiency and pituitary adenomas that decrease the ability of the thyropophs
to synthesize TSH. Secondary hypothyroidism (especially in the presence of a
pituitary tumor) may be accompanied by a decreased biosynthesis of other
pituitary hormones such as adrenocorticotropin hormone (ACTH), growth hormone,
follicle-stimulating hormone, and luteinizing hormone.
surgery is also a prominent cause of secondary hypothyroidism. Less frequently,
external radiation to the head and neck area, either for treatment of pituitary,
nasopharyngeal, or laryngeal tumors, may lead to secondary
In this case, it usually takes several years for
impaired pituitary function to cause hypothyroidism. In patients with a previous
history of external radiation to the head and neck, pituitary function should be
evaluated. It is also important to obtain a thorough history and physical exam,
noting specifically the presence of optic abnormalities. In rare instances,
may also produce
secondary hypothyroidism. Autoimmune hypophysitis may also occur, usually in
Laboratory studies in symptomatic secondary hypothyroidism typically show
decreased levels of free T4 and T3 and low or undetectable
TSH. It is important to consider that results of the immunoassay reflect the
amount of detectable TSH. However, TSH biologic activity may not always
correlate with TSH immunoreactivity. A classic example of this occurs in
patients with pituitary or hypothalamic tumors in which a normal level of TSH is
found in conjunction with decreased free T4 and symptoms of
hypothyroidism.[74, 78, 79] Based on the normal TSH level, the
unsuspecting clinician may conclude that the patient does not have
hypothyroidism. However, in this scenario, the amount immunoreactive TSH is
higher and is not concordant with the level of biologically active TSH. The
mechanism by which this occurs relates to abnormalities in TSH biosynthesis that
involve functionally relevant alterations in glycosylation or amino acid
sequence.[74, 79] Secondary hypothyroidism resulting from mutations
of the TRH receptor is characterized by low levels of TSH and thyroid
hormones. These patients exhibit no response to exogenous TSH.
Tertiary hypothyroidism is caused by
hypothalamic dysfunction and results in a decreased production and/or reduced
delivery of TRH to the pituitary gland.[20, 80, 81]
hypothyroidism usually occurs in conjunction with pituitary disease, it can
occur independently. Hypothyroidism develops because the pituitary receives
inadequate stimulation from TRH to support the secretion of sufficient
biologically active TSH. This condition can develop years after cranial
Hypothyroidism is a relatively common disorder,
in most cases caused by primary dysfunction of the thyroid. Hypothyroidism
can be confirmed by laboratory assessment of thyroid function. Higher than
normal levels of TSH almost always indicate hypothyroidism.
Consequences of Hypothyroidism
The wide-ranging effects of thyroid hormone are exemplified by the
consequences of thyroid hormone deficiency and excess. One of the earliest
recognized physiologic actions of thyroid hormone was its effect on the basal
Subsequently, the effects of thyroid hormone
deficiency on growth and development, on intermediary metabolism, on central
nervous system development and function, and on cardiovascular, skeletal,
gastrointestinal, and reproductive system activity have been characterized. They
are briefly summarized in the following section.
Growth and development
Thyroid hormone exerts profound effects on growth
and development during the first 2 decades of life. The manifestations of
hypothyroidism are age dependent, and the majority become evident during infancy
and early childhood. Thyroid hormone deficiency adversely affects the
development of the central nervous system,[83-85]
and skeletal system.
Hypothyroidism also delays
dental development and eruption.
Maternal thyroid function during early pregnancy is an important determinant
of early fetal brain development, because the fetal thyroid is unable to produce
any T4 before 12-14 weeks' gestation. The combination of maternal and
fetal hypothyroxinemia produced by iodine deficiency is associated with
irreversible fetal central nervous system damage. Preliminary
evidence suggests that low maternal free thyroxine concentration may impair
neurodevelopment in the healthy fetus.[90-92] A recent study
indicates that maternal hypothyroxinemia produces alterations in the activity of
neurotransmitter metabolic enzymes that have putative neurotropic functions in
By contrast, fetal thyroid hormone deficiency in the presence of normal
maternal thyroid function appears to result in minimal detrimental effects on
normal development, as somatic growth and linear bone growth appear normal or at
most minimally delayed. Although the function of the fetal
hypothalamic-pituitary axis develops autonomously of the mother, it is dependent
on maternal supply of iodine derived mostly from placental deiodination of
T4. The placenta is impermeable to TSH and permeable to TRH. Under
normal circumstances, neither T3 nor T4 freely crosses the
placenta to a large extent. However, it appears that the maternal contribution
of T4 increases in cases of congenital hypothyroidism. In a study of
infants who were unable to synthesize T4, cord serum levels of
T4 were 35-70 nmol/L. This suggests an increased
transport of T4 from the mother to the fetus. Thus, transplacental
movement of maternal T4 may provide a partial explanation for the
relatively normal clinical appearance at birth of most infants with congenital
Because two thirds of postnatal brain growth and differentiation occurs
during the first 2 years of life, thyroid replacement initiated shortly after
birth minimizes the risk of permanent brain damage. However, recent studies
suggest that even early thyroid hormone replacement may not completely abrogate
the detrimental effects of congenital hypothyroidism on cognitive
function.[95-98] Some have suggested that starting thyroid hormone
replacement therapy within 2 weeks of birth and at slightly higher dose than
previously recommended may prevent any long-term detrimental effects on
cognitive development.[99, 100] Thyroid hormone deficiency that
develops after 3 years of age is not associated with mental impairment, but is
associated with delayed somatic and linear bone growth and delayed eruption of
permanent teeth. Early detection and treatment of hypothyroidism in infants and
children enables normal prepubertal and pubertal growth and achievement of
maximal potential adult height.
In general, thyroid hormone deficiency results in a reduction
in the metabolic rate. This is manifest as the intolerance to cold temperatures
experienced by many hypothyroid patients. Thyroid hormone is also an important
modulator of intermediary metabolism.
Hypothyroidism is associated with an increase in serum concentrations of
intermediate-density lipoprotein and low-density lipoprotein (LDL) cholesterol.
Hyperlipidemia may contribute to the higher risk for developing coronary artery
disease associated with hypothyroidism. Although serum levels of
total cholesterol and low-density lipoprotein cholesterol (LDL) are often
increased in hypothyroid individuals, there is either no change or a modest
increase in high-density lipoprotein cholesterol (HDL).[103, 104] The
LDL particles of hypothyroid patients appear to be more susceptible to
oxidation, which potentially makes them more atherogenic.
Thyroid hormone replacement therapy may slow the progression of coronary artery
disease because of its beneficial effects on lipids.[103,
Glucose homeostasis may be altered due to the slower rate of glucose
absorption from the gastrointestinal tract. Insulin secretion in response to a
glucose load varies in hypothyroid individuals, but there is evidence of insulin
resistance and reduced glucose utilization.[108, 109]
Hypothyroid patients generally exhibit a decreased appetite. Contrary to
popular belief, obesity is not a feature of hypothyroidism. Although some
patients experience weight gain, the amount is modest and mostly attributed to
In addition to the important role of thyroid hormone in
central nervous system development during gestation and infancy, there are
numerous neurologic symptoms associated with hypothyroidism. The generalized
neurologic manifestations of hypothyroidism include headache, vertigo or
tinnitus, relaxation of deep tendon reflexes, psychiatric disorders, cognitive
deficits, and visual disturbances. Sensory disorders such as numbness, tingling,
and paresthesias are frequently reported. Hypothyroidism-associated hearing loss
usually resolves with thyroid hormone replacement.
to the hearing loss of adult-onset hypothyroidism, the sensorineural deafness of
Pendred's syndrome does not respond to thyroid hormone.
hypothyroid patients often manifest symptoms of depression,
has been recommended that thyroid function be evaluated in these patients,
especially if they are elderly, prior to initiating any form of
If symptoms of affective disorders are related to
hypothyroidism, they may improve or resolve on re-establishing euthyroidism.
The cardiovascular effects of hypothyroidism are
extensive and produce symptoms consistent with heart failure.
The etiology of cardiovascular abnormalities is related to the cardiac
enlargement due to myxedematous changes of the myocytes. As a result, the
contractility of the cardiac muscle is reduced. This causes profound changes in
indices of cardiac function. Pulse rate and stroke volume are diminished, and
cardiac output is often decreased to half the normal value.
Pericardial effusion is evident as an increase in the transverse diameter of the
Thyroid hormone replacement therapy reverses most
of these pathologic changes.[117, 118]
Elderly patients with coronary
artery disease and hypothyroidism should be treated cautiously with thyroid
hormone to avoid precipitating or exacerbating angina pectoris, acute myocardial
infarction, ventricular arrhythmias, and congestive heart
Attention should be directed to ensure that a
significant pericardial effusion is not present in hypothyroid patients,
especially in those with severe or prolonged disease.
Patients with hypothyroidism may present with
generalized muscle fatigue, myalgia, and cramps. One of the most obvious
manifestations of hypothyroidism is the delayed relaxation of deep tendon
Hypothyroid patients may also exhibit arthralgias, joint effusions, and
pseudogout. Although in most hypothyroid adults, bone density
and levels of calcium and phosphate are normal, there is some evidence of
reduced bone turnover. In children, hypothyroidism is associated
with delayed linear bone growth and skeletal maturation.
The effect of thyroid hormone deficiency on the
gastrointestinal system is attributable, at least in part, to the reduced
metabolic rate. Constipation and gaseous distension are a result of the reduced
appetite and prolonged gastric emptying and intestinal transit.
Achlorhydria caused by atrophic body gastritis, which is characterized by
atrophy of the gastric body mucosa, has been associated with
Parietal cell antibodies have been found in
patients with Hashimoto's thyroiditis
and pernicious anemia is
thought to occur more often in patients with autoimmune thyroid
The effects of hypothyroidism on fertility are
mediated by a disruption of gonadotropin secretion and steroidogenesis. In
hypothyroid patients, levels of follicle-stimulating hormone and leuteinizing
hormone (LH) may be increased, normal, or decreased, and the preovulatory LH
surge may be absent.
In females, hypothyroidism is associated
with menstrual irregularities, anovulation, and infertility.
males, hypothyroidism is associated with abnormalities of gonadal
Hypothyroidism is a rare cause of delayed
and some children with juvenile hypothyroidism exhibit
unexplained precocious puberty.
Early detection and treatment of
hypothyroidism in infants and children enable normal prepubertal and pubertal
growth and achievement of normal adult height following normal
Thyroid hormone replacement therapy may restore
reproductive function in patients with underlying
However, thyroid function testing may be useful
in screening subsets of patients with specific reproductive dysfunctions and not
as a routine appraisal of the infertile population.
