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THYROID DISEASE
DIAGNOSIS,
TREATMENT AND
HEALTH PREVENTION:
AN OVERVIEW
Jassin M. Jouria, MD
Dr. Jassin M. Jouria is a medical doctor,
professor of academic medicine, and medical
author. He graduated from Ross University
School of Medicine and has completed his clinical clerkship training in various
teaching hospitals throughout New York, including King’s County Hospital Center and
Brookdale Medical Center, among others. Dr. Jouria has passed all USMLE medical
board exams, and has served as a test prep tutor and instructor for Kaplan. He has
developed several medical courses and curricula for a variety of educational
institutions. Dr. Jouria has also served on multiple levels in the academic field
including faculty member and Department Chair. Dr. Jouria continues to serves as a
Subject Matter Expert for several continuing education organizations covering
multiple basic medical sciences. He has also developed several continuing medical
education courses covering various topics in clinical medicine. Recently, Dr. Jouria
has been contracted by the University of Miami/Jackson Memorial Hospital’s
Department of Surgery to develop an e-module training series for trauma patient
management. Dr. Jouria is currently authoring an academic textbook on Human
Anatomy & Physiology.
Abstract
Management of the common forms of thyroid disease has undergone
significant study and development, as evidenced by the latest
guidelines to diagnose and treat the thyroid. Because the thyroid
gland’s role is so pervasive in the body, it is important for clinicians to
understand the common symptoms of various thyroid diseases,
including those not so commonly known. The diagnosis, treatment and
prevention of thyroid conditions are discussed.
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Policy Statement
This activity has been planned and implemented in accordance with
the policies of NurseCe4Less.com and the continuing nursing education
requirements of the American Nurses Credentialing Center's
Commission on Accreditation for registered nurses. It is the policy of
NurseCe4Less.com to ensure objectivity, transparency, and best
practice in clinical education for all continuing nursing education (CNE)
activities.
Continuing Education Credit Designation
This educational activity is credited for 4 hours. Nurses may only claim
credit commensurate with the credit awarded for completion of this
course activity.
Statement of Learning Need
The thyroid gland is active in virtually every cell of the body,
regulating cellular respiration, energy expenditure, overall metabolism,
growth and development of cells and tissues. It is important to
understand the symptoms of thyroid diseases, and to know the
management and treatment of these conditions.
Course Purpose
To provide advanced learning for clinicians interested in the diagnosis,
treatment and prevention of thyroid disease.
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Target Audience
Advanced Practice Registered Nurses and Registered Nurses
(Interdisciplinary Health Team Members, including Vocational Nurses
and Medical Assistants may obtain a Certificate of Completion)
Course Author & Planning Team Conflict of Interest Disclosures
Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA,
Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures
Acknowledgement of Commercial Support
There is no commercial support for this course.
Please take time to complete a self-assessment of knowledge,
on page 4, sample questions before reading the article.
Opportunity to complete a self-assessment of knowledge
learned will be provided at the end of the course.
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1. The thyroid gland has been called the “Master Gland”
because it
a. produces parathormone.
b. is a member of the hormone-responsive nuclear transcription
factors superfamily.
c. is active in virtually every cell of the body.
d. plays a vital role in controlling calcium and phosphate levels.
2. True or False: Embryologically, the developing thyroid forms
the floor of the pharynx, around the base of the tongue,
descending the neck to its adult location.
a. True
b. False
3. The thyroid is supplied by the superior and inferior thyroid
arteries, and on rare occasions, there is an additional artery
known as the
a.
b.
c.
d.
innominate artery.
subclavian artery.
deep artery.
thyroidea ima.
4. Thyroid hormone is
a. required for normal human growth and development.
b. required for the regulation of metabolism in infants and
adolescents.
c. mostly active during the neonatal and pre-adolescent periods.
d. primarily used for the production of iodine.
5. Thyroid hormone ____________ begins with the
organification of iodide to iodine and then condensed onto
tyrosine residues found on thyroglobulin protein.
a.
b.
c.
d.
absorption
secretion
synthesis
conversion
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Introduction
The thyroid gland has been called the Master Gland because it is active
in virtually every cell of the body, regulating cellular respiration,
energy expenditure, overall metabolism, growth and development of
cells and tissues. Because the thyroid gland’s role is so pervasive in
the body, it is important to understand the symptoms of the types of
thyroid disease such as hypothyroidism and hyperthyroidism, and to
know the management and treatment of these conditions.
Anatomy Of The Thyroid
The anatomy of the thyroid gland is reviewed in this first section of
this course to provide a basic understanding of thyroid structures,
hormones, and the blood and nerve supply. There are various ways to
evaluate the thyroid gland to rule out pathology, which is covered in
later course sections and as well as in subsequent course series on
thyroid disease, diagnostic testing, pathology and treatment.1-6
The thyroid gland consisting of two lobes and connected by an
isthmus, is located at the anterior neck, just below the cricoid
cartilage, roughly at the level of C5 to T1 and overlaying the second to
the fourth tracheal rings. The parathyroid glands are four small glands
usually located at the posterior portions of the thyroid and which
produce parathyroid hormone (PTH) and play a vital role in controlling
calcium and phosphate levels. The parathyroid glands share blood
supply, lymphatic drainage and venous supply with the thyroid.
Embryologically, the developing thyroid forms the floor of the pharynx,
around the base of the tongue, descending the neck in the adult. As it
descends during the 4th to 8th week of gestation, the thyroglossal duct,
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a duct that has regressed in the
adult, guides the thyroid gland. In
about half of individuals, however,
the distal portion of the thyroglossal
duct remains, essentially as an extra
lobe of thyroid tissue with no
apparent clinical significance.
Thyroglossal cysts, resulting from
persistent sections of the
thyroglossal duct, occur relatively
commonly. These can be diagnosed
with ultrasonography. The most
common complications of a
thyroglossal cyst are infection and
malignancy, occurring in 1 to 4% of individuals.
The mass and dimensions of the thyroid can vary, but tends to be
slightly heavier in females, enlarging during monthly cycles and in
pregnancy. In both males and females, the mass is 25 – 30 gm with
each lobe 50 – 60 mm. The thyroid gland is principally enervated by
the autonomic nervous system with parasympathetic fibers from the
vagus, and sympathetic enervation is derived from the superior,
middle and inferior ganglia of the sympathetic trunk. The fibers enter
the gland alongside the vasculature and appear to primarily regulate
perfusion rates.
The basic structural unit of the thyroid are the follicles, formed by
multiple septae, dividing the gland into lobes and lobules, with the
follicles consisting of a layer of epithelial cells surrounding a colloid-
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filled center surrounded by fenestrated capillaries, lymphatic vessels
and sympathetic nerves. Within the colloid, iodothyroglobulin (the
precursor of the thyroid hormones) can be found. The principle or
follicular cells secrete the colloid. The parafollicular cells, embedded
within the basal laminae and adjacent to the follicles secrete calcitonin
(a hormone that regulates calcium in the blood).
Vascular and Lymphatic Anatomy of the Thyroid
The superior and inferior thyroid arteries supply the thyroid. Relatively
rarely, there is an additional artery, the thyroidea ima that originates
from the aortic arch or the innominate artery, entering the gland at
the inferior border of the isthmus. The arterial supply has numerous
anastomoses that are present both ipsilaterally and contralaterally.
The superior thyroid artery is the first branch (anterior) off the
external carotid. After branching, it descends laterally to the larynx,
posterior to the omohyoid and sternohyoid muscles. It then runs
superficially along the anterior border, delivering a deep branch before
curving towards the isthmus. The superior thyroid artery then
anastomoses with the contralateral artery. The inferior thyroid artery
branches off from the thyrocervical trunk (a branch of the subclavian
artery). After branching off, the inferior thyroid artery ascends
superiorly and then laterally, entering the tracheoesophageal groove
posterior to the carotid sheath. Sub-branches then enter along the
posterior portion of the lobes.
The recurrent pharyngeal nerve is closely associated with the inferior
thyroid artery, but the exact relationship is variable — it can be found
deep, superficial or between branches of the artery and can be
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asymmetric, comparing the right to the left side. Extralaryngeal
branches may be present, and these must be preserved in
thryoidectomies. The recurrent pharyngeal nerve emerges from the
superior thoracic outlet in an anatomic triangle bounded by the
common carotid artery (laterally), the trachea (medially) and the
thyroid (superiorly). It enters the larynx between the cricoid cartilage
and the inferior cornu of the thyroid cartilage.
Venous drainage of the thyroid is through three pairs of veins — the
superior, middle and inferior thyroid veins. The inferior veins may form
a common trunk, the thyroid ima vein. The superior thyroid vein
ascends alongside the internal jugular vein while the middle thyroid
vein follows a more direct course passing lateral to the internal jugular
vein; both superior and middle thyroid veins drain into the internal
jugular vein. The inferior thyroid vein can be asymmetric in form and
drains into the brachiocephalic vein.
Lymphatic drainage follows many directions and is extensive but can
be variable. The periglandular, prelaryngeal, pretracheal and
paratracheal nodes are found along the path of the recurrent
pharyngeal nerve, passing to the mediastinal lymph nodes.
Nerve Supply of the Thyroid
The thyroid is enervated by the sympathetic nervous system through
the superior, middle and inferior sympathetic ganglia. Parasympathetic
enervation is through the vagus nerve. The nerves follow the course of
the superior and inferior thyroid arteries.
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Functions Of The Thyroid Gland
The main function of the thyroid gland is to produce the thyroid
hormones, thyroxine (T4) and triiodothyrodine (T3). Thyroid hormone
is required for both normal growth and development as well as for the
regulation of metabolism in the adult. Parafollicular cells (C cells)
secrete calcitonin in response to hypercalcemia, causing a decrease in
serum calcium levels. Triiodothyrodine (T3) is the active form of
hormone while T4 has a longer half-life than T3. Thyroxine (T4) is
converted to T3 in most tissues, thus serving as a prohormone.
Thyroid functions and hormonal regulation are highlighted below.6-18
Sites of Thyroid Hormone Action
Thyroid hormone is essential for growth, development and metabolism
acting in nearly all cells. Thyroid hormone status is also related to
body weight and total energy expenditures. Thyroid hormones exert
effects on lipogenesis, lipolysis, energy storage/expenditure (Basal
Metabolic Rate or BMR), carbohydrate metabolism, circadian rhythms,
appetite, insulin sensitivity and production, among other effects.
Thyroid Hormone Receptors
Thyroid hormone receptors should be briefly discussed here to provide
a whole overview of how T3 functions. Firstly, thyroid-stimulating
hormone (TSH) is part of the feedback system in the body that helps
regulate T4 and T3, and is produced by the pituitary gland. The TSH
test is frequently ordered along with or preceding a free T4 test. Other
thyroid tests that may be ordered include a free T3 test and thyroid
antibodies (if autoimmune-related thyroid disease is suspected).
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Sometimes TSH, free T4 and free T3 are ordered together as a thyroid
panel. Triiodothyrodine (T3) action is primarily exerted through its
nuclear thyroid receptor (nTR) isoform. There are two primary isoforms
of the nTR — the α and the β isoforms. Both isoforms undergo
posttranslational modification. This posttranslational modification is
essential for both positive and negative gene regulation by thyroid
hormone, including that of genes important for overall metabolic
regulation.
Tissue specificity and relative levels of isoforms is important within
different tissues; nTR- α2, a splice product, does not bind to T3 and is
an inhibitor of T3. And, nTR β2 is primarily expressed in the brain,
pituitary, liver, and cardiac ventricles while nTR-α is primarily
expressed in white adipose tissue (WAT), brain and cardiac atria.
Brown adipose tissue (BAT) contains both the isoforms.
Isoform-specific actions forming the basis for clinical thyroid hormone
resistance is highlighted in the table below. For patients having short
stature, showing developmental delays, bony deformities, and chronic
constipation, elevated cholesterol and increased BMI, there is a
corresponding defect and effect upon the hypothalamic-pituitarythyroid (HPT) axis.
Importantly, nuclear thyroid receptors are involved in crosstalk with
other nuclear hormone receptors. While there is much work to be done
in this area, it appears that the crosstalk allows for finer control and
coordination of carbohydrate and lipid metabolism. Thyroid hormone
also has non-genomic actions including interactions with membrane
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integrin receptors and cytoplasmic effects on signal transduction
pathways.
Defect
Reduced T3
binding and
irreversible
interactions with
corepressors.
HypothalamicPituitary-Thyroid
Axis Effects
Resistance or nonresponsiveness to
feedback.
More commonly
seen.
Clinical Expression/Metabolic
Effect
Clinical: Goiter, enhanced
metabolic rates, hyperphagia.
Generally euthyroid, with
possible tachycardia. Possible,
short stature, impaired hearing,
bone defects, ADHD
↑ T4, T3
~ Normal TSH
Reduced T3
binding and
irreversible
interactions with
corepressors.
Pituitary is
normally sensitive
to feedback.
Rarely seen.
Short stature, developmental
delay, chronic constipation, bone
deformities.
Elevated cholesterol, BMI
↑ T3/T4
~ Normal TSH, absolute values
T3, T4
Thyroid Hormone Synthesis
Thyroid hormone synthesis begins with the conversion (organification)
of iodide to iodine and condensed onto tyrosine residues found on
thyroglobulin. Iodide, derived from nutritional sources, is pumped
across the cell membrane with a Na+-I- symport.
The mono- or di-iodinated thyroglobulin is the primary component of
the follicular colloid. The second step is the coupling of the mono- or
di-iodinated molecules. If a mono-iodinated tyrosine is coupled with a
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di-iodinated tyrosine, the result is T3. If two di-iodinated tyrosines are
coupled, T4 is the result. This second reaction is the major reaction.
De-iodination by three different deiodinases, D1, D2 and D3, found in
different levels in various tissues, including the liver, is an important
control point for thyroid hormone biosynthesis.
The deiodinases are peroxidases. D1 is not significant in the pituitary,
so is not believed to be critical for the control by feedback inhibition of
thyroid hormone synthesis. D1 is found at high levels in the liver,
kidney and in the thyroid gland itself and is expressed on the cellular
membrane in these tissues. D1 is suppressed in response to various
stressors, decreasing the conversion of T4 to T3. These stressors
include weight gain, depression, leptin resistance, insulin resistance,
diabetes, inflammation, hypoxia and chronic pain. Selenium deficiency
is also associated with D1 suppression.