The management of hypothyroidism during pregnancy is complex, as the
requirement for exogenous thyroid hormone typically increases by more than 50%
during gestation. Most of this increased requirement occurs
during the first half of gestation. Inadequate thyroid hormone replacement
during pregnancy increases the risk of giving birth to a low-weight or stillborn
infant. The maternal complications of hypothyroidism include miscarriage,
preterm delivery, hypertension, and postpartum hemorrhage. Although recent
reports have suggested that maternal hypothyroidism is associated with cognitive
defects in the offspring, these studies were small in number, and more data will
be required to confirm this hypothesis.[90-92] A restoration of
prepregnancy requirements for thyroid hormone occurs during the postpartum
The manifestations of hypothyroidism are diverse
and numerous. Thyroid hormone is important for normal growth and
development and for the proper functioning of the cardiovascular,
skeletal, gastrointestinal, and reproductive systems.
Evaluating the Patient
Medical history and physical exam
A comprehensive medical history and
physical exam can uncover symptoms that suggest hypothyroidism. A physical exam
should be conducted at the initial visit. Patients may report previous history
of transient hypothyroidism, family history of thyroid disease, radiotherapy of
the head and neck, or use of concomitant medications that interfere with thyroid
The manifestations of hypothyroidism are generally independent of its causes.
Table 3 lists some of the clinical symptoms of hypothyroidism. Most of the signs
are nonspecific and can be overlooked if the disease is mild or if the patient
has coexisting conditions that have similar symptoms. This is especially true in
Table 3. Clinical Signs and Symptoms of Hypothyroidism
Dry, brittle hair
Thick, brittle nails
Pitting edema of lower extremities
Compared with the obvious benefits of screening newborn
infants for hypothyroidism, the routine screening of healthy adults is not
recommended. The strongest case for routine thyroid function testing can be made
for elderly women who have symptoms consistent with
hypothyroidism.[134,135] The assessment of thyroid status remains an
important consideration for those patients at increased risk for developing
thyroid dysfunction (Table 1). Although the prevalence of abnormal thyroid
hormone status is relatively high in patients with acute
illness, an assessment of thyroid function is appropriate if
there is a positive history or if symptoms suggestive of thyroid disease are
Assessment of Thyroid Status
Because hypothyroidism is a relatively common disorder and its symptoms may
be subtle, laboratory tests are usually required to assess thyroid dysfunction.
The transition from the euthyroid to the hypothyroid state may first be
manifested as a slightly elevated TSH level in the presence of normal levels of
. This is because as thyroid hormone levels begin
to decrease, a compensatory increase in TSH secretion occurs, thus maintaining
normal levels of T3
. As thyroid failure progresses,
levels of thyroid hormones continue to decrease despite further increases in
TSH. In general, a TSH level below the normal range suggests high thyroid
hormone activity at the tissue level. Conversely, a higher-than-normal TSH
suggests that cells are receiving inadequate stimulation by thyroid hormone.
Levels of TSH are correlated with serum free T4
is the principal hormone produced by the
thyroid gland in response to TSH stimulation.
healthy individuals may have normal TSH levels despite having low free
values, suggesting that there are individual variations in the
threshold for TSH inhibition.
Of course, the presence of a
pituitary tumor or disease should be excluded when the TSH is low relative to
the levels of T4
. Table 4 shows the typical clinical findings of the
different forms of hypothyroidism.
Table 4. Typical Clinical Features of Hypothyroidism
D = decreased; N = normal; I =
The measurement of TSH as an initial step in the diagnosis
of hypothyroidism is appropriate because, in most patients, the amount of
thyroid hormone reaching the pituitary is comparable to that reaching the
peripheral tissues. Furthermore, almost no other disease increases serum TSH
levels, and individuals with primary hypothyroidism may have high TSH levels
even when serum thyroid hormones are in the normal range. Because of this,
measurement of total or free T4 and free T3 as the initial
step in the diagnosis of hypothyroidism is not recommended. However, the
assessment of both TSH and free T4 is required to achieve a
definitive diagnosis and to develop an appropriate treatment approach. It has
been suggested that in rare instances, thyroid hormones, and not TSH, are the
most relevant and appropriate indicators of thyroid status, but this approach is
not widely accepted. The utility of using TSH for screening
purposes depends on the presence of a normal pituitary gland.
Primary hypothyroidism is the most common cause of elevated TSH. Serum
T4 is decreased early in the disease, whereas T3 remains
normal until a substantial deterioration of thyroid function occurs. Table 5
shows the typical relationships between TSH and free T4 in the
various forms of hypothyroidism.
Table 5. TSH and Free T4 in Hypothyroidism
|Form of Hypothyroidism
|Central (pituitary, hypothalamic)
|Thyroid hormone resistance
D= decreased; N = normal; I =
Measurement of TSHThe sensitivity of TSH assays has improved
significantly over the last 20 years. The measurement of TSH is currently
performed by a "third generation" immunometric assay that is capable of
detecting and discriminating a TSH level as low as 0.01 mU/L, which is typical
of hyperthyroidism, from those near the euthyroid range of approximately 0.4-4.0
mU/L.[12, 138] The values of TSH are not normally distributed; most
patients have TSH values between 0.5 to 1.5 mU/L. Furthermore,
TSH may vary to some extent based on the time of day at which it is drawn, as it
exhibits a diurnal variation in secretion, reaching a peak at the onset of sleep
and a nadir during the afternoon hours. This does not usually
affect the detection of disease, as most outpatient evaluations of TSH are
usually conducted between 8:00 AM and 5:00 PM. Alterations in TSH levels are
associated with pathologic states such as starvation, moderate
and severe illness, and neuropsychiatric disorders. [139,
142] The mechanisms underlying the effects on thyroid function are
unknown. It is not recommended that the reference range for serum TSH assays be
adjusted to take into account coexisting physiologic conditions.
It is preferable, from the perspective of cost and efficiency, to measure
free T4 rather than total T4, as this eliminates the
possibility of abnormal levels of circulating binding proteins. On the other
hand, because a cost-effective assay for free T3 is not widely
available, total T3 is usually measured. However, total T3
is not a sensitive marker of thyroid status, as it is within normal limits in
approximately 20% of patients with hypothyroidism. Because of the utility and
accuracy of the third-generation assay for TSH, the TRH-stimulation test is
rarely required to make a diagnosis of hypothyroidism in patients with an intact
hypothalamic-pituitary axis.[143, 144] However, the TRH-stimulation
test can help identify central (pituitary, hypothalamic) hypothyroidism in
patients with borderline-low serum free T4 and normal TSH, as they
have an exaggerated TSH response. It may also be helpful in distinguishing
between hypothalamic and pituitary hypothyroidism, and between
these two disorders and nonthyroidal illness.
Another test that may be useful in the evaluation of patients suspected of
having hypothyroidism is ultrasonography of the neck, which may detect nodules
or infiltrative disease. A radionuclide scan with either iodine-123 or
technetium-99 may show heterogeneous uptake. Radioactive iodine uptake above the
normal range frequently occurs in hypothyroidism associated with an
organification defect.[146, 147] There are instances when it may be
important to visualize the pituitary gland directly using magnetic resonance
imaging, such as to distinguish microprolactinomas from functional
hyperprolactinemia. However, prolonged primary hypothyroidism,
especially in younger individuals, may be associated with enlargement of the
pituitary gland and even the erosion of the sella turcica, suggesting the
presence of a pituitary tumor. In a few instances, these patients exhibit a
dramatic decrease in the size of the pituitary after treatment with exogenous
thyroid hormone replacement.[148, 149] Therefore, in such
circumstances, a surgical approach to such putative clinical tumors must be very
Additional laboratory tests that may be useful for the diagnosis of
hypothyroidism include the measurement of thyroglobulin and/or thyroperoxidase
antibodies. Thyroperoxidase or thyroglobulin antibodies are present in most
patients with Hashimoto's thyroiditis.[150, 151] Antibodies that
block the TSH receptor may also occur in this setting. Patients
who have TSH receptor antibodies that inhibit TSH action generally present with
small or nonpalpable thyroid glands that exhibit low radioactive iodine
A comprehensive medical history and physical
exam may suggest hypothyroidism. However, because patients may experience
few symptoms, laboratory assessment of thyroid function is required to
confirm the diagnosis.
Etiology of Hypothyroidism
The most common cause of hypothyroidism in the
United States is chronic autoimmune or Hashimoto's thyroiditis.
The incidence is approximately 0.3-5 cases per 1000 individuals per year, and it
occurs 15-20 times more frequently in women than in men.[1, 155, 156]
There is evidence that the incidence is increasing.
thyroiditis is an autoimmune disorder associated with specific T and B cell
that result in the presence of microsomal
thyroid peroxidase or thyroglobulin antibodies.[160, 161]
antibodies may be a marker for Hashimoto's thyroiditis, or they may be involved
in the pathogenesis of the disease by decreasing thyroid peroxidase activity.
The majority of patients with Hashimoto's thyroiditis present with an
enlarged, palpable thyroid gland that demonstrates irregular uptake on
radionuclide scanning and moderate to high titers of thyroglobulin and thyroid
peroxidase antibodies.[160, 161] The Hashimoto goiter has a firm
consistency and although it may regress with time, in many cases it
persists. Hashimoto's thyroiditis can be identified by examining
biopsies obtained by fine needle aspiration. The characteristic finding in
Hashimoto's thyroiditis is a polyclonal lymphocytic
In general, patients with Hashimoto's thyroiditis experience a variable but
lengthy period of subclinical hypothyroidism, and the disease progresses over
time. They may present with either a normal or an elevated TSH. If the TSH is
normal at the time of initial evaluation, patients should be regularly
evaluated, perhaps once a year, for the development of elevated TSH levels
indicative of overt hypothyroidism. This probably occurs at the rate of 1%-3%
per year, especially in individuals over the age of 50. By age 60, the
likelihood of having a high TSH is approximately 10%-15% in females and 3%-5% in
men. Patients with Hashimoto's thyroiditis are particularly susceptible to
developing overt biochemical and clinical hypothyroidism following the
administration of iodine (either in the form of radiocontrast dyes such as those
used in computerized tomography scans or after the administration of exogenous
iodine or lithium).
The appropriate evaluation of a patient with Hashimoto's thyroiditis includes
assessment of free T4, total T3, TSH, and thyroglobulin
and thyroid peroxidase antibodies. It is important to obtain an accurate and
thorough history and physical exam. Once the thyroid gland is enlarged, or if
the diagnosis is in doubt, it might be reasonable to obtain a fine needle
aspiration biopsy and also perform ultrasonographic examination and/or a
radionuclide scan. However, the utility of a radionuclide scan has been
diminishing with the advent of ultrasonography and fine needle aspiration
biopsy. The rationale for performing ultrasonography and/or a fine needle
aspiration biopsy varies with each patient, but these procedures may be helpful
to secure a specific diagnosis as well as to identify thyroid nodules and follow
their progression. In the future, positron emission tomography may also have a
role in assessing thyroid nodules.
The risk for developing thyroid lymphoma is greatly increased in patients
with Hashimoto's thyroiditis.[164, 165] Therefore, if a patient who
has been followed for many years suddenly experiences difficulty swallowing or
develops a goiter, lymphoma should be strongly suspected, especially if the
patient is over age 40 years of age. These patients are candidates for immediate
evaluation of the thyroid by fine needle aspiration biopsy. Cytologic assessment
of cells involves sorting for monoclonality. In cases where lymphoma is
suspected, it is recommended that radiographic studies be performed to evaluate
the stage of the disease. Surgery is also used for diagnostic and perhaps
Hashimoto's thyroiditis may be associated with a higher frequency of other
autoimmune disorders such as lupus erythematosus, scleroderma, Sjogren's
syndrome, and adrenal insufficiency.[166-168] It is probably not
appropriate to screen each patient with Hashimoto's thyroiditis for other
autoimmune disorders, but a specific history and physical exam directed at that
possibility should be performed and appropriate laboratory data should be
obtained. The patient should also be advised of the possibility of developing
other autoimmune disorders over time. Furthermore, Hashimoto's thyroiditis is a
familial disease, but the genetic basis of this disorder has not been identified
or characterized. Because of this, the patient should advise
family members that they are predisposed to develop autoimmune disease of the
thyroid or other systems and that they should see a physician if symptoms of
autoimmune disease develop.
Although the concept remains controversial, there are many similarities
between Hashimoto's thyroiditis and Graves' disease--such that they probably are
caused by similar underlying immunologic dysfunction and represent the spectrum
of autoimmune thyroid disease.[170, 171] The panoply of antibodies
that are expressed in Hashimoto's thyroiditis varies widely and is similar to
those associated with Graves' disease.[172, 173] Antibodies that
stimulate the TSH receptor and those that block the TSH receptor are expressed
singly or together in Graves' disease and in Hashimoto's
thyroiditis,[173-176] and the clinical manifestation of the disease
probably depends on the predominance of specific antibody type. Approximately
15%-20% of patients with Hashimoto's thyroiditis and hypothyroidism express TSH
receptor-blocking antibodies. These patients have hypothyroidism most commonly
associated with a small, nonpalpable gland that exhibits decreased radioactive
The symptoms of Graves' disease and Hashimoto's thyroiditis frequently
overlap. For example, Graves' ophthalmopathy is somewhat of a misnomer, because
Hashimoto's patients occasionally manifest this condition as
well. In addition, familial autoimmune thyroid disease may
present as hyperthyroidism in one individual, whereas children or other
first-degree relatives of the patient may be hypothyroid. If TSH
receptor-blocking antibodies are predominant, the patient may initially present
with hypothyroidism. However, if over time the titer TSH receptor-stimulating
antibodies increase, the patient may become hyperthyroid. Conversely, a patient
with overt Graves' disease may initially present with a high titer of TSH
receptor-stimulating antibodies but over time may develop blocking antibodies
and eventually become hypothyroid.
Reversible autoimmune hypothyroidism
In approximately 1%-5% of patients
with chronic autoimmune thyroiditis, spontaneous recovery of thyroid function
takes place. Circumstances that increase the likelihood of this occurring
include the presence of a goiter and thyrotropin levels higher than
Silent or painless thyroiditis and postpartum thyroiditis are variant forms
of chronic autoimmune thyroiditis that are usually self-limiting.[179,
180] There is a transient progression from thyrotoxicity to hypothyroidism
to euthyroidism over a period of several weeks or months. Pharmacologic doses of
cytokines can also produce a transient hypothyroidism, which is usually reversed
after discontinuing treatment.
Postoperative and postradiation hypothyroidism
The vast majority of
patients who undergo thyroidectomy for Graves' disease develop hypothyroidism,
with the majority developing the disease during the first year after surgery.
After the first year there is a cumulative increase in hypothyroidism that has
underlying thyroiditis as its cause. Of course, the occurrence of hypothyroidism
in these patients depends on the amount of thyroid tissue removed and the nature
of the underlying thyroid disease. We prefer that an experienced surgeon perform
a near total thyroidectomy to decrease the likelihood of a recurrence of Graves'
disease. Patients who are under the care of a skilled thyroid surgeon experience
a low incidence of postoperative complications.
A leading cause of hypothyroidism is radioactive iodine treatment for Graves'
disease and sporadic nontoxic goiter.[181, 182] The incidence of
hypothyroidism is directly correlated to the dose of radioactive iodine, and the
symptoms may either appear immediately or not emerge until years later. Although
various alternate treatment strategies have been developed to diminish the
incidence of hypothyroidism, they are also associated with a higher prevalence
of persistent thyrotoxicosis. Permanent hypothyroidism is the
therapeutic goal of treatment with iodine-131. It is preferred that
hypothyroidism occur as soon as possible after treatment, ideally within 3
months. The frequency of external radiation-induced hypothyroidism depends to a
large extent on the dose of radiation received by the thyroid.
It is particularly common after irradiation for Hodgkins' and non-Hodgkins'
lymphoma, especially when the thyroid has not been shielded.
Generally, it takes years for hypothyroidism to develop in these circumstances.
Amiodarone is an important drug for the treatment of
ventricular and supraventricular arrrythmias. The ability of amiodarone to cause
hyper- or hypothyroidism is partly a result of its iodine content and its
chemical structure. It can affect the outcome of thyroid function tests, even in
the absence of thyroid dysfunction. In the United States, where there is
relative iodine abundance, hypothyroidism is the most common manifestation of
amiodarone thyrotoxicity. In Europe, which is widely iodine deficient,
hyperthyroidism is more common.
Hyperthyroidism associated with
amiodarone may be difficult to detect in part because amiodarone inhibits
conversion in the periphery and in the
Amiodarone-induced hypothyroidism often has a varied presentation. Most
patients with amiodarone-induced hypothyroidism have an elevated TSH. If
amiodarone inhibits T4to T3 conversion dramatically,
T4 clearance is delayed, and T4may be higher than is
normally observed in hypothyroidism. In general, if TSH is elevated, patients
may be treated judiciously, because of the danger of worsening already serious
underlying cardiac disease. The goal of treating amiodarone-induced
hypothyroidism is to achieve clinicaleuthyroidism, normal TSH, and relatively
normal or normal serum free T4 andfree T3.
It is not unusual for amiodarone to also cause hyperthyroidism.
Thyroid function in psychiatric disease
Psychiatric disease be
associated with transient increases in free T4
and free T3
in a majority of patients, especially in those admitted to the hospital. Lithium
has a dramatic effect on thyroid function tests in approximately one third of
patients taking the drug.[189, 190]
Patients will present with
elevated TSH levels, and a percentage of those will have overt hypothyroidism.
If the lithium regimen cannot be stopped, treatment of the underlying
hypothyroidism with exogenous levothyroxime (L-T4
) and careful
monitoring of lithium and L-T4
levels should be undertaken.
Occasionally, hypothyroidism may precipitate or aggravate psychiatric
illness.[113, 191, 192] There is evidence that therapy with L-T4
improves some indices of neuropsychological function.[193, 194]
Pharmacologic agents that affect the thyroid
Many pharmacologic agents
can interfere with thyroid physiology, the biochemical assessment of thyroid
function, and the pharmacokinetics of levothyroxine.[68, 195-197]
magnitude and clinical importance of these effects are likely to vary among
patients. Table 6 lists some medications that affect thyroid function.
Table 6. Drugs That May Affect Thyroid Physiology
Dopamine and dopamine
Hypothyroidism is most frequently caused by
chronic autoimmune (Hashimoto's) thyroiditis. Hypothyroidism should be
suspected when there is evidence of underlying thyroid, pituitary, or
hypothalamic disease or when the patient has been previously exposed to
any treatment that may disrupt the function of the
hypothalamic-pituitary-thyroid axis. Drugs such as lithium and amiodarone
can cause hypothyroidism.
Nonthyroidal Illness Syndrome
The nonthyroidal illness syndrome, alternately known as the euthyroid sick
syndrome, usually occurs in individuals who have nonthyroidal illness of varying
severity. Thyroid test results are abnormal even though the thyroid gland is
functioning normally and patients usually are not hypothyroid. Generally, the
conversion from T4
is impaired, resulting in low and
sometimes undetectable levels of T3
that are not accompanied by high
levels of TSH. Because TSH is usually normal, patients are considered euthyroid.
However, in some cases where the illness is severe, levels of T4
, and TSH may be decreased.
The decrease in T4 to T3 conversion is thought to be an
adaptive mechanism to limit metabolic activity during illness, as persistent
normal values of T3 are thought to be catabolic and perhaps
detrimental to the patient. There is evidence that a decreased
synthesis of TRH plays an important role in the pathogenesis of the nonthyroidal
illness syndrome. Levels of total T4 in this syndrome
vary widely, and although they are most often in the normal range, they may be
very low (< 1 or 2 mcg/dL). Occasionally total T4 is elevated.
Free T4 is usually normal, but may be decreased. The majority of clinicians do
not treat nonthyroidal illness syndrome if the TSH level is normal, but once the
TSH is elevated, L-T4 therapy is usually considered. Although there
is disagreement over the dose of L -T4 to use, it is usually 50 to100
mcg a day.
Because different physiologic conditions will have wide-ranging effects on
thyroid function tests, the entire clinical presentation should be considered. A
thorough history and physical exam should be performed to determine whether
these patients have a history of a previous thyroidectomy or other ablative
Thyroid Hormone Resistance
Thyroid hormone resistance syndromes are rare disorders that can be
classified as 2 entities: generalized resistance to thyroid hormone and central
resistance to thyroid hormone.[5,6,66]
Patients with generalized
resistance exhibit a reduced peripheral sensitivity to thyroid hormone. In both
syndromes there is resistance to thyroid hormone at the hypothalamic or
pituitary level, causing inappropriate TSH secretion. In fact, these two
entities overlap clinically.
Thyroid hormone resistance is a familial condition that is caused by
mutations of the T3 receptor, which results in a lower affinity for
thyroid hormone. Usually this is a single base mutation, although the patients
initially studied by Refetoff and colleagues[199,200] had a larger
deletion in the T3-receptor beta gene. In both disorders, mutations
to the thyroid hormone receptor are localized to the hormone-binding domain. As
a result, the action of thyroid hormone at the receptor is impaired and
circulating levels of thyroid hormone will not accurately reflect the amount of
thyroid hormone acting on the cell.
Patients with generalized resistance are most often euthyroid although
occasionally they may be hypo- or hyperthyroid. Typically, they have normal or
elevated free T4 , free T3, and an inappropriately normal
TSH. This syndrome should not be confused with hyperthyroidism, in which free
T4 and T3 are elevated and TSH is undetectable.
Selective pituitary resistance is accompanied by normal sensitivity in
peripheral tissues but defective pituitary receptors. In this
scenario, pituitary receptors will be inadequately stimulated by circulating
thyroid hormones. As a result, patients will present with inappropriately
elevated TSH, high thyroid hormone levels, and clinical thyrotoxicosis because
the peripheral tissues remain sensitive to the effects of thyroid hormones.