Highly expressed in the brain, pituitary, thyroid and BAT, D2 is the
primary deiodinase providing active T3 derived from the de-iodination
of T4. Polymorphisms of D2 are associated with type 2 diabetes,
insulin resistance, and obesity in some studies, but this association has
not been universal. D3 inactivates T4 and is found in the skin, vascular
tissue and the placenta.
De-iodination of T4 can result in reverse T3 (RT3). RT3, a metabolite
of T4, develops to conserve body energy by converting T4 into RT3, an
inactive form of T3 that is incapable of delivering oxygen and energy
to the cells as does T3. Elevated rT3 levels (>10-24 ng/dL) may also
be associated with sick euthyroid syndrome, but may also be elevated
in patients on propylthiouracil, ipodate, propranolol, amiodarone,
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dexamethasone and halothane. Dilantin displaces rT3 from
thyroglobulin and increases rT3 clearance. Currently, measurement of
rT3 levels appears to be most useful in critically ill or elderly patients
with little justification for routine testing. Some patients, particularly
those with a specific D2 gene polymorphism, may benefit from a
combination of T3/T4 (synthetic or desiccated extract) over T4 alone,
particularly those who are still symptomatic with normal TSH values
and an elevated free T4/free T3 ratio.
In some tissues, T4 may enter cells via passive transport. However, in
other tissues, particularly the brain, the monocarboxylate transporter
8 (MCT8) is required though not necessarily obligatory; a genetic
disorder, the Allan-Herndon-Dudley Syndrome, presenting with low
serum T4, and elevated serum T3, and severe neurologic deficits, was
shown to be due to a mutation in the MCT8 gene. Treatment with
diiodothyropropionic acid (DITPA) in humans resulted in improvement
in patients with the MCT8 mutation, and may indicate that there are
other transporters, which while not as efficient as the MCT8
transporter, allowed tissues to remain sensitive to the effects of
thyroid hormone.
The Role of the Deiodinases
Thyroid hormone enters the target cells via the thyroid hormone
receptors, but must be converted to the active form, T3 with a
deiodinase. Differentially expressed deiodinase allows specific cell
types to play an active role in thyroid hormone signaling, essentially
“customizing” the signaling to become tissue specific and, importantly
for clinical purposes, not necessarily reflecting the measured levels of
TSH, free T4 and free T3 commonly used for diagnostic purposes.
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As mentioned above, the deiodinases are expressed in various tissues
and appear to have varied functions. D1 appears to perform primarily
a scavenger function, clearing sulfated thyroid hormone for excretion
in the bile and the urine. D1 is considered to be important for
adaptation to iodine deficiency and to abrogate the effects of high
levels of T4 in hyperthyroidism. D3, located at the cellular membrane,
is expressed at high levels in the placenta where it may function to
protect a developing fetus from high levels of maternal T4. D3 may
also perform similar functions in the skin and the vasculature. Its
expression is stimulated by hypoxia, mediated by hypoxia-inducible
factor (HIF-1). D2 is expressed in the endoplasmic reticulum in the
cells of the brain, pituitary, thyroid and BAT. D2 appears to be the
primary controller responsible for the conversion of T4 to T3, both
intracellularly and in producing measured T3 levels in the serum.
As with the other deiodinases, D2 is selenium dependent —
deficiencies of nutritional selenium and thereby defects in
selenoproteins are associated with abnormal thyroid hormone
production, metabolism and feedback control. D2 has a short half-life
because it is prone to ubiquitination and degradation by proteosomes.
De-ubinquitination can increase D2 activity and is stimulated by low
levels of T4 and by adrenergic activation, preserving T3 levels in those
tissues where it is located. D2 has been linked to metabolic
phenotypes in at least two ways. As mentioned, D2 polymorphisms
have been associated with type 2 diabetes, insulin resistance, and
obesity. In addition, D2 activity may be associated with the stimulation
of bile acid secretion via the G-protein coupled receptor for bile acids
(TGR5).
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Interestingly, bile salt synthesis has recently been shown as controlled
by pituitary TSH. It is believed that various stimuli such as bile acid
secretion, adrenergic stimuli, endoplasmic reticulum stress (a
disruption in endoplasmic reticulum homeostasis associated with
obesity, insulin resistance and Type 2 Diabetes), cold exposure and
generalized stress can affect D2 expression by both transcriptional and
post-transcriptional control mechanisms, reducing D2 activity and thus
reducing intracellular T3 levels in a tissue-specific manner. D2mediated T3 production plays a critical role in the pituitaryhypothalamic-thyroid T4/T3 mediated feedback loop.
During periods of iodine deficiency, T4 levels decrease while T3 levels
can remain stable. This results by the expected feedback mechanisms,
an increase in serum TSH. In patients acutely given large amounts of
propylthiouracil, the serum levels of T3 drop while the T4 levels remain
stable. Somewhat surprisingly, under these conditions, TSH levels also
increase. The decrease in T3 levels is sensed by neurons in the
paraventricular nucleus of the hypothalamus with the pituitary
thyrotrophs responding by de-repressing the expression of both the
TRH and TSH-β genes. This is in contrast to the mechanisms based on
T4 levels — D2 is required to convert the existing T4 to T3, which can
then de-repress the TRH and TSH genes.
Regulation of Thyroid Hormone Production
The hypothalamus detects T3 levels produced by the action of the D2
deiodinase. The monocarboxylate transporter 8 (MCT8) is required for
the transport of T4 into both hypothalamic and pituitary cells.
Thyrotropin releasing hormone (TRH) is released when T3 levels reach
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a threshold, but can also be released via the action of leptin in the
hypothalamus.
Leptin stimulates Signal Transducer and Activator of Transcription 3
(STAT3) phosphorylation. This phosphorylation directly stimulates the
production of TRH. TRH acts on the cells of the pituitary gland, binding
to TRH receptors and resulting in an increase in TSH release. TSH
secretion, in turn, can be modulated by a number of different
molecules and states — these include dopamine, somatostatin, leptin,
renal failure, starvation, moods such as depression and anxiety,
cortisol, growth hormone, reproductive hormones and sleep
deprivation. In addition, adrenergic regulation is an important factor in
the secretion of both TRH and TSH as well as in the overall regulation
of energy balance as an effect of T4/T3 action.
The various hypothalamic nuclei receive multiple inputs from diverse
sources including sensory (i.e., taste, odor of foods), motor (i.e., the
process of digestion) and metabolic (i.e., absorption, glucose levels)
and respond to signals such as the levels of fatty acids, lipids, the
aforementioned glucose as well as hormones associated with appetite,
i.e., insulin, estrogens and T4/T3. The hypothalamus functions to
integrate these diverse signals to modulate hepatic insulin sensitivity
and resistance, control WAT fat depots and fatty acid oxidation in
skeletal muscle and overall energy expenditure in the BAT.
Once released, TSH stimulates the production and the release of T4
into the bloodstream by the thyroid gland. Local and both
hypothalamic and pituitary deiodinases serve to provide T3 for
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feedback inhibition, resulting in decreases in both TRH and TSH
production until the set point for lowered T3 is reached.
Central Control of Thyroid Hormone and Feeding Behavior
Follicular cells are enervated by sympathetic fibers utilizing
norepinephrine (NE). Norepinephrine release increases T4 to T3
conversion. The sympathetic nervous system (SNS) plays a critical
role. While the physiological relevance is not completely clear, SNS
stimulation of BAT is correlated with increased de novo lipogenesis
specifically in the hypothalamus. This occurs via AMP-activated protein
kinase (AMPK). During fasting, hypothalamic D2 is increased and there
is a concomitant increase in hypothalamic T3 levels. During this same
timeframe, pituitary and liver D2 is decreased.
Leptin
Leptin is an adipocyte hormone that acts as a signal from adipose
tissue to the brain, regulating appetite by inhibiting both food intake
and increasing energy expenditure by interacting with leptin receptors
in the hypothalamus. Leptin inhibits transmitters in the ventromedial
hypothalamus, and activates melanin-concentrating hormone and
corticotropin-releasing hormone. In obesity, there is significant leptin
resistance and leptin does not stimulate TRH. In addition, in animal
studies, leptin resistance allows for a euthyroid state in the face of
obesity. Notably, thyroid hormone can influence feeding behaviors
such as appetite and hunger through several related pathways. During
fasting periods, there is increased T3 production, which stimulates
mitochondrial proliferation and rebound feeding.
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Thermogenesis, Body Weight And Thyroid Hormone
Adrenergic-mediated thermogenesis is, in part, due to direct actions
on the brown adipose tissue (BAT). However, both central and
peripheral actions of thyroid hormone can play an important role in
energy balances. Thyroid hormone plays a role in maintaining the
basal metabolic rate, adaptive thermogenesis, appetite, food intake,
and body weight.1-3,22-31
Basal Metabolic Rate
The basal metabolic rate or BMR is the main source of energy outlay —
significant reductions in BMR can result in weight gain and obesity
while increases in BMR can result in weight loss and undernutrition.
Resting energy expenditure is highly sensitive to changes in thyroid
hormone levels and the BMR correlates with both lean body mass and
the levels of thyroid hormone. In general, thyroid hormone increases
the BMR by increasing the production of ATP, the main source of
cellular energy, though the specific targets of thyroid hormone action
are not entirely clear. It is known that thyroid hormone stimulates ion
gradients, the primary ones being the Na+/K+ gradient across the cell
membrane and the Ca2+ gradient found between the cytoplasm and
sarcoplasmic reticulum. For example, one action of thyroid hormone is
to alter the levels of sodium and potassium, thus requiring ATP
consumption (via Na+/K+-ATPase).
Thyroid hormone also directly stimulates the Na+/K+-ATPase pump as
well, but this effect appears to be most significant under conditions of
hyperthyroidism rather than strictly physiologic. The expression of the
sarcoplasmic/endoplasmic reticulum Ca2+-dependent ATPase (SERCA)
in skeletal muscle is also regulated by thyroid hormone, producing
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heat during ATP hydrolysis. Thyroid hormone affects the ryanodine
receptors in both cardiac and skeletal muscle, stimulating efflux of
Ca2+ ions and requiring ATP to pump calcium back into the
sarcoplasmic reticulum.
Facultative Thermogenesis
Facultative or adaptive thermogenesis can be defined as the regulated
production of heat in response to environmental changes in
temperature and diet. It is adaptive in that it “resets” the CNS-defined
set point. Shivering is another mechanism to produce heat but is
essentially inefficient because it also induces convective heat loss.
Clinically and practically, the reset is reflected in the difficulty many
patients have in losing weight and keeping it off. Much of the
resistance to sustained weight maintenance may be due to the actions
of leptin and the “interactions of genes favoring energy conservation
and storage with an environment which enables access to food calories
and a more sedentary lifestyle.” Evolution tended to favor individuals
able to store calories efficiently and to sustain fetal and maternal
energy stores. This, however, does not favor many individuals eating
calorie dense foods without the extra physical activity that might
reduce energy storage.
Both the sympathetic nervous system and thyroid hormone are
needed to maintain core body temperature. The expression of proteins
(UCPs or uncoupling proteins) is regulated both by norepinephrine and
by thyroid hormone in BAT stores, functioning synergistically. D2
knockout mice raised in temperatures at or slightly above mouse body
temperature (30OC), develop insulin resistance, obesity and hepatic
steatosis because of impaired BAT thermogenesis. These same mice,
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when raised at levels below normal body temperature (22o C), activate
alternative heat production pathways.
In humans, there is both visceral and subcutaneous BAT, and until
recently was considered important only in neonates and hibernating
animals. However, it is becoming clear that in the adult, BAT
thermogenesis has important functions as well, mainly to generate
classical non-shiver related heat. The mitochondria in BAT have very
high numbers of mitochondria containing UCP-1 that when activated
stimulates the respiratory chain.
Thyroid Hormones and Regulation of Body Weight
Changes in TSH levels have been associated with changes in weight in
normal individuals and those with either hypo- or hyper-thyroid states.
Treatment with T4 replacement, with the establishment of a euthyroid
state, have been associated with reduction in body weight as well as
an increase in resting energy expenditure (REE) in hypothyroid
patients, but the loss in body weight is primarily through the excretion
of excess water with no changes in total body fat, though this effect
may be due to an increased caloric intake or altered leptin levels.
Treatment with T3 (as a monotherapy) resulted in significant weight
loss accompanied by other changes such as decreases in total
cholesterol and apolipoprotein B levels without any increased
cardiovascular risk.
Carbohydrate Metabolism and Thyroid Hormone
Thyroid hormones affect nearly all aspects of carbohydrate
metabolism, including enhancement of insulin-dependent glucose
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transport, gluconeogenesis and glycogenolysis. Hyperthyroid states
are associated with increased gluconeogenesis and glycogenolysis in
the liver and peripheral tissues. In the liver, the rate-limiting step in
gluconeogenesis is phosphoenolpyruvate carboxykinase (PEPCK) and
the gene for this enzyme is upregulated by T3. Rats with a mutation
affecting the thyroid receptor beta chain have impaired
gluconeogenesis and are more insulin sensitive. Inactivation of D2 or
hypothyroid states is associated with insulin resistance, pre-diabetic
states and obesity.
There exists a relationship between thyroid hormone status and
diabetes, but it is complex, particularly Type 2 diabetes. Patients with
Type 1 diabetes have an increased risk of autoimmune thyroid disease.
In Type 2 diabetes, a significant number of diabetic patients have
abnormal serum TSH levels. In a recent prospective study, there was
an association between higher levels of TSH and diabetes while higher
free T4 levels were associated with a lower risk. In the same study,
the risk of progression from prediabetes to diabetes was higher in
clinical and subclinical hypothyroid states. T3 bound to its receptor
directly upregulate target genes and the gluconeogenic enzymes in the
liver. T3 also increases gluconeogenesis. Also, the inhibition of insulin
signaling pathways may stimulate hepatic glucose production.
Cholesterol and Lipid Metabolism
The primary sites of action regarding cholesterol and lipid metabolism
are the liver and BAT. Thyroid-hormone dependent regulation of lipid
metabolism is regulated via T3, TRβ and crosstalk between nuclear
hormone receptors.
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In the liver, regulation of lipid homeostasis is directly by T3 and
indirectly via crosstalk between nutrient-dependent nuclear receptors.
Both HMG-CoA reductase, the rate-limiting enzyme in cholesterol
synthesis and sterol response element binding protein (SREBP2) are
directly stimulated by T3. Indirect actions are via other nuclear
receptors. In addition, T3 increases fatty acid (FA) uptake in the liver
using fatty acid transporter proteins and to increase hepatic
lipogenesis via the upregulation of a number of proteins and
carbohydrate-responsive element-binding protein.
Clinically, these effects can be seen in patients with hypothyroidism:

Decreased basal metabolic rate

Cholesterolemia (due to decreased hepatic low-density
lipoprotein receptor (LDL-R) expression)

Hyperlipdemia

Increased risk of non-alcoholic fatty liver disease (NAFLD)

Weight gain with an increased risk of obesity

Increased risk of Type 2 diabetes
In patients with hyperthyroid disease:

Increased basal metabolic rate

Weight loss

Decreased total cholesterol

Decreased triglyceride levels

Increased hepatic lipid oxidation

Hyperglycemia and worsening glycemic control in Type 2
diabetes patients
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Common Thyroid and Hyperthyroid Conditions
The more common conditions of the thyroid gland may be due to
hormone production, excess or deficiency. Additionally, illness related
to the thyroid gland may be due to a growth or mass in the neck, and
may involve nodule or lump formation within the thyroid. The following
sections highlight the more common thyroid conditions, including
etiology, genetic influences and diagnostic testing to identify a thyroid
condition in order to treat.3,33-41,45-59
Simple Nontoxic Goiter
Simple nontoxic goiter is a non-inflammatory or non-neoplastic
hypertrophy of the thyroid that may appear diffusely or as nodules. It
is noncancerous and may be asymptomatic with the exception of an
enlarged, palpable, non-tender goiter. Thyroid function often remains
normal except in cases of severe iodine deficiency. Endemic goiter can
occur if greater than 10% of a population exhibits it, as can be seen in
iodine-deficient areas of the world.
Simple nontoxic goiter may be somewhat dependent on reproductive
hormone interactions — it is frequently found during puberty,
pregnancy and at menopause or perimenopause. Known causes of
goiter include:

Iodine deficiency

Congenital errors of thyroid hormone synthesis

Ingestion of large amounts of goitrogens such as cassava,
broccoli, cauliflower and cabbage, predominantly in areas with a
high risk of iodine deficiency
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
Medications that inhibit the synthesis of thyroid hormone,
particularly iodine contain drugs such as amiodarone, iodine
supplements, interferon-α, interleukin-2

TSH receptor agonists including TSH receptor antibodies,

Pituitary resistance to thyroid hormone

Hypothalamic or pituitary adenomas

Human chorionic gonadotropin-producing tumors
Thyroid function tests are usually within the range of normal values, as
are thyroidal radioactive iodine uptake tests. Thyroid antibodies are
also usually normal.
Goiter is about 4 times more common in women than in men,
increasing risk is associated with age. Nodules are also less frequent in
men, but have a greater tendency to be malignant, when found.
Nodular goiter occurs where areas of involution and fibrosis become
interspersed with areas of hyperplasia. Some nodules may be “hot”
appearing on scintigraphy with high levels of isotope (99mTc) uptake
while others are less active. In a minority of patients, high thyroid
function may result in thyrotoxicosis. The rate of malignancy is low in
both multinodular and uninodular goiter.
Table salt has been iodized since the 1920s to prevent cretinism and
endemic goiter. The NHANES II study indicated that iodine status is
generally adequate for the U.S. population, but there were some
groups, notably non-Hispanic African-Americans, that were at higher
risk for iodine deficiency. Median urinary iodine of 100-199μg/L is
considered as reflecting adequate iodine intake.
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The use of table salt has been discouraged in the U.S. and around the
world to control hypertension. It is believed that other foods contain
sufficient iodine. However, in some populations such as in children
with food restrictions or adults avoiding dairy products intake of iodine
may not be adequate. A recent review of iodine nutrition indicated that
in both developed and developing countries, iodine deficiency is a
cause for concern, particularly in pregnant mothers and in those for
whom a reduced salt intake has been recommended. In 2014, the
Office of Dietary Supplements (ODS: a division of the NIH) convened
workshops around the concern that pregnant women may be at risk of
iodine deficiency and hypothyroidism and that their infants may be at
risk for hypothyroxinemia, congenital hypothyroidism or abnormal
cognitive development.
Clinically, a non-toxic goiter is palpable and non-tender. It generally
grows outward but can compress the trachea and the esophagus. The
patient may complain of difficulty in swallowing or other obstructive
symptoms such as a dry cough, dyspnea, and stridor, especially with
exertion. Recent or an accelerated rate of growth or a lobe or
nodule(s) should arouse a suspicion of malignancy. The history should
include an examination of dietary iodine deficiency or dietary or
medication-based excess of iodine. Evaluation of the family history
should include any history of familial papillary thyroid carcinomas or
medullary thyroid cancer including multiple endocrine neoplasia
(MENs).
Nodules may be evaluated using a thin-needle aspiration biopsy.
The differential diagnosis of an enlarged thyroid can include:
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
Carcinoma
 Follicular Thyroid Carcinoma
 Medullary Thyroid Carcinoma
 Papillary Thyroid Carcinoma

Thyroiditis
 Hashimoto Thyroiditis
 Riedel Thyroiditis
 Subacute Thyroiditis
 Lymphoma
•
Thyroid Lymphoma

Thyroid Nodule
Malignancies occur in approximately 7–15% of nodules, but the
incidence of both thyroid nodules and malignancy has been increasing.
While many patients with non-toxic goiter will present with essentially
normal levels of TSH, some may present with either high levels
(hypothyroidism) or low levels (hyperthyroidism) of TSH. Free T3 and
free T4 levels may be particularly useful if the TSH is within normal
range or at the limits of normal ranges. Thyroid antibodies should be
tested (i.e., serum antithyroid peroxidase (anti-TPO) antibody and
antithyroglobulin (anti-Tg) antibody levels particularly if there is a
family history of thyroid diseases or autoimmune disease.
Scintigraphy is not necessarily a routine test, though if scintigraphy is
performed, it should be noted that 5-8% of warm or cold nodules are
malignant.
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Ultrasonography is a highly sensitive tool in determining the number
and sizes of thyroid nodules. Combining ultrasonography with Doppler
and spectral analysis to determine vascularization is proving useful in
discerning malignant from benign nodules.
Fine needle aspiration biopsy (FNAB) is highly accurate and specific for
the diagnostic evaluation of thyroid nodules. Ultrasonography-guided
FNAB is becoming more and more common. Patients with any follicular
cytopathology seen on FNAB or if there is any abnormalities on U.S.
should be referred to a surgeon. For atypical cytopathology, FNAB
should be repeated within 3-6 months.
Graves’ Disease
In Graves’ disease, also known as
Toxic Nodular Goiter (TNG), there
are independently functioning
thyroid nodules with a resultant
hyperthyroidism. Iodine deficiency
(overt or subclinical) leads to
compensation via hyperplasia. The
hyperplasia may increase the risk
of somatic mutation of the TSH
receptor or activation of the TSH
receptor. In areas with endemic
goiter or in the elderly, toxic
nodular goiter is the most common
cause of hyperthyroidism.
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In the U.S., Graves’ disease is the more common cause of
hyperthyroid disease. TNG is a spectrum of disorders that can range
from a single nodule (toxic adenoma) producing thyroid hormone to
multiple nodules hypersecreting the hormone. Most patients with TNG
will present with signs and symptoms of hyperthyroidism.
Elderly patients may have somewhat atypical symptoms including
weight loss as the most common complaint. Constipation is more
common than frequent bowel movements in this population along with
tremors that may be easily confused with essential senile tremor.
Cardiovascular complications are much more common in the elderly
population as well. Finally, some elderly patients may present with
apathetic hyperthyroidism, characterized by a lack of hyperkinetic
motor activity, slowed cognitive processes and a blunted affect,
resembling severe hypothyroidism. In TNG, the most common lab
finding is a decreased TSH with a normal free T4.
Physical examination may reveal findings less severe than those found
in Graves’ disease. There may be a single dominant nodule or multiple
nodules along with hoarseness, tracheal deviation, proximal muscle
weakness, rapid deep tendon reflexes, tremor, moistened and cool
skin, tachycardia and hyperkinesis.
The stigmata of Graves’ disease are not generally seen (orbitopathy,
pretibial mixedema and dermopathy). Differential diagnosis primarily is
to exclude Graves’ disease (Diffuse Toxic Goiter), though it can also
include the following conditions:
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
Carcinoma
 Papillary Thyroid Carcinoma

Thyroiditis
 Hashimoto Thyroiditis
 Riedel Thyroiditis
 Subacute Thyroiditis

Lymphoma
 Thyroid Lymphoma

Thyroid Nodule

Non-toxic goiter

Struma ovarii
In Graves’ disease, treatment options usually are the use of
antithyroid drugs, ablation with radioactive iodine and surgery. In toxic
nodular goiter, the options are generally reduced to ablation and
surgery as these patients rarely go into remission.
Other signs and symptoms of Graves’ disease include ophthalmopathy,
thyroid dermopathy, and thyroid acropachy. Thyroid dermopathy is
rare, occurring in 1-4% of patients. Nearly all patients with
dermopathy have the orbitopathy as well. Lesions are primarily at the
pretibial area and are typically areas of slightly pigmented and
thickened skin.
Acropachy is the most rare extrathyroidal manifestation of Graves’
disease and is the clubbing of the fingers and toes. Complications
include cardiovascular events such as atrial fibrillation, congestive
heart failure and embolic stroke. A very serious complication that is
more common in Asian-background patients is thyrotoxic periodic
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paralysis, occurring in 2% of patients in Japan. In the U.S., the
incidence is approximately 0.2%.
A triad of muscle paralysis, acute hypokalemia, and thyrotoxicosis
characterizes thyrotoxic periodic paralysis. The condition is caused by
a shift of potassium into the muscle cells: thyroid hormones control
the transcription of potassium channels and it is believed that aberrant
transcription may be the underlying cause of the disorder. Treatment
consists of replacement with low doses of potassium and a nonselective β-blocker to prevent arrhythmias and restore muscle
function. Finally, long-standing and poorly controlled Graves’ disease
increases the risk of osteoporosis, gynecomastia, infertility and
menstrual irregularities.
Pathophysiology of Graves’ Disease
Graves’ disease is an autoimmune disorder. As with many if not most
autoimmune disorders, it is more common in women and more
common with increasing age. Graves’ disease involves both B- and Tlymphocyte mediated immunity directed at least at four different
antigens:

Thyroid Stimulating Hormone (TSH/ thyrotropin) receptors

Thyroglobulin

Thyroid peroxidase

The Na+/ I- symporter
Graves’ disease has a strong genetic component. The pathogenesis of
Graves’ disease and Hashimoto’s Thyroiditis share a number of
similarities, one being shared susceptibility genes. These shared genes
can carry a strong risk.
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The TSH-receptor antibodies so prevalent in Graves’ disease have been
recognized in the etiology of Graves’ disease for decades, but until
recently, the specific variant has been relatively elusive. It is
postulated that increased expression on thyrocytes could lead to a
localized inflammatory reaction and to an eventual autoimmune
response.
In Graves’ disease and Hashimoto’s thyroiditis, the mechanism
appears to be a suppression of T-cell activation and disruption of the
regulatory network. T-cell receptor signal transduction utilizes several
enzymes. Inhibitors of T-cell receptor signaling is associated with
Graves’ disease and Hashimoto’s, though it is not clear how the
suppression of cell signaling leads to an autoimmune response.
Epigenetic Influences In Graves’ Disease
Epigenentics can be defined as the heritable changes in the expression
and activity of genes occurring without alterations in the gene
sequence. The two major alterations are the methylationdemethylation of cytosine residues in DNA and histone modification.
Histone modification can take the form of acetylation-deacetylation or
methylation-demethylation. The epigenome integrates all the
information in the genome with information derived from the
intracellular, extracellular and environmental influences, such as food,
xenobiotics, stress, radiation and chemical exposures. The epigenetic
changes manifested in the genome represent an adaptation to
environmental stimuli.
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While currently it is not very clear how to integrate many epigenetic
findings into clinical practice, it is becoming clearer that while genetic
influences on disease are important, environmental and lifestyle
factors also play a critical role in the risk of the development of
disease, including thyroid disease. The Genome Wide Association
Studies (GWAS) indicated that most of the genetic loci associated with
thyroid disease had very low odds ratios associated with them — other
studies indicate that these loci are indeed correlated with the disease
process, demonstrating that there are other factors at play. One of the
most important factors that can impact a disease process is
epigenetics.
Recently, it was discovered that a transcription factor, IRF-1, binds to
the thyroglobulin gene promoter only in association with a diseaselinked variant of the promoter — and that the binding of IRF-1 was
dependent on epigenetic changes in the histone methylation pattern —
this methylation pattern was further associated with viral infection.
The authors postulated that during a viral infection, with increasing
levels of alpha-interferon and IRF-1, the permissive variant of the
thyroglobulin promoter binds IRF-1. This binding may disrupt the
regulatory processes with autoimmunity as the result.
Non-genetic Factors Involved in Graves’ Disease
Other non-genetic (but potentially epigenetic) factors appear to be
involved in the pathogenesis of Graves’ disease. These include Vitamin
D levels, selenium levels and infection with Yersinia enterocolitica,
which exhibits molecular mimicry with the TSH receptor.
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Vitamin D Level:
Low vitamin D levels (below 12.5 ng/ml) are considered an important
risk factor for Graves’ disease. Low vitamin D levels are also
associated with chronic autoimmune thyroiditis. There is also an
association with disease and polymorphisms in the gene encoding the
vitamin D binding receptor as well as the receptor for the active form
of vitamin D - 1,25-(OH)(2)D(3). These polymorphisms may also be
important in the development of thyroid cancer. Whether
supplementation has preventive or therapeutic value is currently being
investigated.
Selenium:
Selenium is an essential trace mineral, which binds to cysteine,
forming selenocysteine, the core of a group of enzymes known as the
selenoproteins. The selenoproteins are intimately involved in
antioxidant and anti-inflammatory reactions. Selenium has been
shown to help protect the thyroid follicular cells from apoptosis.
Selenium deficiency can result in several conditions, including impaired
immunity and an increased risk of autoimmune disease and is strongly
associated with Graves’ disease. Selenium, however, also has a
relatively narrow therapeutic window and deficiency in not uniform —
in areas with sufficient selenium, there may be little need to
supplement as selenium is found in adequate amounts. In other areas,
however, the soil is selenium deficient and supplementation may be
therapeutically useful.
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Iodine:
The role of iodine deficiency in the etiology of Graves’ disease has
been accepted for decades. Iodine excess can also have deleterious
effects, however. High levels of iodine are associated with the
infiltration into the thyroid of T-helper17 cells and inhibit the
development of regulatory T cells. In addition, high levels of iodine
increase the expression of tumor necrosis factor-related apoptosisinducing ligand (TRAIL) in thyrocytes. TRAIL induces apoptosis and
parenchymal destruction. In a mouse model of Graves’ disease, high
levels of iodine can alter thyroglobulin, altering its antigenic potential.
Thyroid Eye Disease
Thyroid orbitopathy is an autoimmune inflammatory disorder that
occurs in 90% of patients with Graves’ disease. Approximately 5% of
patients with thyroid orbitopathy are hypothyroid while the remainder
are euthyroid. Approximately 25% of patients with Graves’ disease will
experience some ophthalmopathy. Orbital inflammation is
characterized by cytokines and by the overexpression of macrophagederived inflammatory cytokines. Oxidative stress is also a significant
factor in thyroid orbitopathy.
Treatment of thyroid orbitopathy consists of systemic corticosteroids,
orbital radiation (though this is controversial as treatment with
radioactive iodine has been shown in some studies to exacerbate
Graves’ orbitopathy. A number of potential therapeutic agents are in
pre-clinical or clinical trials. These include Rotuximab, Tocilzumab,
Adalimumab, Infliximab, Etanercept, Org 274179-0113,
NCGC00229600114 and NCGC0024259560 (which block the signal
transduction of TSH), Teprotumumab, and Sodium selenite.
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Graves’ Disease Treatment
The commonly used antithyroid drugs are thionamide and include
propylthiouracil, thiamazole, and carbimazole. All these drugs are
actively transported into the thyroid. The thionamides are inhibitors of
thyroid peroxidase and the coupling of the iodotyrosines to synthesize
T4 to T3. Propylthiouracil also inhibits the conversion of T4 to T3 in
peripheral tissues.
Thiamazole is the preferred antithyroid drug except in the first
trimester of pregnancy and in patients who cannot tolerate it.
Thiamazole, as compared to propylthiouracil, has a longer half-life and
duration of action allowing a once-daily dosing protocol. Thiamazole
also has better efficacy.
Antithyroid drugs may be used in one of two ways: 1) Titration to find
the dosage to maintain a euthyroid state, and 2) High dose antithyroid
drug plus levothyroxine to replace thyroid hormone.
The block and replace method has the disadvantage of a higher
incidence of side effects. Antithyroid drugs, once discontinued, show a
high rate of relapse. Relapse is more frequent in the first year and
uncommon after 5 years.
Major side effects of the antithyroid drugs include agranulocytosis and
hepatotoxicity both of which can occur in up to 0.3% of patients.
Antithyroid drug treatment should be withdrawn as soon as the thyroid
function becomes normalized.
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Factors To Consider
Block and Replace
Titrate
Stability
Euthyroid state easier to
maintain
May cycle: Hypo↔Hyper
Lab monitoring
Fewer
More
Adverse Effects
High risk
Low risk
Remission
6-12 months, cannot be
predicted
12-18 months. Early
remission can be
predicted by dose
reduction success
Cost
High
Low
Compliance
Considerations
More complex
Easier to follow
Radioactive Iodine
Radioactive ablation of the thyroid is a safe, effective and often firstline treatment of Graves’ disease, toxic adenomas and toxic
multinodular goiter. Contraindications include pregnancy, lactation,
intention to get pregnant and the inability to comply with safety
recommendations. Radioactive ablation is also contraindicated in
patients who are suspected of having thyroid cancer.
The treatment may worsen or cause orbitopathy, but this is
controversial. In those patients with existing orbitopathy, radiation
treatment should be followed by daily prednisone (0·3–0·5 mg/kg of
prednisone daily, beginning 1–3 days after radioactive iodine. The
prednisone is tapered over a 3-month period). Pretreatment with
antithyroid drugs may be required for some patients with
comorbidities, particularly cardiovascular comorbidities or severe
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thyrotoxicosis. This again is controversial, but if done, antithyroid drug
therapy should be stopped at least 3-5 days prior to ablation and
restarted within 3-7 days after radioactive iodine treatment.
Surgery
Surgery is overall the most successful treatment for Graves’ disease,
but patients must take replacement hormone for the rest of their lives.
Total thyroidectomy is most commonly recommended as it has
significantly better surgical outcomes than partial thyroidectomy.
Thyroidectomy is recommended especially for those with “large goitres
or low uptake of radioactive iodine (or both); suspected or
documented thyroid cancer; moderate-to-severe ophthalmopathy, for
which radioactive iodine therapy is contraindicated; and, finally, a
preference for surgery.” Pregnancy is considered a relative
contraindication.
Hyperthyroidism
As mentioned above, in those areas with endemic goiter or in the
elderly, toxic nodular goiter is the most common cause of
hyperthyroidism or thyrotoxicosis. In the U.S., and areas without
endemic goiter (i.e., areas of low iodine intake), Graves’ disease is the
most common cause of hyperthyroid disease. Other causes of
hyperthyroidism include those outlined in the section below.
Thyroiditis
Thyroiditis is a generalized term referring to an inflammation of the
thyroid gland. The term can include Hashimoto’s thyroiditis and others.
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Subacute Thyroiditis
Subacute thyroiditis is self-limiting and has three phases of 1) hyper-,
2) hypo- and 3) euthyroid. Subacute thyroiditis is important to
recognize because it generally needs no treatment. While the etiology
is different in each of the three types of subacute thyroiditis, the
clinical course is similar. The first phase is hyperthyroid, with thyroid
follicles undergoing destruction with concomitant release of T4. The
initial hyperthyroid phase can last for up to 10-12 weeks. This
hyperthyroid phase is then followed by a hypothyroid phase.
Thyroid Hormone Depletion
Most commonly, hypothyroidism is mild, with no need for treatment
with replacement hormone unless there are overt signs and symptoms
of hypothyroidism. This phase can last 8 weeks, although in some
patients it will extend to 6 months. Most patients (~ 95%) will revert
to a euthyroid state with only supportive treatment.

Acute complications can include:
 Severe and permanent hypothyroidism
 Multiple system organ failure
 Pancreatitis
 Vocal cord paralysis
Subacute (nonsuppurative) granulomatous thyroiditis is also known as
de Quervain’s thyroiditis, which is described here.

A painful condition, usually with a diffusely tender thyroid. Patients
often present with chills, fever and neck pain. The accepted cause
is a viral illness and the condition most that often occurs is upper
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respiratory infections. The causative virus has been variably
identified as influenza, adenovirus, mumps, and coxsackievirus.
There may be a transient increase in autoantibodies, but subacute
granulomatous thyroiditis is not considered an autoimmune
disease. The condition is linked (75%) to HLA-Bw35.

May also be caused by medical treatments that manipulate or
affect the immune system in various ways. Examples of
treatments that appear to induce subacute granulomatous
thyroiditis include IL-2, TNF-α, γ-IFN, influenza vaccinations,
peginterferon α-2a and others.
 More common in women.
 Subacute (Silent) lymphocytic thyroiditis appears to be autoimmune
in nature, but is also self-limiting — it occurs most commonly
during the postpartum period.
 Histologic examination reveals lymphocyte infiltration. Fine
needle aspiration biopsy provides a definitive diagnosis
 Physical exam reveals a non-tender thyroid
 Antibodies to thyroid peroxidase are often found. Less
common are antibodies to thyroglobulin.
 Treatment may include β-blocker during hyperthyroid
phase and thyroid hormone replacement during
hypothyroid phase
 Antithyroid drugs, radiation or surgery are contraindication

Subacute (Postpartum) thyroiditis (Commonly identical to
subacute lymphocytic thyroiditis)
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 Most postpartum thyroiditis involves an inflammatory
lymphocytic infiltration
 Hypothyroidism may become permanent
 Commonly recurs in subsequent pregnancy

Drug induced thyroiditis
Drug Induced Thyroiditis
As discussed, several drugs are known to induce a higher risk of
thyroiditis. Most commonly, drug induced thyroiditis is lymphocytic in
nature. The drugs known to induce thyroiditis include those listed
below.
Amiodarone (Cordarone, Nexterone, Pacerone):
•
This form of subacute (lymphocytic) thyroiditis is more common
in men and generally occurs after prolonged therapy and occurs
in 15-20% of patients treated with the drug. Amiodarone is an
antiarrhythmic agent.
•
Amiodarone-induced thyroiditis can be characterized either as
type 1 (hyperthyroidism) which is less common than type 2
(destructive thyroiditis often leading to eventual
hypothyroidism). Mixed and indeterminate forms exist as well.
•
Treatment of type 1 includes thionamides, potassium perchlorate
and if needed, oral glucocorticoids. For type 2, glucocorticoids
are first-line treatment. Amiodarone should be discontinued in
either type or indeterminate types.