Because increased or detectable TSH is an unusual presentation for typical
hyperthyroidism, tests should be conducted to exclude the presence of
generalized thyroid hormone resistance or pituitary tumors.
The majority of patients with generalized resistance to thyroid hormone do
not require any treatment. Treatment for an incorrect diagnosis of
hyperthyroidism should be avoided.[202, 203] Many medications have
been utilized to try to affect thyroid hormone action at the periphery and at
the pituitary, but they have been unsuccessful. These include D-thyroxine,
3,5,3'-triiodothyroacetic acid (TRIAC), and other thyronine
analogues.[204-206] However, in select circumstances, supplementation
with exogenous thyroid hormone may be indicated if there are signs of thyroid
deficiency in peripheral tissues. Children with generalized thyroid hormone
deficiency may benefit from supraphysiologic doses of thyroid hormone to
maintain normal growth and development. Because most patients are thought to be
euthyroid, they do not require exogenous L-T4 therapy.
Selective pituitary resistance is difficult to treat. Thyroid ablation or
antithyroid drugs will lower thyroid hormone levels, but may further stimulate
It is appropriate to measure thyroid function tests in first-degree relatives
of patients suspected of having thyroid hormone resistance. Approximately half
of the first-degree relatives of the patient may be expected to exhibit similar
results on thyroid function testing, and this may assist the clinician in making
the diagnosis. It is difficult in a clinical setting to characterize the
specific mutations of the T3 receptor.
Thyroid function test abnormalities may occur in
nonthyroidal illness. Thyroid hormone resistance, although rare, should be
suspected when thyroid function tests disagree with the clinical
Myxedema coma refers to the rare, life-threatening condition resulting from
the progressive deterioration of thyroid function. Mental dysfunction, stupor,
cardiovascular collapse, and/or coma develop after the worsening of a
long-standing thyroid hormone deficiency. The diagnosis depends on an accurate
and thorough history and physical exam. However, because this is a
life-threatening condition that requires immediate intevention, there may not be
time to wait for results of thyroid function tests. In the proper clinical
setting, especially if the patient exhibits changes in mental capacity or is
comatose, has hypothermia, or has cardiac involvement such as pericardial
effusion, it is appropriate to initiate treatment.[220, 221]
Treatment is aimed at correcting systemic or underlying abnormalities,
normalizing body temperature, eliminating the possibility of an infectious
process by blood and urine cultures, and ensuring adequate adrenal function by
either measuring serum cortisol or preferably by performing an ACTH-stimulation
test. There are several methods of treatment. I prefer to intravenously
administer 50 to 100 mcg of L-T4 a day, while monitoring clinical and
biochemical parameters. Alternately, some clinicians prefer to begin with a
higher dose of L-T4 to rapidly replace depleted thyroid hormone
stores and then decrease to a maintenance dose of 50 to 100 mcg per day. Others
prefer to administer exogenous triiodothyronine (L-T3) or
combinations of L-T4 and L-T3. It is customary to
administer hydrocortisone while waiting for the results of laboratory analysis
of cortisol to ensure that there is not an associated adrenal insufficiency. In
this situation, the patient is treated with 50 mg of hydrocortisone every 8
hours for several days, and then the dose of hydrocortisone is gradually
decreased at a rate based on the results of the ACTH-stimulation test.
In myxedema coma, TSH is almost always increased, with levels ranging from
slightly higher than normal to greater than 50 mU/L. Although levels of T4
and free T4 may vary, they usually tend to be low. Of course,
if a patient is undergoing treatment with steroids, phenytoin, or dopamine
agonists, TSH may be suppressed and even close to or within the normal range,
and both free T4 and total T4 will be decreased, depending
on the dose and half-life of the medications.
In my opinion, the popular term subclinical hypothyroidism
inappropriately, because it actually describes a syndrome of mild
. Many of the symptoms of subclinical hypothyroidism are
subtle, and few, if any, are unique to the disease. For example, fatigue may be
caused by subclinical hypothyroidism, but it may be a symptom of a variety of
other disorders. In subclinical hypothyroidism, although the patient is usually
asymptomatic and clinically euthyroid with apparently normal free T4
and free T3
, TSH is higher than the upper limit of normal and
thyroid peroxidase and thyroglobulin antibodies are frequently present.[1,
The prevalence of subclinical hypothyroidism is approximately 7% in women and
3% in men. There is a much higher prevalence in those over 60
years of age.[210, 211] Parle and colleagues observed
that approximately 17% of patients over 60 years of age with subclinical
hypothyroidism progressed to overt hypothyroidism over a 12-month period. The
number of patients progressing to overt hypothyroidism may be higher over a more
prolonged period of time. The causes of subclinical hypothyroidism are similar
to those that cause overt hypothyroidism. Most patients have Hashimoto's
thyroiditis, as defined by positive titers of thyroid peroxidase antibodies. A
previous history of ablative therapy for the thyrotoxicosis of Graves' disease
is another major cause. Drugs such as lithium or iodine-containing medications
such as amiodarone, as well as external radiation to the neck, may also cause
Although a TRH-stimulation test is rarely necessary to confirm the diagnosis
of subclinical hypothyroidism, patients may exhibit an exaggerated TSH response
to TRH stimulation. It is recommended that a thorough history
and physical exam be performed on all patients with subclinical hypothyroidism.
The evaluation should include measurements, on at least 2 separate occasions, of
TSH, free T4, free T3, and thyroglobulin and
thyroperoxidase antibodies. Repeated measures would detect transient elevations
in TSH, such as those associated with nonthyroidal illness. If there are
palpable thyroid abnormalities, an ultrasonographic exam should be considered. A
radionuclide scan is generally not useful for making a diagnosis. For example,
radioactive iodine uptake by the thyroid gland may be inappropriately elevated
in Hashimoto's thyroiditis.
There is an ongoing debate as to whether patients with subclinical
hypothyroidism (eg, TSH between 5-10 mU/L) should be treated with thyroid
hormone replacement. Several double-blind, controlled studies indicate that
patients with subclinical hypothyroidism experience subtle improvements in
symptoms, such as psychomotor functioning, after being treated with
L-T4.[194,214-217] Most clinicians agree that individuals
with a TSH level higher than 10 mU/L should undergo thyroid hormone replacement
therapy, but there is some uncertainty about how to manage those with TSH levels
between 5-10 mU/L. My approach is to measure free T4 and TSH over
several weeks or months to assess the consistency of testing and to ensure that
the patient is not experiencing transient silent thyroiditis. If TSH values are
consistent, and especially if thyroid antibody titers are high, treatment with
L-T4 should be strongly considered. The decision to treat should be
achieved jointly by the physician and patient after the potential advantages and
disadvantages of therapy are discussed. If the decision is made not to treat,
then thyroid function should be assessed at regular intervals.
In general, once treatment with L-T4 is started, it usually
continues indefinitely. The diagnosis of subclinical hypothyroidism has been
complicated by a recent report of TSH resistance developing in some patients
with elevated levels of TSH and normal circulating T4 and
T3, thus leading to confusion as to whether subclinical
hypothyroidism was actually present in these individuals. It is
important to consider that resistance to TSH is considered extremely rare, and
these patients would not be expected to have high titers of thyroglobulin and
thyroid peroxidase antibodies. Furthermore, the presence of antibodies indicates
that more overt hypothyroidism will eventually develop.
Therefore, in mild hypothyroidism, if treatment with L-T4 is not
initiated, patients should have their thyroid function evaluated as often as
every 6 to 12 months. Because TSH resistance is rare, the vast majority of
patients with elevated TSH levels are considered to have subclinical
Treatment of Hypothyroidism
The treatment of routine hypothyroidism depends on the underlying cause of
the disease. Thyroid hormone replacement should be started cautiously, as it is
believed that in some patients an abrupt increase in levels of thyroid hormone
may increase myocardial oxygen demand and result in cardiac
Therefore, the clinician must balance the need to
restore thyroid hormone levels to normal as quickly as possible with the
potential adverse effects.
The goals of thyroid hormone replacement are to relieve symptoms and to
provide sufficient thyroid hormone to decrease raised serum TSH levels to the
reference range (0.4-4.0 mU/L). In the majority of patients, the optimum
maintenance dose of L-T4 is approximately 1.7 mcg/kg.
Children may require higher doses of L-T4, whereas the elderly may
require less. In some individuals, especially those with severe disease, half
this dose may be given for several weeks while the patient is being closely
monitored. If the patient responds well, the amount of L-T4 can be
increased to the maintenance dose. Follow-up thyroid hormone tests should be
conducted 4 to 6 weeks after starting treatment to allow for stabilization of
thyroid hormone levels. The goal on follow-up is to achieve a TSH value in the
lower part of the normal range. Once the patient is maintained on this dose,
thyroid function should be assessed every 6 to 12 months by an appropriate
physical exam and laboratory tests.
Several brands of L-T4 are currently available on the market.
Because patients may experience a change in thyroid status when switching from
one manufacturer's brand to another, physicians should recommend that patients
be maintained on the identical preparation of L-T4. If product
substitution is undertaken, patients will require a re-evaluation of thyroid
status in response to treatment and possibly an adjustment of the
Levothyroxine is the only preparation that should be used for chronic
treatment of the hypothyroid patient. Although I prefer not to use
L-T3, either initially or in conjunction with L-T4, a
recent study suggests that this approach may provide some psychological
benefits. In my opinion, these results await confirmation, as
the study included a small number of patients and the end points were relatively
subjective. The use of thyroid extract is obsolete because of concerns about its
Oral L-T4 should be administered on an empty stomach. Table 7
lists some drugs that have been shown to decrease the absorption of
L-T4 from the gastrointestinal tract.[195,196]
Table 7. Drugs That Decrease L-T4 Absorption
A serum TSH value in the low-normal range is probably the
best indicator of appropriate thyroid hormone replacement
therapy. Serum T4 is less sensitive, as it may be
increased without symptoms of thyrotoxicosis, and it may vary
depending on the time the sample is collected relative to the ingestion of
thyroid hormone. A clinical exam and history are also important.
If thyroid hormone levels vary dramatically over time, it usually indicates that
the patient is not being compliant with therapy. However, in very unusual
circumstances, it may be related to development of comorbidities such as
nephrotic syndrome, in which the excretion of thyroid hormone is increased.
Patients with subclinical hypothyroidism are
usually asymptomatic and have normal free T4 and free T3
, but a high TSH. If levels of TSH are consistently between 5-10
mU/L, L-T4 therapy should be strongly considered. Myxedema coma
is a rare, life-threatening manifestation of hypothyroidism that requires
New Concepts and New Aspects of Hypothyroidism
Attention has recently focused on using the combination of L-T3
for treating hypothyroidism. This approach is based on the
hypothesis that because not all tissues are equally able to convert
, some patients respond poorly to treatment
alone. Bunevicius and colleagues recently reported that in
some hypothyroid patients, the combination of L-T4
may result in improved mood and psychological function compared
with treatment with L-T4
However, additional studies are needed before L-T3/
L-T4 combination therapy will be widely embraced. There is
uncertainty about the subjective nature of study end points and the duration of
treatment. Clinical experience suggests that L-T3 use my cause
cardiac arrythmias. In addition, it is important to note that the measurement of
peripheral thyroid hormones will be disrupted when L-T3 is
administered. And finally, many decades of clinical experience
show the usefulness of using L-T4 alone.
Because the majority of the effects of hypothyroidism can be prevented or
reversed by thyroid hormone replacement, the clinician must be able to identify
those patients who are most at risk for developing hypothyroidism and recognize
the subtle clinical signs and symptoms of the disease. It is important to
consider that there may be a wide variation in the clinical presentation.
Routine screening programs identify hypothyroid neonates, so that treatment can
be started shortly after birth. Hypothyroidism should be suspected when there is
evidence of underlying thyroid, pituitary, or hypothalamic disease or when the
patient has been previously exposed to any treatment that may disrupt the
function of the hypothalamic-pituitary-thyroid axis. Laboratory assessment of
thyroid function is the optimal approach to confirm the diagnosis. However,
thyroid function tests may not accurately reflect thyroid status in individuals
with nonthyroidal illness, conditions that affect thyroid binding to plasma
proteins, and thyroid hormone resistance. Consequently, the clinician must
integrate clinical observations with laboratory data to properly diagnose and
manage the hypothyroid patient. The goals of thyroid hormone replacement are to
relieve symptoms and to provide sufficient thyroid hormone to decrease raised
serum TSH levels to the reference range. Many decades of experience show the
efficacy of treating hypothyroidism with L-T4
- Tunbridge WM, Evered DC, Hall R, et al. The spectrum of Thyroid disease in
a community: the Whickham survey. Clin Endocrinol (Oxf).
- Sawin C, Castelli WP, Hershman JM, McNamara P, Bacharach P. The aging
Thyroid. Thyroid deficiency in the Framingham Study. Arch Intern
- Wiersinga WM. Subclinical hypoThyroidism and hyperThyroidism. I.
Prevalence and clinical relevance. Neth J Med. 1995;46:197-204.
- Cristian A, Berlow A, Ravishankar T, Root B. HypoThyroidism: its incidence
and prevalence in adults older than 55 years of age in an acute rehabilitation
unit. Arch Phys Med Rehabil. 1999;80:468-9.
- Chatterjee VK. Resistance to thryoid hormone. Horm Res.
- Kopp P, Kitajima K, Jameson JL. Syndrome of resistance to Thyroid hormone:
insights into Thyroid hormone action. Proc Soc Exp Biol Med.
- Surks MI, Schadlow AR, Stock JM, Oppenheimer JH. Determination of
iodothyronine absorption and conversion of L-thyroxine (T 4 ) to
L-triiodothyronine (T 3 ) using turnover rate techniques. J Clin
- Sawin CT, Hershman JM, Chopra IJ. The comparative effect of T4 and T3 on
the TSH response to TRH in young adult men. J Clin Endocrinol
- Oppenheimer JH, Koerner D, Schwartz HL, Surks MI. Specific nuclear
triiodothyronine binding sites in rat liver and kidney. J Clin
Endocrinol Metab. 1972;35:330-333.
- Braverman LE, Ingbar SH, Sterling K. Conversion of thyroxine (T4) to
triiodothyronine (T3) in athyreotic human subjects. J Clin
- Robbins J, Cheng SY, Gershengorn MC, Glinoer D, Cahnmann HJ, Edelnoch H.
Thyroxine transport proteins of plasma. Molecular properties and biosynthesis.
Recent Prog Horm Res. 1978;34:477-519.
- The National Academy of Clinical Biochemistry. Standards of Laboratory
Practice. Laboratory Support for the Diagnosis & Monitoring of Thyroid
Disease. American Association of Clinical Chemistry; 1996:1-64.
- Robbins J. Thyroxine transport and the free hormone hypothesis.
- Bartalena L, Robbins J. Variations in Thyroid hormone transport proteins
and their clinical implications. Thyroid. 1992;2:237-245.
- Langsteger W, Stockigt JR, Docter R, Koltringer P, Lorenz O, Eber O.
Familial dysalbuminaemic hyperthyroxinaemia and inherited partial TBG
deficiency: first report. Clin Endocrinol (Oxf). 1994;40:751-758.
- Langsteger W. Diagnosis of Thyroid hormone transport protein anomalies: an
overview. Acta Med Austriaca. 1996;23:31-40.
- Ladenson PW. Diagnosis of HypoThyroidism. In: Braverman LE, Utiger RD,
eds. Werner and Ingbar's The Thyroid. Seventh Edition.
Philadelphia: Lippincott-Raven Publishers; 1996:880.
- Persani L. Hypothalamic thyrotropin-releasing hormone and thyrotropin
biological activity. Thyroid. 1998;8:941-946.
- Chin WW, Carr FE, Burnside J, Darling DS. Thyroid hormone regulation of
thyrotropin gene expression. Recent Prog Horm Res.
- Fliers E, Wiersinga WM, Swaab DF. Physiological and pathophysiological
aspects of thyrotropin-releasing hormone gene expression in the human
hypothalamus. Thyroid. 1998;8:921-928.
- Dahl GE, Evans NP, Thrun LA, Karsch FJ. A central negative feedback action
of Thyroid hormones on thyrotropin-releasing hormone secretion.
- Lechan RM, Kakucska I. Feedback regulation of thyrotropin-releasing
hormone gene expression by Thyroid hormone in the hypothalamic paraventricular
nucleus. Ciba Found Symp. 1992;168:144-158.
- Saiardi A, Falasca P, Civitareale D. The Thyroid hormone inhibits the
thyrotropin receptor promoter activity: evidence for a short loop regulation.
Biochem Biophys Res Commun. 1994;205:230-237.
- Vigneri R, Squatrito S, Pezzino V, Filetti S, Polosa P. The effect of
short-term triiodothyronine administration on thyroxine response to exogenous
TSH in man. J Clin Endocrinol Metab. 1975;41:974-976.
- Nicoloff JT, Spencer CA. Integration of Thyroid hormones with hypothalamic
factors on pituitary TSH secretion. Acta Med Austriaca.
- Beck-Peccoz P, Mariotti S, Guillausseau PJ. Treatment of hyperThyroidism
due to inappropriate secretion of thyrotropin with somatostatin analogue SMS
201-995. J Clin Endocrinol Metab. 1989;68:208-214.
- Ahlquist JA, Franklyn JA, Wood DF, et al. Hormonal regulation of
thyrotropin synthesis and secretion. Horm Metab Res Suppl.
- Re RN, Kourides IA, Ridgway EC, Weintraub BD, Maloof F. The effect of
glucocorticoid administration of human pituitary secretion of thyrotropin and
prolactin. J Clin Endocrinol Metab. 1976;43:338-346.
- Weeke J, Hansen AAP, Lundbaek K. Inhibition by somatostatin of basal
levels of serum thyrotropin (TSH) in normal men. J Clin Endocrinol
- van Haasteren GA, van der Meer MJ, Hermus AR, et al. Different effects of
continuous infusion of interleukin-1 and interleukin-6 on the
hypothalamic-hypophysial-Thyroid axis. Endocrinology.
- Van der Poll T, Romijn JA, Wiersinga WM, Sauerwein HP. Tumor necrosis
factor: A putative mediator of the sick euThyroid syndrome in man. J
Clin Endocrinol Metab. 1990;71:1567-1572.
- Van den Berghe G, de Zegher F. Anterior pituitary function during critical
illness and dopamine treatment. Crit Care Med. 1996;24:1580-1590.
- Holdaway IM, Evans MC, Sheehan A, Ibbertson HK. Low thyroxine levels in
some hyperprolactinemic patients due to dopaminergic suppression of
thyrotropin. J Clin Endocrinol Metab. 1984;59:608-613.
- Sharp B, Morley JE, Carlson HE, et al. The role of opiates and endogenous
opioid peptides in the regulation of rat TSH secretion. Brain
- Lewinski A, Pawlikowski M, Cardinali DP. Thyroid growth-stimulating and
growth-inhibiting factors. Biol Signals. 1993;2:313-351.
- Dumont JE, Lamy F, Roger P, Maenhaut C. Physiological and pathological
regulation of Thyroid cell proliferation and dirrerentiation by thyrotropin
and other factors. Physiol Rev. 1992;72:667-697.
- Vassart G, Dumont JE. The thyrotropin receptor and the regulation of
thyrocyte function and growth. Endocr Rev. 1992;13:596-611.
- Pohl V, Abramowicz M, Vassart G, Dumont JE, Roger PP. Thyroperoxidase mRNA
in quiescent and proliferating Thyroid epithelial cells: expression and
subcellular localization studied by in situ hybridization. Eur J Cell
- Abramowicz MJ, Vassart G, Christophe D. Thyroid peroxidase gene promoter
confers TSH responsiveness to heterologous reporter genes in transfection
experiments. Biochem Biophys Res Commun. 1990;166:1257-1264.
- Gerard CM, Lefort A, Christophe D, et al. Distinct transcriptional effects
of cAMP on 2 Thyroid specific genes: thyroperoxidase and thyroglobulin.
Horm Metab Res Suppl. 1990;23:38-43.
- Cavalieri RR. Iodine metabolism and Thyroid physiology: current concepts.
- Wolff J. Transport of iodide and other anions in the Thyroid gland.
Physiol Rev. 1964;44:45-90.
- Becks GP, Eggo MC, Burrow GN. Regulation of differentiated Thyroid
function by iodide: preferential inhibitory effect of excess iodide on Thyroid
hormone secretion in sheep Thyroid cell cultures. Endocrinology.
- Dai G, Levy O, Carrasco N. Cloning and characterization of the Thyroid
iodide transporter. Nature. 1996;379:458-460.
- Smanik PA, Liu Q, Furminger TL, et al. Cloning of the human sodium lodide
symporter. Biochem Biophys Res Commun. 1996;13:339-345.
- Kogai T, Endo T, Saito T, Miyazaki A, Kawaguchi A, Onaya T. Regulation by
Thyroid-stimulating hormone of sodium/iodide symporter gene expression and
protein levels in FRTL-5 cells. Endocrinology.
- Levy O, De la Vieja A, Carrasco N. The Na+/I- symporter (NIS): recent
advances. J Bioenerg Biomembr. 1998;30:195-206.
- Kosugi S, Sato Y, Matsuda A, et al. High prevalence of T354P sodium/iodide
symporter gene mutation in Japanese patients with iodide transport defect who
have heterogeneous clinical pictures. J Clin Endocrinol Metab.