α- Interferon (Intron® A (interferon alfa-2b), Roferon®-A
(interferon alfa-2a))
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•
This can occur in up to 40% of patients receiving α-interferon
therapy for Hepatitis C and commonly occurs within 3 months
after therapy has begun. It is associated with autoantibodies.
Hashimoto’s thyroiditis and Graves’ disease occurs in up to 20%
of patients. Recent analysis has indicated genetic associations

Lithium can induce the release of preformed thyroid hormone

Antiretroviral therapy
May be autoimmune or involve the release of preformed thyroid
hormone

Tyrosine kinase inhibitors
May be autoimmune or involve the release of preformed thyroid
hormone
Other Causes or Associations of Thyroiditis
•
Radiation induced thyroiditis: Radiation induced thyroiditis is
commonly associated with radioiodine treatment of Graves’
disease. Inflammation is transient].
•
TSH secreting pituitary adenoma
 Excess TSH secreted by the adenoma induces excess thyroid
hormone production
•
Molar pregnancy, choriocarcinomas and hyperemesis gravidarum
 β- human chorionic gonadotropin can stimulate thymocytes
•
Nonautoimmune autosomal dominant hyperthyroidism
 Germline mutation causes a constitutive activation of TSH
receptor
•
Toxic solitary or multinodular goiter, also known as Plummer
disease
•
Thyrotoxicosis factitia due to conscious or unconscious excess
intake of thyroid hormone
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•
Excess ingestion of iodine
•
Metastatic thyroid cancer
•
Struma ovarii
 Ovarian teratoma with functioning thyroid tissue
Subacute
thyroiditis: includes
granulomatous,
lymphocytic
postpartum
Initial Lab Findings
(Phase 1:
Hyperthyroid)
Subacute
thyroiditis: includes
granulomatous,
lymphocytic
postpartum
Lab Findings
(Phase 2:
Hypothyroid)
Subacute thyroiditis:
includes
granulomatous,
lymphocytic
postpartum
Lab Findings
(Phase 3:
Euthyroid)
TSH
WNL
fT4
WNL
fT3
WNL
ESR
I
uptake
123
Low
TSH= Thyroid Stimulating Hormone; fT4= free T4; fT3= free T3
ESR= Erythrocyte Sedimentation Rate
Thyroid Storm
Thyroid storm is a severe and often sudden form of hyperthyroidism –
it may result from untreated or inadequately treated Graves’ disease,
multinodular goiter, solitary nodules or ingestion of excess thyroid
hormone, either as levothyroxine or as a glandular preparation.
Thyroid storm may be life threatening, commonly because of
cardiovascular effects such as tachycardia, arrhythmias or
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cardiovascular collapse. Symptoms are often florid with muscle
weakness, extreme restlessness, emotional swings, confusion,
psychosis, nausea, vomiting, and diarrhea. Labs indicated significantly
lower than normal TSH with high fT3 and fT4.
ATA Guidelines: Hyperthyroidism
In 2016, the American Thyroid Association produced guidelines of the
diagnosis and management of hyperthyroidism and thyrotoxicosis. This
is outlined in the following table.60
American Thyroid Association produced guidelines of the diagnosis and
management of hyperthyroidism and thyrotoxicosis
Causes of
Thyrotoxicosis
In general, thyrotoxicosis can occur if (i) the thyroid is
excessively stimulated by trophic factors; (ii)
constitutive activation of thyroid hormone synthesis
and secretion occurs, leading to autonomous release of
excess thyroid hormone; (iii) thyroid stores of
preformed hormone are passively released in excessive
amounts owing to autoimmune, infectious, chemical, or
mechanical insult; or (iv) there is exposure to
extrathyroidal sources of thyroid hormone, which may
be either endogenous (struma ovarii, metastatic
differentiated thyroid cancer) or exogenous (factitious
thyrotoxicosis).
Hyperthyroidism is generally considered overt or
subclinical, depending on the biochemical severity of
the hyperthyroidism, although in reality the disease
represents a continuum of overactive thyroid function.
Overt hyperthyroidism is defined as a subnormal
(usually undetectable) serum thyrotropin (TSH) with
elevated serum levels of triiodothyronine (T3) and/or
free thyroxine estimates (free T4).
Subclinical hyperthyroidism is defined as a low or
undetectable serum TSH with values within the normal
reference range for both T3 and free T4.
Both overt and subclinical disease may lead to
characteristic signs and symptoms, although
subclinical hyperthyroidism is usually considered
milder.
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Overzealous or suppressive thyroid hormone
administration may cause either type of thyrotoxicosis,
particularly subclinical thyrotoxicosis.
Endogenous overt or subclinical thyrotoxicosis is
caused by excess thyroid hormone production and
release or by inflammation and release of hormone by
the gland.
Endogenous hyperthyroidism is most commonly due to
GD or nodular thyroid disease. GD is an autoimmune
disorder in which thyrotropin receptor antibodies
(TRAb) stimulate the TSH receptor, increasing thyroid
hormone production and release.
The development of nodular thyroid disease includes
growth of established nodules, new nodule formation,
and development of autonomy over time. In TAs,
autonomous hormone production can be caused by
somatic activating mutations of genes regulating
thyroid growth and hormone synthesis.
Germline mutations in the gene encoding the TSH
receptor can cause sporadic or familial nonautoimmune
hyperthyroidism associated with a diffuse enlargement
of the thyroid gland.
Autonomous hormone production may progress from
subclinical to overt hyperthyroidism, and the
administration of pharmacologic amounts of iodine to
such patients may result in iodine-induced
hyperthyroidism.
GD is the most common cause of hyperthyroidism in
the United States. Although toxic nodular goiter is less
common than GD, its prevalence increases with age
and in the presence of dietary iodine deficiency.
Therefore, toxic nodular goiter may actually be more
common than GD in older patients, especially in regions
of iodine deficiency.
Unlike toxic nodular goiter, which is progressive
(unless triggered by excessive iodine intake),
remission of mild GD has been reported in up to 30%
of patients without treatment.
Less common causes of thyrotoxicosis include the
entities of painless and subacute thyroiditis, which
occur due to inflammation of thyroid tissue with
release of preformed hormone into the circulation.
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Painless thyroiditis caused by lymphocytic
inflammation appears to occur with a different
frequency depending on the population studied: in
Denmark it accounted for only 0.5% of thyrotoxic
patients, but it was 6% of patients in Toronto and 22%
of patients in Wisconsin.
Painless thyroiditis may occur during lithium, cytokine
(i.e., interferon-α), or tyrosine kinase inhibitor therapy,
and in the postpartum period it is referred to as
postpartum thyroiditis. A painless destructive
thyroiditis (not usually lymphocytic) occurs in 5%–
10% of amiodarone-treated patients.
Subacute thyroiditis is thought to be caused by viral
infection and is characterized by fever and thyroid
pain.
Clinical
consequences of
thyrotoxicosis
The cellular actions of thyroid hormone are mediated
by T3, the active form of thyroid hormone. T3 binds to
two specific nuclear receptors (thyroid hormone
receptor α and β) that regulate the expression of many
genes. Nongenomic actions of thyroid hormone include
regulation of numerous important physiologic
functions.
Thyroid hormone influences almost every tissue and
organ system. It increases tissue thermogenesis and
basal metabolic rate and reduces serum cholesterol
levels and systemic vascular resistance. Some of the
most profound effects of increased thyroid hormone
levels occur within the cardiovascular system.
Untreated or partially treated thyrotoxicosis is
associated with weight loss, osteoporosis, atrial
fibrillation, embolic events, muscle weakness, tremor,
neuropsychiatric symptoms, and rarely cardiovascular
collapse and death.
Only moderate correlation exists between the degree
of thyroid hormone elevation and clinical signs and
symptoms. Symptoms and signs that result from
increased adrenergic stimulation include tachycardia
and anxiety and may be more pronounced in younger
patients and those with larger goiters.
The signs and symptoms of mild, or subclinical,
thyrotoxicosis are similar to those of overt
thyrotoxicosis but differ in magnitude. Measurable
changes in basal metabolic rate, cardiovascular
hemodynamics, and psychiatric and neuropsychological
function can be present in mild thyrotoxicosis.
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HOW SHOULD
CLINICALLY OR
INCIDENTALLY
DISCOVERED
THYROTOXICOSIS
BE EVALUATED
AND INITIALLY
MANAGED?
Assessment of
disease severity
Assessment of thyrotoxic manifestations, and
especially potential cardiovascular and neuromuscular
complications, is essential in formulating an
appropriate treatment plan. Although it might be
anticipated that the severity of thyrotoxic symptoms is
proportional to the elevation in the serum levels of free
T4 and T3, in one small study of 25 patients with GD,
the Hyperthyroid Symptom Scale did not strongly
correlate with free T4 or T3 and was inversely
correlated with age. The importance of age as a
determinant of the prevalence and severity of
hyperthyroid symptoms has recently been confirmed.
Cardiac evaluation may be necessary, especially in the
older patient, and may require an echocardiogram,
electrocardiogram, Holter monitor, or myocardial
perfusion studies.
The need for evaluation should not postpone therapy of
the thyrotoxicosis. In addition to the administration of
β-blockers, treatment may be needed for concomitant
myocardial ischemia, congestive heart failure, or atrial
arrhythmias. Anticoagulation may be necessary in
patients in atrial fibrillation.
Goiter size, obstructive symptoms, and the severity of
Graves' orbitopathy (GO), the inflammatory disease
that develops in the orbit in association with
autoimmune thyroid disorders, can be discordant with
the degree of hyperthyroidism or hyperthyroid
symptoms.
All patients with known or suspected hyperthyroidism
should undergo a comprehensive history and physical
examination, including measurement of pulse rate,
blood pressure, respiratory rate, and body weight.
Thyroid size, tenderness, symmetry, and nodularity
should also be assessed along with pulmonary, cardiac,
and neuromuscular function and the presence or
absence of peripheral edema, eye signs, or pretibial
myxedema.
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Biochemical
Evaluation
Serum TSH measurement has the highest sensitivity
and specificity of any single blood test used in the
evaluation of suspected thyrotoxicosis and should be
used as an initial screening test. However, when
thyrotoxicosis is strongly suspected, diagnostic
accuracy improves when a serum TSH, free T4, and
total T3 are assessed at the initial evaluation.
The relationship between free T4 and TSH when the
pituitary–thyroid axis is intact is an inverse log-linear
relationship; therefore, small changes in free T4 result
in large changes in serum TSH concentrations. Serum
TSH levels are considerably more sensitive than direct
thyroid hormone measurements for assessing thyroid
hormone excess.
In overt hyperthyroidism, serum free T4, T3, or both
are elevated, and serum TSH is subnormal (usually
<0.01 mU/L in a third-generation assay). In mild
hyperthyroidism, serum T4 and free T4 can be normal,
only serum T3 may be elevated, and serum TSH will be
low or undetectable. These laboratory findings have
been called “T3-toxicosis” and may represent the
earliest stages of hyperthyroidism caused by GD or an
autonomously functioning thyroid nodule. As with T4,
total T3 measurements are affected by protein binding.
Assays for estimating free T3 are less widely validated
and less robust than those for free T4. Therefore,
measurement of total T3 is frequently preferred over
free T3 in clinical practice.
Subclinical hyperthyroidism is defined as a normal
serum free T4 and normal total T3 or free T3, with
subnormal serum TSH concentration. Laboratory
protocols that store sera and automatically retrieve the
sample and add on free T4 and total T3 measurements
when the initial screening serum TSH concentrations
are low avoid the need for subsequent blood draws.
In the absence of a TSH-producing pituitary adenoma
or thyroid hormone resistance, or in the presence of
spurious assay results due to interfering antibodies, a
normal serum TSH level precludes the diagnosis of
thyrotoxicosis.
The term “euthyroid hyperthyroxinemia” has been
used to describe a number of entities, primarily thyroid
hormone–binding protein disorders, which cause
elevated total serum T4 concentrations (and frequently
elevated total serum T3 concentrations) in the absence
of hyperthyroidism.
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These conditions include elevations in T4 binding
globulin (TBG) or transthyretin; the presence of an
abnormal albumin, which binds T4 with high capacity
(familial dysalbuminemic hyperthyroxinemia); a
similarly abnormal transthyretin; and, rarely,
immunoglobulins that directly bind T4 or T3.
TBG excess may occur as a hereditary X-linked trait, or
it may be acquired as a result of pregnancy or estrogen
administration, hepatitis, acute intermittent porphyuria
or during treatment with 5-fluorouracil, perphenazine,
or some narcotics.
Other causes of euthyroid hyperthyroxinemia include
drugs that inhibit T4 to T3 conversion, such as
amiodarone or high-dose propranolol, acute psychosis,
extreme high altitude, and amphetamine abuse.
Estimates of free thyroid hormone concentrations
frequently also give erroneous results in these
disorders. Spurious free T4 elevations may occur from
heterophilic antibodies or in the setting of heparin
therapy, due to in vitro activation of lipoprotein lipase
and release of free fatty acids that displace T4 from its
binding proteins.
Heterophilic antibodies can also cause spurious high
TSH values, and this should be ruled out by repeating
the TSH in another assay, measurement of TSH in serial
dilution, or direct measurement of human anti-mouse
antibodies. Ingestion of high doses of biotin may cause
spurious results in assays that utilize a streptavidin–
biotin separation technique.
In immunometric assays, frequently used to measure
TSH, excess biotin displaces biotinylated antibodies
and causes spuriously low results, while in competitive
binding assays, frequently used to measure free T4,
excess biotin competes with biotinylated analogue and
results in falsely high results.
Patients taking high doses of biotin or supplements
containing biotin, who have elevated T4 and
suppressed TSH, should stop taking biotin and have
repeat measurements at least 2 days later.
After excluding euthyroid hyperthyroxinemia, TSHmediated hyperthyroidism should be considered when
thyroid hormone concentrations are elevated and TSH
is normal or elevated. A pituitary lesion on magnetic
resonance imaging (MRI) and a disproportionately high
ratio of the serum level of the α-subunit of the pituitary
glycoprotein hormones to TSH supports the diagnosis
of a TSH-producing pituitary adenoma.
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A family history and genetic testing for mutations in
the thyroid hormone receptor β (THRB) gene supports
the diagnosis of resistance to thyroid hormone.
Determination of
Etiology
The etiology of thyrotoxicosis should be determined.
If the diagnosis is not apparent based on the clinical
presentation and initial biochemical evaluation,
diagnostic testing is indicated and can include,
depending on available expertise and resources,
(1) measurement of TRAb, (2) determination of the
radioactive iodine uptake (RAIU), or (3) measurement
of thyroidal blood flow on ultrasonography.
A 123I or 99mTc pertechnetate scan should be
obtained when the clinical presentation suggests a TA
or TMNG.
Symptomatic
Management
Beta-adrenergic blockade is recommended in all
patients with symptomatic thyrotoxicosis, especially
elderly patients and thyrotoxic patients with resting
heart rates in excess of 90 beats per minute or
coexistent cardiovascular disease.
HOW SHOULD
OVERT
HYPERTHYROIDIS
M DUE TO GD BE
MANAGED?
Patients with overt Graves' hyperthyroidism should be
treated with any of the following modalities: RAI
therapy, ATDs, or thyroidectomy.
Clinical situations that favor a particular modality as
treatment for Graves' hyperthyroidism
RAI therapy:
Women planning a pregnancy in the future (in more
than 6 months following RAI administration, provided
thyroid hormone levels are normal), individuals with
comorbidities increasing surgical risk, and patients
with previously operated or externally irradiated necks,
or lack of access to a high-volume thyroid surgeon, and
patients with contraindications to ATD use or failure to
achieve euthyroidism during treatment with ATDs.
Patients with periodic thyrotoxic hypokalemic
paralysis, right heart failure pulmonary hypertension,
or congestive heart failure should also be considered
good candidates for RAI therapy.
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ATDs:
Patients with high likelihood of remission (patients,
especially women, with mild disease, small goiters, and
negative or low-titer TRAb); pregnancy; the elderly or
others with comorbidities increasing surgical risk or
with limited life expectancy; individuals in nursing
homes or other care facilities who may have limited
longevity and are unable to follow radiation safety
regulations; patients with previously operated or
irradiated necks; patients with lack of access to a highvolume thyroid surgeon; patients with moderate to
severe active GO; and patients who need more rapid
biochemical disease control.
Surgery:
Women planning a pregnancy in <6 months provided
thyroid hormone levels are normal (i.e., possibly before
thyroid hormone levels would be normal if RAI were
chosen as therapy); symptomatic compression or large
goiters (≥80 g); relatively low uptake of RAI; when
thyroid malignancy is documented or suspected (i.e.,
suspicious or indeterminate cytology); large thyroid
nodules especially if greater than 4 cm or if