- Matsuda A, Kosugi S. A homozygous missense mutation of the sodium/iodide
symporter gene causing iodide transport defect. J Clin Endocrinol
- Pohlenz J, Refetoff S. Mutations in the sodium/iodide symporter (NIS) gene
as a cause for iodide transport defects and congenital hypoThyroidism.
- Pohlenz J, Medeiros-Neto G, Gross JL, Silveiro SP, Knobel M, Refetoff S.
HypoThyroidism in a Brazilian kindred due to iodide trapping defect caused by
a homozygous mutation in the sodium/iodide symporter gene. Biochem
Biophys Res Commun. 1997;240:488-491.
- Joba W, Spitzweg C, Schriever K, Heufelder AE. Analysis of human
sodium/iodide symporter, Thyroid transcription factor-1, and
paired-box-protein-8 gene expression in benign Thyroid diseases.
- Saito T, Endo T, Kawaguchi A, et al. Increased expression of the Na+/I-
symporter in cultured human Thyroid cells exposed to thyrotropin and in
Graves' Thyroid tissue. J Clin Endocrinol Metab.
- Endo T, Kogai T, Nakazato M, Saito T, Kaneshige M, Onaya T. Autoantibody
against Na+/I- symporter in the sera of patients with autoimmune Thyroid
disease. Biochem Biophys Res Commun. 1996;224:92-95.
- Morris JC, Bergert ER, Bryant WP. Binding of immunoglobulin G from
patients with autoimmune Thyroid disease to rat sodium-iodide symporter
peptides: evidence for the iodide transporter as an autoantigen.
- Lazar V, Bidart JM, Caillou B, et al. Expression of the Na+/I- symporter
gene in human Thyroid tumors: a comparison study with other Thyroid-specific
genes. Thyroid. 1999;84:3228-3234.
- Brent GA. The molecular basis of Thyroid hormone action. N Engl J
- Lazar MA. Thyroid hormone receptors: multiple forms, multiple
possibilities. Endocr Rev. 1993;14:184-193.
- Schwartz HL, Strait KA, Oppenheimer JH. Molecular mechanisms of Thyroid
hormone action. A physiologic perspective. Clin Lab Med.
- Oppenheimer JH. Evolving concepts of Thyroid hormone action.
- Usala SJ, Young WSd, Morioka H, Nikodem VM. The effect of Thyroid hormone
on the chromatin structure and expression of the malic enzyme gene in
hepatocytes. Mol Endocrinol. 1988;2:619-626.
- Thompson CC, Weinberger C, Lebo R, Evans RM. Identification of a novel
Thyroid hormone receptor expressed in the mammalian central nervous system.
- Sap J, Munoz A, Damm K, et al. The c-erb-A protein is a high-affinity
receptor for Thyroid hormone. Nature. 1986;324:635-640.
- Weinberger C, Thompson CC, Ong ES, Lebo R, Gruol DJ, Evans RM. The c-erb-A
gene encodes a Thyroid hormone receptor. Nature.
- Davis PJ, Davis FB. Nongenomic actions of Thyroid hormone.
- Refetoff S, Weiss RE, Usala J. The syndromes of resistance to Thyroid
hormone. Endocr Rev. 1993;14:348-399.
- De Nayer P. The Thyroid hormone receptors: molecular basis of Thyroid
hormone resistance. Horm Res. 1992;38:57-61.
- Gittoes NJ, Franklyn JA. Drug-induced Thyroid disorders. Drug
- Shirota T, Shinoda T, Aizawa T, et al. Primary hypoThyroidism and multiple
endocrine failure in association with hemochromatosis in a long-term
hemodialysis patient. Clin Nephrol. 1992;38:105-109.
- Bell NH. Endocrine complications of sarcoidosis. Endocrinol Metab
Clin North Am. 1991;20:645-654.
- Rich MW. HypoThyroidism in association with systemic amyloidosis.
Head Neck. 1995;17:343-345.
- Collu R, Tang J, Castagne J, et al. A novel mechanism for isolated central
hypoThyroidism: inactivating mutations in the thyrotropin-releasing hormone
receptor gene. J Clin Endocrinol Metab. 1997;82:1561-1565.
- Lee KO, Persani L, Tan M, Sundram FX, Beck-Peccoz P. Thyrotropin with
decreased biological activity, a delayed consequence of cranial irradiation
for nasopharyngeal carcinoma. J Endocrinol Invest.
- Beck-Peccoz P, Amr S, Menezes-Ferreira MM, Faglia G, Weintraub BD.
Decreased receptor binding of biologically inactive thyrotropin in central
hypoThyroidism. Effect of treatment with thyrotropin-releasing hormone.
N Engl J Med. 1985;312:1085-1090.
- Samuels MH, Ridgway EC. Central hypoThyroidism. Endocrinol Metab
Clin North Am. 1992;21:903-919.
- Jawadi MH, Hanson TJ, Schemmel JE, Beck P, Katz FH. Hypothalamic
sarcoidosis and hypopituitarism. Horm Res. 1980;12:1-9.
- Lazarus JH. Clinical manifestations of postpartum Thyroid disease.
- Papandreou MJ, Persani L, Asteria C, Ronin C, Beck-Peccoz P. Variable
carbohydrate structures of circulating thyrotropin as studied by lectin
affinity chromatography in different clinical conditions. J Clin
Endocrinol Metab. 1993;77:393-398.
- Persani L, Borgato S, Romoli R, Asteria C, Pizzocaro A, Beck-Peccoz P.
Changes in the degree of sialylation of carbohydrate chains modify the
biological properties of circulating thyrotropin isoforms in various
physiological and pathological states. J Clin Endocrinol Metab.
- Katakami H, Katom Y, Inada M, Imura H. Hypothalamic hypoThyroidism due to
isolated thyrotropin-releasing hormone (TRH) deficiency. J Endocrinol
- Fliers E, Guldenaar SE, Wiersinga WM, Swaab DF. Decreased hypothalamic
thyrotropin-releasing hormone gene expression in patients with nonThyroidal
illness. J Clin Endocrinol Metab. 1997;82:4032-4036.
- Freake HC, Oppenheimer JH. Thermogenesis and Thyroid function. Annu
Rev Nutr. 1995;15:263-291.
- Rodriguez-Pena A. Oligodendrocyte development and Thyroid hormone. J
- Bernal J, Nunez J. Thyroid hormones and brain development. Eur J
- Dussault JH, Ruel J. Thyroid hormones and brain development. Annu
Rev Physiol. 1987;49:321-336.
- Sohmer H, Freeman S. The importance of Thyroid hormone for auditory
development in the fetus and neonate. Audiol Neurootol.
- Williams GR, Robson H, Shalet SM. Thyroid hormone actions on cartilage and
bone: interactions with other hormones at the epiphyseal plate and effects on
linear growth. J Endocrinol. 1998;157:391-403.
- Pirinen S. Endocrine regulation of craniofacial growth. Acta Odontol
- Fisher DA. Fetal Thyroid function: diagnosis and management of fetal
Thyroid disorders. Clin Obstet Gynecol. 1997;40:16-31.
- Haddow JE, Palomaki GE, Allan WC, et al. Maternal Thyroid deficiency
during pregnancy and subsequent neuropsychological development of the child.
N Engl J Med. 1999;341:549-555.
- Lazarus JH. Thyroid hormone and intellectual development: a clinician's
view. Thyroid. 1999;9:659-660.
- Pop VJ, Kuijpens JL, van Baar AL, et al. Low maternal free thyroxine
concentrations during early pregnancy are associated with impaired psychomotor
development in infancy. Clin Endocrinol (Oxf). 1999;50:149-155.
- Evans IM, Sinha AK, Pickard MR, Edwards PR, Leonard AJ, Elkins RP.
Maternal hypothyroxinemia disrupts neurotransmitter metabolic enzymes in
developing brain. J Endocrinol. 1999;161:273-279.
- Vulsma T, Gons MH, DeVijlder JMM. Maternal fetal transfer of thyroxine in
congenital hypoThyroidism due to a total organification defect of Thyroid
dysgenesis. N Eng J Med. 1989;321:13-16.
- Rovet JF. Congenital hypoThyroidism: long-term outcome.
- Simons WF, Fuggle PW, Grant DB, Smith I. Educational progress, behaviour,
and motor skills at 10 years in early treated congenital hypoThyroidism.
Arch Dis Child. 1997;77:219-222.
- Derksen-Lubsen G, Verkerk PH. Neuropsychologic development in early
treated congenital hypoThyroidism: analysis of literature data. Pediatr
- Kooistra L, Laane C, Vulsma T, Schellekens JM, van der Meere JJ,
Kalverboer AF. Motor and cognitive development in children with congenital
hypoThyroidism: a long-term evaluation of the effects of neonatal treatment.
J Pediatr. 1994;124:903-909.
- Delange F. Neonatal screening for congenital hypoThyroidism: results and
perspectives. Horm Res. 1997;48:51-61.
- Van Vliet G. Neonatal hypoThyroidism: treatment and outcome.
- Dickerman Z, De Vries L. Prepubertal and pubertal growth, timing and
duration of puberty and attained adult height in patients with congenital
hypoThyroidism (CH) detected by the neonatal screening programme for CH--a
longitudinal study. Clin Endocrinol (Oxf). 1997;47:649-654.
- O'Brien T, Dinneen SF, O'Brien PC, Palumbo PJ. Hyperlipidemia in patients
with primary and secondary hypoThyroidism. Mayo Clin Proc.
- Yildirimkaya M, Ozata M, Yilmaz K, Kilinc C, Gundogan MA, Kutluay T.
Lipoprotein(a) concentration in subclinical hypoThyroidism before and after
levo-thyroxine therapy. Endocr J. 1996;43:731-736.
- Althaus B, Staub JJ, Ryff-De Leche A, Oberhansli A, Stahelin HB.
LDL/HDL-changes in subclinical hypoThyroidism: possible risk factors for
coronary heart disease. Clin Endocrinol (Oxf). 1988;28:157-163.
- Sundaram V, Hanna AN, Koneru L, Newman HA, Falko JM. Both hypoThyroidism
and hyperThyroidism enhance low density lipoprotein oxidation. J Clin
Endocrinol Metab. 1997;82:3421-3424.
- Perk M, O'Neill BJ. The effect of Thyroid hormone therapy on angiographic
coronary artery disease progression. Can J Cardiol.
- Fowler PB, McIvor J, Sykes L, Macrae KD. The effect of long-term thyroxine
on bone mineral density and serum cholesterol. J R Coll Physicians
- Pedersen O, Richelsen B, Bak J, Arnfred J, Weeke J, Schmitz O.
Characterization of the insulin resistance of glucose utilization in
adipocytes from patients with hyper- and hypoThyroidism. Acta Endocrinol
- Ober KP. Acanthosis nigricans and insulin resistance associated with
hypoThyroidism. Arch Dermatol. 1985;121:229-231.