nonfunctioning, or hypofunctioning on 123I or 99mTc
pertechnetate scanning; coexisting
hyperparathyroidism requiring surgery; especially if
TRAb levels are particularly high.
For patients with moderate to severe active GO.
RAI therapy:
Definite contraindications include pregnancy,
lactation, coexisting thyroid cancer, or suspicion of
thyroid cancer, individuals unable to comply with
radiation safety guidelines and used with informed
caution in women planning a pregnancy within 4–6
months.
ATDs:
Definite contraindications to ATD therapy include
previous known major adverse reactions to ATDs.
Surgery:
Factors that may mitigate against the choice of surgery
include substantial comorbidity such as
cardiopulmonary disease, end-stage cancer, or other
debilitating disorders, or lack of access to a highvolume thyroid surgeon.
Pregnancy is a relative contraindication, and surgery
should only be used in the circumstance when rapid
control of hyperthyroidism is required and antithyroid
medications cannot be used.
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Thyroidectomy is best avoided in the first and third
trimesters of pregnancy because of teratogenic effects
associated with anesthetic agents and increased risk of
fetal loss in the first trimester and increased risk of
preterm labor in the third. Optimally, thyroidectomy is
performed in the second trimester; however, although
it is the safest time, it is not without risk (4.5%–5.5%
risk of preterm labor). Thyroid surgery in pregnancy is
also associated with a higher rate of complications,
including hypoparathyroidism and recurrent laryngeal
nerve (RLN) injury.
Patient values that may impact choice of therapy:
RAI therapy:
Patients choosing RAI therapy as treatment for GD
would likely place relatively higher value on definitive
control of hyperthyroidism, the avoidance of surgery,
and the potential side effects of ATDs, as well as a
relatively lower value on the need for lifelong thyroid
hormone replacement, rapid resolution of
hyperthyroidism, and potential worsening or
development of GO.
ATDs:
Patients choosing ATD as treatment for GD would place
relatively higher value on the possibility of remission
and avoidance of lifelong thyroid hormone treatment,
the avoidance of surgery, and exposure to radioactivity
and a relatively lower value on the avoidance of ATD
side effects, and the possibility of disease recurrence.
Surgery:
Patients choosing surgery as treatment for GD would
likely place a relatively higher value on prompt and
definitive control of hyperthyroidism, avoidance of
exposure to radioactivity, and the potential side effects
of ATDs and a relatively lower value on potential
surgical risks, and need for lifelong thyroid hormone
replacement.
IF RAI THERAPY
IS CHOSEN, HOW
SHOULD IT BE
ACCOMPLISHED?
Preparation of
patients with GD
for RAI therapy
Because RAI treatment of GD can cause a transient
exacerbation of hyperthyroidism, β-adrenergic
blockade should be considered even in asymptomatic
patients who are at increased risk for complications
due to worsening of hyperthyroidism (i.e., elderly
patients and patients with comorbidities).
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In addition to β-adrenergic blockade, pretreatment
with MMI prior to RAI therapy for GD should be
considered in patients who are at increased risk for
complications due to worsening of hyperthyroidism.
MMI should be discontinued 2–3 days prior to RAI.
In patients who are at increased risk for complications
due to worsening of hyperthyroidism, resuming MMI 3–
7 days after RAI administration should be considered.
Medical therapy of any comorbid conditions should be
optimized prior to RAI therapy.
Administration of
RAI in the
treatment of GD
Sufficient activity of RAI should be administered in a
single application, typically a mean dose of 10–15 mCi
(370–555 MBq), to render the patient with GD
hypothyroid.
A pregnancy test should be obtained within 48 hours
prior to treatment in any woman with childbearing
potential who is to be treated with RAI. The treating
physician should obtain this test and verify a negative
result prior to administering RAI.
The physician administering RAI should provide written
advice concerning radiation safety precautions
following treatment.
If the precautions cannot be followed, alternative
therapy should be selected.
Follow-up within the first 1–2 months after RAI
therapy for GD should include an assessment of free
T4, total T3, and TSH. Biochemical monitoring should
be continued at 4- to 6-week intervals for 6 months, or
until the patient becomes hypothyroid and is stable on
thyroid hormone replacement.
When hyperthyroidism due to GD persists after 6
months following RAI therapy, retreatment with RAI is
suggested. In selected patients with minimal response
3 months after therapy additional RAI may be
considered.
IF ATDs ARE
CHOSEN AS
INITIAL
MANAGEMENT OF
GD, HOW SHOULD
THE THERAPY BE
MANAGED?
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Initiation of ATD
therapy for the
treatment of GD
MMI should be used in virtually every patient who
chooses ATD therapy for GD, except during the first
trimester of pregnancy when PTU is preferred, in the
treatment of thyroid storm, and in patients with minor
reactions to MMI who refuse RAI therapy or surgery.
Patients should be informed of side effects of ATDs and
the necessity of informing the physician promptly if
they should develop pruritic rash, jaundice, acolic
stools or dark urine, arthralgias, abdominal pain,
nausea, fatigue, fever, or pharyngitis. Preferably, this
information should be in writing.
Before starting ATDs and at each subsequent visit, the
patient should be alerted to stop the medication
immediately and call their physician if there are
symptoms suggestive of agranulocytosis or hepatic
injury.
Prior to initiating ATD therapy for GD, we suggest that
patients have a baseline complete blood count,
including white blood cell (WBC) count with
differential, and a liver profile including bilirubin and
transaminases.
Monitoring of
Patients Taking
ATD’s
A differential WBC count should be obtained during
febrile illness and at the onset of pharyngitis in all
patients taking antithyroid medication. There is
insufficient evidence to recommend for or against
routine monitoring of WBC counts in patients taking
ATDs.
Liver function and hepatocellular integrity should be
assessed in patients taking MMI or PTU who experience
pruritic rash, jaundice, light-colored stool or dark
urine, joint pain, abdominal pain/bloating, anorexia,
nausea/fatigue.
There is insufficient information to recommend for or
against routine monitoring of liver function tests in
patients taking ATDs.
Minor cutaneous reactions may be managed with
concurrent antihistamine therapy without stopping the
ATD. Persistent symptomatic minor side effects of
antithyroid medication should be managed by
cessation of the medication and changing to RAI or
surgery, or switching to the other ATD when RAI or
surgery are not options.
In the case of a serious allergic reaction, prescribing
the alternative drug is not recommended.
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Measurement of TRAb levels prior to stopping ATD
therapy is suggested because it aids in predicting
which patients can be weaned from the medication,
with normal levels indicating greater chance for
remission.
If MMI is chosen as the primary therapy for GD, the
medication should be continued for approximately 12–
18 months, then discontinued if the TSH and TRAb
levels are normal at that time.
If a patient with GD becomes hyperthyroid after
completing a course of MMI, consideration should be
given to treatment with RAI or thyroidectomy.
Continued low-dose MMI treatment for longer than 12–
18 months may be considered in patients not in
remission who prefer this approach.
Persistently
Elevated TRAb
Patients with persistently high TRAb could continue
ATD therapy (and repeat TRAb after an additional 12–
18 months) or opt for alternate definitive therapy with
RAI or surgery.
In selected patients (i.e., younger patients with mild
stable disease on a low dose of MMI), long-term MMI is
a reasonable alternative approach. Another study
reported that MMI doses of 2.5–10 mg/d for a mean of
14 years were safe and effective for the control of GD
in 59 patients.
A recent retrospective analysis compared long-term
outcomes (mean follow-up period of 6–7 years) of
patients who had relapsed after a course of ATDs, who
were treated with either RAI and levothyroxine or
long-term ATD therapy. Those patients treated with
RAI (n = 114) more often had persistent thyroid eye
disease, continuing thyroid dysfunction, and
experienced more weight gain compared with patients
receiving long-term ATD treatment (n = 124).
If continued MMI therapy is chosen, TRAb levels might
be monitored every 1–2 years, with consideration of
MMI discontinuation if TRAb levels become negative
over long-term follow-up.
For patients choosing long-term MMI therapy,
monitoring of thyroid function every 4–6 months is
reasonable, and patients can be seen for follow-up
visits every 6–12 months.
Negative TRAb
If TRAb is negative and thyroid function is normal at
the end of 12–18 months of MMI therapy, it is
reasonable to discontinue the drug.
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If a patient experiences a relapse in follow-up, RAI
therapy or surgery can be considered.
Technical remarks: In patients with negative TRAb,
relapses tend to occur relatively later than those that
develop in patients whose MMI is stopped when TRAb
is still positive, although 5% occurred within the first 2
months in one study. Therefore, in this population,
thyroid function testing should be monitored at 2- to 3month intervals for the first 6 months, then at 4- to 6month intervals for the next 6 months, and then every
6–12 months in order to detect relapses as early as
possible.
The patient should be counseled to contact the treating
physician if symptoms of hyperthyroidism are
recognized. Should a relapse occur, patients should be
counseled about alternatives for therapy, which would
include another course of MMI, RAI, or surgery.
If ATD therapy is chosen, patients should be aware that
agranulocytosis can occur with a second exposure to a
drug, even many years later, despite an earlier
uneventful course of therapy.
If the patient remains euthyroid for more than 1 year
(i.e., they are in remission), thyroid function should be
monitored at least annually because relapses can occur
years later, and some patients eventually become
hypothyroid.
HOW SHOULD
THYROIDECTOMY
BE
ACCOMPLISHED IF
CHOSEN FOR
TREATMENT OF
GD?
Preparation of
patients with GD
for thyroidectomy
If surgery is chosen as treatment for GD, patients
should be rendered euthyroid prior to the procedure
with ATD pretreatment, with or without β-adrenergic
blockade.
A KI-containing preparation should be given in the
immediate preoperative period.
Calcium and 25-hydroxy vitamin D should be assessed
preoperatively and repleted if necessary, or given
prophylactically.
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Calcitriol supplementation should be considered
preoperatively in patients at increased risk for
transient or permanent hypoparathyroidism.
In exceptional circumstances, when it is not possible to
render a patient with GD euthyroid prior to
thyroidectomy, the need for thyroidectomy is urgent,
or when the patient is allergic to ATDs, the patient
should be adequately treated with β-adrenergic
blockade, KI, glucocorticoids, and potentially
cholestyramine in the immediate preoperative period.
The surgeon and anesthesiologist should have
experience in this situation.
THE SURGICAL
PROCEDURE AND
CHOICE OF
SURGEON
If surgery is chosen as the primary therapy for GD,
near-total or total thyroidectomy is the procedure of
choice.
If surgery is chosen as the primary therapy for GD, the
patient should be referred to a high-volume thyroid
surgeon.
POSTOPERATIVE
CARE
Following thyroidectomy for GD, alternative strategies
may be undertaken for management of calcium levels:
serum calcium with or without intact parathyroid
hormone (iPTH) levels can be measured, and oral
calcium and calcitriol supplementation administered
based on these results, or prophylactic calcium with or
without calcitriol prescribed empirically.
ATD should be stopped at the time of thyroidectomy for
GD, and β-adrenergic blockers should be weaned
following surgery.
Communication among different members of the
multidisciplinary team is essential, particularly during
transitions of care in the pre- and postoperative
settings.
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HOW SHOULD
THYROID
NODULES BE
MANAGED IN
PATIENTS WITH
GD?
If a thyroid nodule is discovered in a patient with GD,
the nodule should be evaluated and managed according
to recently published guidelines regarding thyroid
nodules in euthyroid individuals.
HOW SHOULD
THYROID STORM
BE MANAGED?
The diagnosis of thyroid storm should be made
clinically in a severely thyrotoxic patient with evidence
of systemic decompensation. Adjunctive use of a
sensitive diagnostic system should be considered.
Patients with a Burch–Wartofsky Point Scale (BWPS) of
≥45 or Japanese Thyroid Association (JTA) categories
of thyroid storm 1 (TS1) or thyroid storm 2 (TS2) with
evidence of systemic decompensation require
aggressive therapy. The decision to use aggressive
therapy in patients with a BWPS of 25–44 should be
based on clinical judgment.
A multimodality treatment approach to patients with
thyroid storm should be used. Multimodality treatment
includes β-adrenergic blockade, ATD therapy, inorganic
iodide, corticosteroid therapy, cooling with
acetaminophen and cooling blankets, volume
resuscitation, nutritional support, and respiratory care
and monitoring in an intensive care unit, as appropriate
for an individual patient.
IS THERE A ROLE
FOR IODINE AS
PRIMARY
THERAPY IN THE
TREATMENT OF
GD?
Potassium iodide may be of benefit in select patients
with hyperthyroidism due to GD, those who have
adverse reactions to ATDs, and those who have a
contraindication or aversion to RAI therapy (or
aversion to repeat RAI therapy) or surgery.
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Treatment may be more suitable for patients with mild
hyperthyroidism or a prior history of RAI therapy.
HOW SHOULD
OVERT
HYPERTHYROIDIS
M DUE TO TMNG
OR TA BE
MANAGED?
It is suggested that patients with overtly TMNG or TA
be treated with RAI therapy or thyroidectomy. On
occasion, long-term, low-dose treatment with MMI may
be appropriate.
IF RAI THERAPY
IS CHOSEN AS
TREATMENT FOR
TMNG OR TA, HOW
SHOULD IT BE
ACCOMPLISHED?
Preparation of
patients with
TMNG or TA for
RAI therapy
Because RAI treatment of TMNG or TA can cause a
transient exacerbation of hyperthyroidism, βadrenergic blockade should be considered even in
asymptomatic patients who are at increased risk for
complications due to worsening of hyperthyroidism
(i.e., elderly patients and patients with comorbidities).
In addition to β-adrenergic blockade (see
Recommendations 2 and 38) pretreatment with MMI
prior to RAI therapy for TMNG or TA should be
considered in patients who are at increased risk for
complications due to worsening of hyperthyroidism,
including the elderly and those with cardiovascular
disease or severe hyperthyroidism.
In patients who are at increased risk for complications
due to worsening of hyperthyroidism, resuming ATDs
3–7 days after RAI administration should be
considered.
Evaluation of
thyroid nodules
before RAI
therapy
Nonfunctioning nodules on radionuclide scintigraphy or
nodules with suspicious ultrasound characteristics
should be managed according to published guidelines
regarding thyroid nodules in euthyroid individuals.
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Administration of
RAI in the
treatment of TMNG
or TA
Sufficient activity of RAI should be administered in a
single application to alleviate hyperthyroidism in
patients with TMNG.
Sufficient activity of RAI should be administered in a
single application to alleviate hyperthyroidism in
patients with TA.
Patient follow-up
after RAI therapy
for TMNG or TA
Follow-up within the first 1–2 months after RAI
therapy for TMNG or TA should include an assessment
of free T4, total T3, and TSH.
Biochemical monitoring should be continued at 4- to 6week intervals for 6 months, or until the patient
becomes hypothyroid and is stable on thyroid hormone
replacement.
Treatment of
persistent or
recurrent
hyperthyroidism
following RAI
therapy for TMNG
or TA
If hyperthyroidism persists beyond 6 months following
RAI therapy for TMNG or TA, retreatment with RAI is
suggested. In selected patients with minimal response
3 months after therapy additional RAI may be
considered.
IF SURGERY IS
CHOSEN, HOW
SHOULD IT BE
ACCOMPLISHED?
Preparation of
patients with
TMNG or TA for
surgery
If surgery is chosen as treatment for TMNG or TA,
patients with overt hyperthyroidism should be
rendered euthyroid prior to the procedure with MMI
pretreatment, with or without β-adrenergic blockade.
Preoperative iodine should not be used in this setting.
The surgical
procedure and
choice of surgeon
If surgery is chosen as treatment for TMNG, near-total
or total thyroidectomy should be performed. A highvolume thyroid surgeon should perform surgery for
TMNG.
If surgery is chosen as the treatment for TA, a thyroid
ultrasound should be done to evaluate the entire
thyroid gland. An ipsilateral thyroid lobectomy, or
isthmusectomy if the adenoma is in the thyroid
isthmus, should be performed for isolated TAs.
It is suggested that a high-volume surgeon perform
surgery for TA.
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If ATDs are chosen
as treatment of
TMNG or TA, how
should the therapy
be managed?
Long-term MMI treatment of TMNG or TA might be
indicated in some elderly or otherwise ill patients with
limited life expectancy, in patients who are not good
candidates for surgery or ablative therapy, and in
patients who prefer this option.
How should GD be
managed in
children and
adolescents?
Children with GD should be treated with MMI, RAI
therapy, or thyroidectomy. RAI therapy should be