- Anand VT, Mann SB, Dash RJ, Mehra YN. Auditory investigations in
hypoThyroidism. Acta Otolaryngol (Stockh). 1989;108:83-87.
- Kopp P. Pendred's syndrome: identification of the genetic defect a century
after its recognition. Thyroid. 1999;9:65-69.
- Manciet G, Dartigues JF, Decamps A, et al. The PAQUID survey and
correlates of subclinical hypoThyroidism in elderly community residents in the
southwest of France. Age Ageing. 1995;24:235-241.
- Jackson IM. The Thyroid axis and depression. Thyroid.
- Polikar R, Burger A, Scherrer U, Nicod P. The Thyroid and the heart.
- Wieshammer S, Keck FS, Waitzinger J, et al. A correlation of clinical and
hemodynamic studies in patients with hypoThyroidism. Br Heart J.
- Kabadi UM, Kumar SP. Pericardial effusion in primary hypoThyroidism.
Am Heart J. 1990;120:1393-1395.
- Moruzzi P, Doria E, Agostoni PG. Medium-term effectiveness of L-thyroxine
treatment in idiopathic dilated cardiomyopathy. Am J Med.
- Bernstein R, Muller C, Midtbo K, Smith G, Haug E, Hertzenberg L. Silent
myocardial ischemia in hypoThyroidism. Thyroid. 1995;5:443-447.
- Aronow WS. The heart and Thyroid disease. Clin Geriatr Med.
- Westphal SA. Unusual presentations of hypoThyroidism. Am J Med
- McLean RM, Podell DN. Bone and joint manifestations of hypoThyroidism.
Semin Arthritis Rheum. 1995;24:282-290.
- Allain TJ, McGregor AM. Thyroid hormones and bone. J
- Kahraman H, Kaya N, Demircali A, Bernay I, Tanyeri F. Gastric emptying
time in patients with primary hypoThyroidism. Eur J Gastroenterol
- Centanni M, Marignani M, Gargano L, et al. Atrophic body gastritis in
patients with autoimmune Thyroid disease: an underdiagnosed association.
Arch Intern Med. 1999;159:1726-1730.
- Kogawa K. Parietal cell antibodies. Part I. Clinical and pathological
studies of parietal cell antibodies. Gastroenterol Jpn.
- Ottesen M, Feldt-Rasmussen U, Andersen J, Hippe E, Schouboe A. Thyroid
function and autoimmunity in pernicious anemia before and during
cyanocobalamin treatment. J Endocrinol Invest. 1995;18:91-97.
- Stradtman EW. Thyroid Dysfunction and Ovulatory Disorders. In: Carr BR,
Blackwell RE, eds. Textbook of Reproductive Medicine. Norwalk,
Connecticut: Appleton & Lange; 1993.
- Joshi JV, Bhandarkar SD, Chadha M, Balaiah D, Shah R. Menstrual
irregularities and lactation failure may precede Thyroid dysfunction or
goitre. J Postgrad Med. 1993;39:137-141.
- Wortsman J, Rosner W, Dufau ML. Abnormal testicular function in men with
primary hypoThyroidism. Am J Med. 1987;82:207-212.
- Bates GW. Normal and Abnormal Puberty. In: Carr BR, Blackwell RE, eds.
Textbook of Reproductive Medicine. Norwalk, Connecticut: Appleton
& Lange; 1993.
- Anasti JN, Flack MR, Froehlich J, Nelson LM, Nisula BC. A potential novel
mechanism for precocious puberty in juvenile hypoThyroidism. J Clin
Endocrinol Metab. 1995;80:276-279.
- Shalev E, Eliyahu S, Ziv M, Ben-Ami M. Routine Thyroid function tests in
infertile women: are they necessary? Am J Obstet Gynecol.
- Mandel SJ, Larsen PR, Seely EW, Brent GA. Increased need for thyroxine
during pregnancy in women with primary hypoThyroidism. N Engl J
- Helfand M, Redfern CC. Clinical guideline, part 2. Screening for Thyroid
disease: an update. American College of Physicians [see comments]. Ann
Intern Med. 1998;129:144-158.
- Danese MD, Powe NR, Sawin CT, Ladenson PW. Screening for mild Thyroid
failure at the periodic health examination: a decision and cost-effectiveness
analysis. JAMA. 1996;276:285-292.
- DeGroot LJ, Mayor G. Admission screening by Thyroid function tests in an
acute general care teaching hospital. Am J Med. 1992;93:558-564.
- Lewis GF, Alessi CA, Imperial JG, Refetoff S. Low serum free thyroxine
index in ambulating elderly is due to a resetting of the threshold of
thyrotropin feedback suppression. J Clin Endocrinol Metab.
- Saller B, Broda N, Heydarian R, Gorges R, Mann K. Utility of third
generation thyrotropin assays in Thyroid function testing. Exp Clin
Endocrinol Diabetes. 1998;106:S29-S33.
- Fisher DA. Physiological variations in Thyroid hormones: physiological and
pathophysiological considerations. Clin Chem. 1996;42:135-139.
- Romijn JA, Adriaanse R, Brabant G, Prank K, Endert E, Wiersinga WM.
Pulsatile secretion of thyrotropin during fasting: a decrease of thyrotropin
pulse amplitude. J Clin Endocrinol Metab. 1990;70:1631-1636.
- Romijn JA, Wiersinga WM. Decreased nocturnal surge of thyrotropin in
nonThyroidal illness. J Clin Endocrinol Metab. 1990;70:35-42.
- Bartalena L, Placidi GF, Martino E, et al. Nocturnal serum thyrotropin
(TSH) surge and the TSH response to TSH-releasing hormone: dissociated
behavior in untreated depressives. J Clin Endocrinol Metab.
- Reinhardt MJ, Moser E. An update on diagnostic methods in the
investigation of diseases of the Thyroid. Eur J Nucl Med.
- Spencer CA, Schwarzbein D, Guttler RB, LoPresti JS, Nicoloff JT.
Thyrotropin (TSH)-releasing hormone stimulation test responses employing third
and fourth generation TSH assays. J Clin Endocrinol Metab.
- Faglia G. The clinical impact of the thyrotropin-releasing hormone test.
- Meller J, Zappel H, Conrad M, Roth C, Emrich D, Becker W. Diagnostic value
of 123iodine scintigraphy and perchlorate discharge test in the diagnosis of
congenital hypoThyroidism. Exp Clin Endocrinol Diabetes.
- el-Desouki M, al-Jurayyan N, al-Nuaim A, et al. Thyroid scintigraphy and
perchlorate discharge test in the diagnosis of congenital hypoThyroidism.
Eur J Nucl Med. 1995;22:1005-1008.
- Gurnell M, Rajanayagam O, Barbar I, Jones MK, Chatterjee VK. Reversible
pituitary enlargement in the syndrome of resistance to Thyroid hormone.
- Groff TR, Shulkin BL, Utiger RD, Talbert LM. Amenorrhea-galactorrhea,
hyperprolactinemia, and suprasellar pituitary enlargement as presenting
features of primary hypoThyroidism. Obstet Gynecol.
- Tamaki H, Amino N, Iwatani Y, Matsuzuka F, Kuma K, Miyai K. Detection of
Thyroid microsomal and thyroglobulin antibodies by new sensitive
radioimmunoassay in Hashimoto's disease; comparison with conventional
hemagglutination assay. Endocrinol Jpn. 1991;38:97-101.
- Mori T, Kriss JP. Measurements by competitive binding radioassay of serum
anti-microsomal and anti-thyroglobulin antibodies in Graves' disease and other
Thyroid disorders. J Clin Endocrinol Metab. 1971;33:688-698.
- Chiovato L, Vitti P, Santini F, et al. Incidence of antibodies blocking
thyrotropin effect in vitro in patients with euThyroid or hypoThyroid
autoimmune Thyroiditis. J Clin Endocrinol Metab. 1990;71:40-45.
- Rieu M, Portos C, Lissak B, et al. Relationship of antibodies to
thyrotropin receptors and to Thyroid ultrasonographic volume in euThyroid and
hypoThyroid patients with autoimmune Thyroiditis. J Clin Endocrinol
- Dayan CM, Daniels GH. Chronic autoimmune Thyroiditis. N Engl J
- Gordin A, Maatela J, Miettinen A, Helenius T, Lamberg B-A. Serum
thyrotrophin and circulating thyroglobulin and Thyroid microsomal antibodies
in a Finnish population. Acta Endocrinol. 1979;90:33-42.
- Inoue M, Taketani N, Sato T, Nakajima H. High incidence of chronic
lymphocytic Thyroiditis in apparently healthy school children: Epidemiological
and clinical study. Endocrinol Jpn. 1975;22:483-488.
- Morinaka S. On the frequency of Thyroid diseases in outpatients in an ENT
clinic. Auris Nasus Larynx. 1995;22:186-191.
- Totterman TH, Maenpaa J, Gordin A, et al. Blood and Thyroid-infiltrating
lymphocyte subclasses in juvenile autoimmune Thyroiditis. Clin Exp
- Jansson R, Totterman TH, Sallstrom J, Dahlberg P. Thyroid-infiltrating T
lymphocyte subsets in Hashimoto's Thyroiditis. J Clin Endocrinol
- Kasagi K, Kousaka T, Higuchi K, et al. Clinical significance of
measurements of antiThyroid antibodies in the diagnosis of Hashimoto's
Thyroiditis: comparison with histological findings. Thyroid.
- Bogner U, Hegedus L, Hansen JM, Finke R, Schleusener H. Thyroid cytotoxic
antibodies in atrophic and goitrous autoimmune Thyroiditis. Eur J
- Hayashi Y, Tamai H, Fukata S, et al. A long-term clinical, immunological,
and histological follow-up study of patients with goitrous chronic lymphocytic
Thyroiditis. J Clin Endocrinol Metab. 1985;61:1172-1178.
- Uematsu H, Sadato N, Ohtsubo T, et al. Fluorine-18-fluorodeoxyglucose PET
versus thallium-201 scintigraphy evaluation of Thyroid tumors. J Nucl
- Pedersen RK, Pedersen NT. Primary non-Hodgkin's lymphoma of the Thyroid
gland: a population based study. Histopathology. 1996;28:25-32.
- Holm LE, Blomgren H, Lowhagen T. Cancer risks in patients with chronic
lymphocytic Thyroiditis. N Engl J Med. 1985;312:601-604.
- Scofield RH. Autoimmune Thyroid disease in systemic lupus erythematosus
and Sjogren's syndrome. Clin Exp Rheumatol. 1996;14:321-330.
- Koshiyama H, Ito M, Yoshinami N, et al. Two cases of asymptomatic
adrenocortical insufficiency with autoimmune Thyroid disease. Endocr
- Kahl LE, Medsger TAJ, Klein I. Prospective evaluation of Thyroid function
in patients with systemic sclerosis (scleroderma). J Rheumatol.
- Gordin A, Maenpaa J, Makinen T, Totterman TH, Tiilikainen A. Immunological
and genetic markers in a family with Hashimoto's disease. Clin
Endocrinol (Oxf). 1979;11:425-435.
- Hamburger JI. The various presentations of Thyroiditis. Diagnostic
considerations. Ann Intern Med. 1986;104:219-224.
- Selenkow HA, Wyman P, Allweiss P. Autoimmune Thyroid disease: an
integrated concept of Graves' and Hashimoto's diseases. Compr
- Gupta MK. Thyrotropin receptor antibodies: advances and importance of
detection techniques in Thyroid diseases. Clin Biochem.
- Kasagi K, Takeda K, Goshi K, et al. Presence of both stimulating and
blocking types of TSH-receptor antibodies in sera from three patients with
primary hypoThyroidism. Clin Endocrinol (Oxf). 1990;32:253-260.
- Takasu N, Oshiro C, Akamine H, et al. Thyroid-stimulating antibody and
TSH-binding inhibitor immunoglobulin in 277 Graves' patients and in 686 normal
subjects. J Endocrinol Invest. 1997;20:452-461.
- Cho BY, Kim WB, Chung JH, et al. High prevalence and little change in TSH
receptor blocking antibody titres with thyroxine and antiThyroid drug therapy
in patients with non-goitrous autoimmune Thyroiditis. Clin Endocrinol
- Cho BY, Shong YK, Lee HK, Koh CS, Min HK. Graves' hyperThyroidism
following primary hypoThyroidism: sequential changes in various activities of
thyrotropin receptor antibodies. Acta Endocrinol (Copenh).
- Bartley GB. The epidemiologic characteristics and clinical course of
ophthalmopathy associated with autoimmune Thyroid disease in Olmsted County,
Minnesota. Trans Am Ophthalmol Soc. 1994;92:477-588.
- Comtois R, Faucher L, Lafleche L. Outcome of hypoThyroidism caused by
Hashimoto's Thyroiditis. Arch Intern Med. 1995;155:1404-1408.
- Krouse RS, Royal RE, Heywood G, et al. Thyroid dysfunction in 281 patients
with metastatic melanoma or renal carcinoma treated with interleukin-2 alone.
J Immunother Emphasis Tumor Immunol. 1995;18:272-278.
- Kung AW, Lai CL, Wong KL, Tam CF. Thyroid functions in patients treated
with interleukin-2 and lymphokine-activated killer cells. Q J
- Le Moli R, Wesche MF, Tiel-Van Buul MM, Wiersinga WM. Determinants of
longterm outcome of radioiodine therapy of sporadic non-toxic goitre.
Clin Endocrinol (Oxf). 1999;50:783-789.
- Kaplan MM, Meier DA, Dworkin HJ. Treatment of hyperThyroidism with
radioactive iodine. Endocrinol Metab Clin North Am.
- Leese GP, Jung RT, Scott A, Waugh N, Browning MC. Long term follow-up of
treated hyperThyroid and hypoThyroid patients. Health Bull
- Tell R, Sjodin H, Lundell G, Lewin F, Lewensohn R. HypoThyroidism after
external radiotherapy for head and neck cancer. Int J Radiat Oncol Biol
- Khoo VS, Liew KH, Crennan EC, D'Costa IM, Quong G. Thyroid dysfunction
after mantle irradiation of Hodgkin's disease patients. Australas
- Martino E, Aghini-Lombardi F, Bartalena L, et al. Enhanced susceptibility
to amiodarone-induced hypoThyroidism in patients with Thyroid autoimmune
disease. Arch Intern Med. 1994;154:2722-2726.
- Newman CM, Price A, Davies DW, Gray TA, Weetman AP. Amiodarone and the
Thyroid: a practical guide to the management of Thyroid dysfunction induced by
amiodarone therapy. Heart. 1998;79:121-127.
- Harjai KJ, Licata AA. Effects of amiodarone on Thyroid function. Ann
Intern Med. 1997;126:63-73.
- Kusalic M, Engelsmann F. Effect of lithium maintenance therapy on Thyroid
and paraThyroid function. J Psychiatry Neurosci. 1999;24:227-233.
- Peet M, Pratt JP. Lithium. Current status in psychiatric disorders.
- Hall RC, Dunlap PK, Pacheco CA, Blakey RK, Abraham J. Thyroid disease and
abnormal Thyroid function tests in women with eating disorders and depression.
J Fla Med Assoc. 1995;82:187-192.
- Mori M, Shoda Y, Yamada M, et al. Central hypoThyroidism due to isolated
TRH deficiency in a depressive man. J Intern Med.
- Cleare AJ, McGregor A, Chambers SM, Dawling S, O'Keane V. Thyroxine
replacement increases central 5-hydroxytryptamine activity and reduces
depressive symptoms in hypoThyroidism. Neuro Endocrinology.
- Monzani F, Del Guerra P, Caraccio N, et al. Subclinical hypoThyroidism:
neurobehavioral features and beneficial effect of L-thyroxine treatment.
Clin Investig. 1993;71:367-371.
- Singh N, Hershman JM. Does calcium carbonate interfere with the absorption
of levothyroxine? [Abstract 139]. 72nd Annual Meeting of the American Thyroid
Association. Palm Beach, Florida; 1999.
- Synthroid® [prescribing information]. Mount Olive, NJ: Knoll
- Vagenakis AG, Braverman LE. Adverse effects of iodides on Thyroid
function. Med Clin North Am. 1975;59:1075-1088.
- McIver B, Gorman CA. EuThyroid sick syndrome: an overview.
- Refetoff S, Robin NI, Alper CA. Study of four new kindreds with inherited
thyroxine-binding globulin abnormalities. Possible mutations of a single gene
locus. J Clin Invest. 1972;51:848-867.
- Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining
deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible
target organ refractoriness to Thyroid hormone. J Clin Endocrinol
- Gershengorn MC, Weintraub BD. Thyrotropin-induced hyperThyroidism caused
by selective pituitary resistance to Thyroid hormone. A new syndrome of
"inappropriate secretion of TSH". J Clin Invest. 1975;56:633-642.
- Gladwin MT, Duell PB. Inappropriate Thyroid gland ablation in patients
with generalized resistance to Thyroid hormone. A common sequela of a rare
disorder. Arch Intern Med. 1996;156:106-109.
- Bantle JP, Seeling S, Mariash CN, Ulstrom RA, Oppenheimer JH. Resistance
to Thyroid hormones. A disorder frequently confused with Graves' disease.
Arch Intern Med. 1982;142:1867-1871.
- Radetti G, Persani L, Molinaro G, et al. Clinical and hormonal outcome
after two years of triiodothyroacetic acid treatment in a child with Thyroid
hormone resistance. Thyroid. 1997;7:775-778.
- Pohlenz J, Knobl D. Treatment of pituitary resistance to Thyroid hormone
(PRTH) in an 8-year-old boy. Acta Paediatr. 1996;85:387-390.
- Dorey F, Strauch G, Gayno JP. Thyrotoxicosis due to pituitary resistance
to Thyroid hormones. Successful control with D thyroxine: a study in three
patients. Clin Endocrinol (Oxf). 1990;32:221-228.
- Bryhni B, Aanderud S, Sundsfjord J, Rekvig OP, Jorde R. Thyroid antibodies
in northern Norway: prevalence, persistence and relevance. J Intern
- Sawin CT, Bigos ST, Land S, Bacharach P. The aging Thyroid. Relationship
between elevated serum thyrotropin level and Thyroid antibodies in elderly
patients. Am J Med. 1985;79:591-595.
- Tanner AR, Scott-Morgan L, Mardell R, Lloyd RS. The incidence of occult
Thyroid disease associated with Thyroid antibodies identified on routine
autoantibody screening. Acta Endocrinol (Copenh). 1982;100:31-35.
- Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in the
elderly. Microsomal antibodies as discriminant for therapy. JAMA.
- Sawin CT, Chopra D, Azizi F, Mannix JE, Bacharach P. The aging Thyroid.
Increased prevalence of elevated serum thyrotropin levels in the elderly.
- Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and
follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the
United Kingdom. Clin Endocrinol (Oxf). 1991;34:77-83.
- Ramtoola S, Maisey MN, Clarke SE, Fogelman I. The Thyroid scan in
Hashimoto's Thyroiditis: the great mimic. Nucl Med Commun.
- Monzani F, Caraccio N, Del Guerra P, Casolaro A, Ferrannini E.
Neuromuscular symptoms and dysfunction in subclinical hypoThyroid patients:
beneficial effect of L-T4 replacement therapy. Clin Endocrinol
- Baldini IM, Vita A, Mauri MC, et al. Psychopathological and cognitive
features in subclinical hypoThyroidism. Prog Neuropsychopharmacol Biol
- Arem R, Escalante DA, Arem N, Morrisett JD, Patsch W. Effect of
L-thyroxine therapy on lipoprotein fractions in overt and subclinical
hypoThyroidism, with special reference to lipoprotein(a).
- Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-Thyroxine therapy
in subclinical hypoThyroidism. A double-blind, placebo-controlled trial.
Ann Intern Med. 1984;101:18-24.
- Levine MA, Ringel MD. Resistance to TSH in patients with normal TSH
receptors--where do we turn when "Sutton's law" proves false? J Clin
Endocrinol Metab. 1997;82:3930-3932.
- Tunbridge WM, Brewis M, French JM, et al. Natural history of autoimmune
Thyroiditis. Br Med J (Clin Res Ed). 1981;282:258-262.
- Jordan RM. Myxedema coma. Pathophysiology, therapy, and factors affecting
prognosis. Med Clin North Am. 1995;79:185-194.
- Smallridge RC. Metabolic and anatomic Thyroid emergencies: a review.
Crit Care Med. 1992;20:276-291.
- Hennessey JV, Evaul JE, Tseng YC, Burman KD, Wartofsky L. L-thyroxine
dosage: a reevaluation of therapy with contemporary preparations. Ann
Intern Med. 1986;105:11-15.
- Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange Jr AJ. Effects of
thyroxine as compared with thyroxine plus triiodothyronine in patients with
hypoThyroidism. N Engl J Med. 1999;340:424-429.
- Jackson IM, Cobb WE. Why does anyone still use desiccated Thyroid USP?
Am J Med. 1978;64:284-288.
- Helfand M, Crapo LM. Monitoring therapy in patients taking levothyroxine.
Ann Intern Med. 1990;113:450-454.
- Pearce CJ, Himsworth RL. Total and free Thyroid hormone concentrations in
patients receiving maintenance replacement treatment with thyroxine. Br
Med J (Clin Res Ed). 1984;288:693-695.
- Ain KB, Pucino F, Shiver TM, Banks SM. Thyroid hormone levels affected by
time of blood sampling in thyroxine-treated patients. Thyroid.
MEDCEU Continuing Education Courses CEU for Nurses and Healthcare