avoided in very young children (<5 years).
RAI therapy in children is acceptable if the activity is
>150 μCi/g (5.55 MBq/g) of thyroid tissue, and for
children between 5 and 10 years of age if the
calculated RAI administered activity is <10 mCi
(<473 MBq).
Thyroidectomy should be chosen when definitive
therapy is required, the child is too young for RAI, and
a high-volume thyroid surgeon can perform surgery.
IF ATD’s ARE
CHOSEN AS
INITIAL
MANAGEMENT OF
GD IN CHILDREN,
HOW SHOULD THE
THERAPY BE
MANAGED?
Initiation of ATD
therapy for the
treatment of GD in
children
MMI should be used in children who are treated with
ATD therapy.
Pediatric patients and their caretakers should be
informed of side effects of ATD preferably in writing,
and the necessity of stopping the medication
immediately and informing their physician if they
develop pruritic rash, jaundice, acolic stools or dark
urine, arthralgias, abdominal pain, nausea, fatigue,
fever, or pharyngitis.
Prior to initiating ATD therapy, we suggest that
pediatric patients have, as a baseline, complete blood
cell count, including WBC count with differential, and a
liver profile including bilirubin, transaminases, and
alkaline phosphatase.
Symptomatic
management of
Graves'
hyperthyroidism in
children
Beta-adrenergic blockade is recommended for children
experiencing symptoms of hyperthyroidism, especially
those with heart rates in excess of 100 beats/minute.
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Monitoring of
children taking
MMI
ATDs should be stopped immediately and WBC counts
measured in children who develop fever, arthralgias,
mouth sores, pharyngitis, or malaise.
Monitoring of
children taking
PTU
In general, PTU should not be used in children. But if it
is used, the medication should be stopped immediately
and liver function and hepatocellular integrity assessed
in children who experience anorexia, pruritus, rash,
jaundice, light-colored stool or dark urine, joint pain,
right upper quadrant pain or abdominal bloating,
nausea, or malaise.
Management of
allergic reactions
in children taking
MMI
Persistent minor cutaneous reactions to MMI therapy in
children should be managed by concurrent
antihistamine treatment or cessation of the medication
and changing to therapy with RAI or surgery. With a
serious adverse reaction to an ATD, prescribing the
other ATD is not recommended.
Duration of MMI
therapy in children
with GD
If MMI is chosen as the first-line treatment for GD in
children, it may be tapered in those children requiring
low doses after 1–2 years to determine if a
spontaneous remission has occurred, or it may be
continued until the child and caretakers are ready to
consider definitive therapy, if needed.
Pediatric patients with GD who are not in remission
following at least 1–2 years of MMI therapy should be
considered for treatment with RAI or thyroidectomy.
Alternatively, if children are tolerating ATD therapy,
ATDs may be used for extended periods. This approach
may be especially useful for the child not considered to
be a candidate for either surgery or RAI.
Individuals on prolonged ATD therapy (>2 years)
should be reevaluated every 6–12 months and when
transitioning to adulthood.
IF RAI IS CHOSEN
AS TREATMENT
FOR GD IN
CHILDREN, HOW
SHOULD IT BE
ACCOMPLISHED?
Preparation of
pediatric patients
with GD for RAI
therapy
It is suggested that children with GD having total T4
levels of >20 μg/dL (260 nmol/L) or free T4 >5 ng/dL
(60 pmol/L) who are to receive RAI therapy be
pretreated with MMI and β-adrenergic blockade until
total T4 and/or free T4 normalize before proceeding
with RAI treatment.
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Administration of
RAI in the
treatment of GD in
children
If RAI therapy is chosen as treatment for GD in
children, sufficient RAI should be administered in a
single dose to render the patient hypothyroid.
THYROIDECTOMY
CHOSEN AS
TREATMENT FOR
GD IN CHILDREN
SHOULD BE
ACCOMPLISHED
AS FOLLOWS
Preparation of
children with GD
for thyroidectomy
Children with GD undergoing thyroidectomy should be
rendered euthyroid with the use of MMI. A KIcontaining preparation should be given in the
immediate preoperative period.
If surgery is chosen as therapy for GD in children, total
or near-total thyroidectomy should be performed.
High-volume thyroid surgeons should perform
thyroidectomy in children.
HOW SHOULD
SUBCLINICAL
HYPERTHYROIDIS
M BE MANAGED?
Prevalence and
causes of SH
The prevalence of subclinical hyperthyroidism (SH) in
an adult population depends on age, sex, and iodine
intake. In a representative sample of U.S. subjects
without known thyroid disease, 0.7% had suppressed
TSH levels (<0.1 mU/L), and 1.8% had low TSH levels
(<0.4 mU/L).
Similar rates have been reported in studies from
Europe, with higher levels in women and older
subjects. The differential diagnosis of an isolated low
or suppressed TSH level includes exogenous thyroid
hormone use, nonthyroidal illness, drug effects, and
pituitary/hypothalamic disease, all of which need to be
ruled out before the diagnosis of SH can be established
in a patient with an isolated low or suppressed TSH
level.
In addition, mean serum TSH levels are lower in black
non-Hispanic Americans, some of whom may have
slightly low TSH levels without thyroid disease.
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Finally, some otherwise healthy older persons may
have low serum TSH levels, low-normal serum levels of
free T4 and total T3, and no evidence of thyroid or
pituitary disease, suggesting an altered set point of the
pituitary–thyroid axis.
The natural history of SH is variable; annually, 0.5%–
7% progression to overt hyperthyroidism and 5%–
12% reversion to normal TSH levels. In one study,
51.2% of patients had spontaneously developed a
normal TSH when first checked at some time within 5
years (mean time to repeat TSH, 13 months).
Progression from SH to overt hyperthyroidism appears
more likely if the TSH is suppressed (<0.01 mU/L),
rather than low but detectable (0.01–0.4 mU/L).
Patients with GD rather than a TMNG as the cause of
SH may be more likely to spontaneously remit. In
patients at high risk of complications from SH, TSH and
free T4 should be repeated within 2–6 weeks.
For all other patients, it is important to document that
SH is a persistent problem by repeating the serum TSH
at 3–6 months, prior to initiating therapy.
In clinical series, TMNG is the most common cause of
SH, especially in older persons.
The second most common cause of SH is GD, which is
more prevalent in younger persons and is also common
in patients who previously received ATD therapy.
Other unusual causes include solitary autonomously
functioning nodules and various forms of thyroiditis,
the latter of which would be more strictly termed
“subclinical thyrotoxicosis.
Clinical
significance of SH
Since SH is a mild form of hyperthyroidism, it is not
surprising that deleterious effects seen in overt
hyperthyroidism might also occur in SH. A large
number of recent studies have elucidated these effects.
When to treat SH
When TSH is persistently <0.1 mU/L, treatment of SH
is recommended in all individuals ≥65 years of age; in
patients with cardiac risk factors, heart disease or
osteoporosis; in postmenopausal women who are not
on estrogens or bisphosphonates; and in individuals
with hyperthyroid symptoms.
When TSH is persistently <0.1 mU/L, treatment of SH
should be considered in asymptomatic individuals <65
years of age without the risk factors listed in
Recommendation 73.
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When TSH is persistently below the lower limit of
normal but ≥0.1 mU/L, treatment of SH should be
considered in individuals ≥65 years of age and in
patients with cardiac disease, osteoporosis, or
symptoms of hyperthyroidism.
When TSH is persistently below the lower limit of
normal but ≥0.1 mU/L, asymptomatic patients under
age 65 without cardiac disease or osteoporosis can be
observed without further investigation of the etiology
of the subnormal TSH or treatment.
How to treat SH
End points to be
assessed to
determine
effective therapy
of SH
If SH is to be treated, the treatment should be based
on the etiology of the thyroid dysfunction and follow
the same principles as outlined for the treatment of
overt hyperthyroidism.
The goal of therapy for SH is to render the patient
euthyroid with a normal TSH. Since the rationale for
therapy of SH is to a large degree preventive, few end
points can be used to document that therapy has been
successful.
Based on the original indication for treatment, it is
reasonable to follow hyperthyroid symptoms or bone
density; otherwise, the major end point is a TSH level
within the age-adjusted reference range.
Prevention of GO
Current therapeutic approaches to GO, including local
measures, corticosteroids, orbital radiation, and
surgery, often fail to significantly improve the QoL of
patients with this debilitating condition. Therefore,
efforts should be made to prevent the development or
progression of GO in patients with Graves'
hyperthyroidism.
Pertinent risk factors for GO are RAI therapy for
hyperthyroidism, untreated hyperthyroidism, smoking,
high serum pretreatment TRAb levels (normal
<1.75 IU/L, high risk for progression if >8.8 IU/L), and
any delay in treating hypothyroidism after therapy for
hyperthyroidism.
High pretreatment levels of T3 and T4 were each
reported to have a predictive role in GO, but these
conclusions were not validated by subsequent studies,
suggesting the possibility of higher TRAb values
measured on less sensitive assays early-on being
partly responsible for this variation.
Euthyroidism should be expeditiously achieved and
maintained in hyperthyroid patients with GO or risk
factors for the development of orbitopathy.
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We recommend clinicians advise patients with GD to
stop smoking and refer them to a structured smoking
cessation program. As both firsthand and secondhand
smoking increase GO risk, patients exposed to
secondhand smoke should be identified and advised of
its negative impact.
Treatment of
hyperthyroidism in
patients with no
apparent GO
In nonsmoking patients with GD without apparent GO,
RAI therapy (without concurrent steroids), ATDs, or
thyroidectomy should be considered equally acceptable
therapeutic options in regard to risk of GO.
In smoking patients with GD without apparent GO, RAI
therapy, ATDs, or thyroidectomy should be considered
equally acceptable therapeutic options in regard to risk
of GO.
Treatment of
hyperthyroidism in
patients with
active GO of mild
severity
In patients with Graves' hyperthyroidism who have
mild active ophthalmopathy and no risk factors for
deterioration of their eye disease, RAI therapy, ATDs,
and thyroidectomy should be considered equally
acceptable therapeutic options.
In the absence of any strong contraindication to GC use
we suggest considering them for coverage of GD
patients with mild active GO who are treated with RAI;
in absence of risk factors for GO deterioration.
In GD patients with mild GO who are treated with RAI
we recommend steroid coverage if there are
concomitant risk factors for GO deterioration.
Treatment of
hyperthyroidism in
patients with
active and
moderate-tosevere or sightthreatening GO
Treatment of GD in
patients with
inactive GO
In patients with active and moderate-to-severe or
sight-threatening GO we recommend against RAI
therapy. Surgery or ATDs are preferred treatment
options for GD in these patients.
In patients with inactive GO we suggest RAI therapy
can be administered without steroid coverage.
However, in cases of elevated risk for reactivation
(high TRAb, CAS ≥1 and smokers) that approach might
have to be reconsidered.
HOW SHOULD
IODINE-INDUCED
AND
AMIODARONEINDUCED
THYROTOXICOSIS
BE MANAGED?
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Iodine-induced
hyperthyroidism
Routine administration of ATDs before iodinated
contrast media exposure is not recommended for all
patients.
Beta-adrenergic blocking agents alone or in
combination with MMI should be used to treat overt
iodine-induced hyperthyroidism.
Amiodaroneinduced
thyrotoxicosis
We suggest monitoring thyroid function tests before
and within the first 3 months following the initiation of
amiodarone therapy, and at 3- to 6-month intervals
thereafter.
The decision to stop amiodarone in the setting of
thyrotoxicosis should be determined on an individual
basis in consultation with the treating cardiologist,
depending on the clinical manifestations and presence
or absence of effective alternative antiarrhythmic
therapy.
In clinically stable patients with AIT, we suggest
measuring thyroid function tests to identify disorders
associated with iodine-induced hyperthyroidism (type
1 AIT), specifically including toxic nodular disease and
previously occult GD.
MMI should be used to treat overt thyrotoxicosis in
patients with proven underlying autonomous thyroid
nodules or GD as the cause of AIT (type 1 disease).
Corticosteroids should be used to treat patients with
overt amiodarone-induced thyroiditis (type 2 disease).
Combined ATD and corticosteroid therapy should be
used to treat patients with overt AIT who are too
unstable clinically to allow a trial of monotherapy or
who fail to respond to single modality therapy, or
patients in whom the etiology of thyrotoxicosis cannot
be unequivocally determined.
Patients with AIT who are unresponsive to aggressive
medical therapy with MMI and corticosteroids should
undergo thyroidectomy.
HOW SHOULD
THYROTOXICOSIS
DUE TO
DESTRUCTIVE
THYROIDITIS BE
MANAGED?
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Subacute
thyroiditis
Patients with mild symptomatic subacute thyroiditis
should be treated initially with β-adrenergic-blocking
drugs and nonsteroidal anti-inflammatory agents
(NSAIDs). Corticosteroids should be used instead of
NSAIDs when patients fail to respond or present
initially with moderate to severe pain and/or
thyrotoxic symptoms.
Painless
thyroiditis
Patients with symptomatic thyrotoxicosis due to
painless thyroiditis should be treated with βadrenergic-blocking drugs to control symptoms.
Acute thyroiditis
How should other
causes of
thyrotoxicosis be
managed?
Acute thyroiditis should be treated with antibiotics and
surgical drainage as determined by clinical judgement.
Beta-blockers may be used to treat symptoms of
thyrotoxicosis.
Patients taking medications known to cause
thyrotoxicosis, including interferon (IFN)-α,
interleukin-2, tyrosine kinase inhibitors, and lithium,
should be monitored clinically and biochemically at 6month intervals for the development of thyroid
dysfunction.
Patients who develop thyrotoxicosis should be
evaluated to determine etiology and treated
accordingly.
TSH-secreting
pituitary tumors
The diagnosis of a TSH-secreting pituitary adenoma
should be based on an inappropriately normal or
elevated serum TSH level associated with elevated free
T4 and total T3 concentrations, generally associated
with a pituitary tumor on MRI or CT and the absence of
a family history or genetic testing consistent with
resistance to thyroid hormone.
Struma ovarii
Patients with struma ovarii should be treated initially
with surgical resection following preoperative
normalization of thyroid hormones.
Choriocarcinoma
Treatment of hyperthyroidism due to choriocarcinoma
should include both MMI and treatment directed
against the primary tumor.
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Euthyroid Sick Syndrome
Euthyroid sick syndrome is also known as non-thyroidal illness
syndrome. Euthyroid sick syndrome occurs in patients with a number
of different non-thyroidal illnesses such as metabolic syndrome, acute
coronary syndrome, other acutely ill cardiac patients, trauma,
starvation, chronic kidney disease, diabetic ketoacidosis, eating
disorders and other conditions. It is primarily a lab diagnosis as there
are often few if any symptoms of thyroid disease. Decreased fT3 and
tissue T3 levels, presumably because of decreased deiodinase activity,
characterize this. fT4 and TSH usually are within the reference ranges.
In more severe cases, the total T4 also decreases and T3 resin uptake
increases as does reverse T3 (rT3). D1 activity is reduced while D3
activity is increased. TSH are usually low-normal or somewhat below
normal. fT4 may in normal, increased or decreased. In euthyroid sick
syndrome the T3 is decreased proportionately more than T4 (the
reverse is true in hypothyroidism).3,61-66
Euthyroid sick syndrome is believed to be cause by inflammatory
cytokines resulting from the primary condition. It may be an adaptive
process that reduces peripheral energy use. Treatment is
controversial; many clinicians believe that the best approach is to treat
the overlying disorder while others believe that supporting thyroid
function can speed recovery overall. Low T3 levels have been shown to
have prognostic significance, particularly in patients with ischemic
heart disease, valvular disease, congestive heart failure,
meningococcal sepsis, cancer (such a lung adenocarcinoma, breast
cancer, squamous cell carcinoma) and other conditions in the setting
of an ICU.
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A recent report indicated that there may be two phases of euthyroid
sick syndrome/non-thyroidal illness, at least in the setting of the ICU.
The first phase, coinciding with admission to the ICU is a “fasting “and
an adaptive response and it may be beneficial to the patient to allow
the adaptation to proceed without interference. This first phase
accounts for the majority of ICU patients. The second phase, however,
occurs in patients with prolonged, chronic illness who are adequately
nourished and who may benefit from treatment.
Hypothyoidism And Associated Conditions
Hypothyroidism may be primary, secondary, tertiary or subclinical.
Hypothyroidism is a hormone deficiency disease diagnosed by physical
signs and symptoms as well as lab results.3,64-70
Primary Hypothyroidism
Primary hypothyroidism is caused by
disease in the thyroid. Across the
world, most hypothyroidism is caused
Consultation with an
endocrinologist is
recommended in the following
situations:


by iodine deficiency. In the U.S., the
most common cause of primary
hypothyroidism is autoimmune and
results in Hashimoto’s thyroiditis. The
second most common cause in the



U.S. is post-therapeutic
hypothyroidism, particularly after the

treatment of goiter or Graves’ disease

with surgery or radiation. This form of

hypothyroidism may not be
In children and infants
In those patients where a
euthyroid state has been
difficult to achieve or
maintain.
In pregnancy or if
planning a pregnancy
In patients with cardiac
disease
In those patients with
goiter, nodule, or other
structural changes in the
thyroid gland
If other endocrinopathies
exist
If lab results present with
unusual results
Unusual causes of
hypothyroidism
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permanent. Primary hypothyroidism may result in goiter, though goiter
is more commonly associated with hyperfunctioning of the thyroid.
Iodine deficiency can also cause congenital hypothyroidism — in the
past, this was known as cretinism (now referred to as congenital
hypothyroidism) because of its effects on cognitive development and
learning.
Primary hypothyroidism can also be drug induced. Drugs that can
induce hypothyroidism include those that can induce hyperthyroidism
— lithium, amiodarone and other iodine-containing drugs, α-interferon,
tyrosine kinase inhibitors and checkpoint inhibitors. Radiation
treatment can also induce hypothyroidism.
The differential diagnosis of hypothyroidism can be difficult because
presenting signs and symptoms are often non-specific. The patient
may complain of fatigue, or the chief complaint can be weight gain.
Diagnostic considerations include anemia and familial or personal
tendency to autoimmune diseases.
Differential diagnoses include:

Addison’s disease

Syndrome of Inappropriate ADH secretion

Other thyroid disorders such as thyroiditis (de Quervains,
Reidel’s, Euthyroid Sick Syndrome, drug/radiation induced
thyroiditis, subacute, postpartum), goiter, thyroid lymphoma,
thyroxine-binding globulin deficiency, iodine deficiency

Types I, II, III Polyglandular Autoimmune Syndrome

Hypopituitarism
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
Pituitary macroadenoma

Prolactin deficiency

Chronic fatigue syndrome

Depression

Gynecologic disorders or states such as anovulation,
dysmenorrhea, menopause, ovarian insufficiency

Eosinophilia, eosinophilia-myalgia syndrome

Familial hypercholesterolemia, polygenic hypercholesterolemia

Hypoalbuminemia

Infectious mononucleosis

Obesity

Sleep apnea. Sleep disorders

Cardiac tamponade, pericardial effusion

Chronic megacolon, ileus, constipation

Obesity
Postpartum Thyroiditis
Postpartum thyroiditis occurs within 2-12 months of delivery. In
women with a personal or family history of autoimmune disease, the
frequency of postpartum thyroiditis is increase. In 2012, guidelines for
the management of thyroid dysfunction during pregnancy and
postpartum were produced:65
ATA Recommendations for Management of Hypothyroidism in Pregnancy
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Management of
hypothyroidism:
maternal and fetal
aspects
It is recommended that caution be exercised in the
interpretation of serum free T4 levels during
pregnancy and that each laboratory establish
trimester-specific reference ranges for pregnant
women if using a free T4 assay.
The nonpregnant total T4 range (5–12 μg/dl or 50–
150 nmol/liter) can be adapted in the second and
third trimesters by multiplying this range by 1.5-fold.
Alternatively, the free T4 index (“adjusted T4”)
appears to be a reliable assay during pregnancy.
Overt maternal hypothyroidism is known to have
serious adverse effects on the fetus. Therefore,
maternal hypothyroidism should be avoided.
Subclinical hypothyroidism (SCH; serum TSH
concentration above the upper limit of the trimesterspecific reference range with a normal free T4) may
be associated with an adverse outcome for both the
mother and offspring, as documented in antibodypositive women.
In retrospective studies, T4 treatment improved
obstetrical outcome, but it has not been proved to
modify long-term neurological development in the
offspring. However, given that the potential benefits
outweigh the potential risks, the panel recommends
T4 replacement in women with SCH who are thyroid
peroxidase antibody positive (TPO-Ab+).
If hypothyroidism has been diagnosed before
pregnancy, we recommend adjustment of the
preconception T4 dose to reach before pregnancy a
TSH level not higher than 2.5 mIU/liter. The T4 dose
usually needs to be incremented by 4 to 6 wk
gestation and may require a 30% or more increase in
dosage.
If overt hypothyroidism is diagnosed during
pregnancy, thyroid function tests should be
normalized as rapidly as possible. T4 dosage should
be titrated to rapidly reach and thereafter maintain
serum TSH concentrations of less than 2.5 mIU/liter
(in an assay using the International Standard) in the
first trimester (or 3 mIU/liter in second and third
trimesters) or to trimester-specific TSH ranges.
Thyroid function tests should be remeasured within
30–40 d and then every 4–6 wk.
Women with thyroid autoimmunity who are
euthyroid in the early stages of pregnancy are at risk
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of developing hypothyroidism and should be
monitored every 4–6 wk for elevation of TSH above
the normal range for pregnancy. After delivery, most
hypothyroid women need to decrease the T4 dosage
they received during pregnancy to the prepregnancy
dose.
Management of
hyperthyroidism:
maternal and fetal
aspects
Management of
maternal
hyperthyroidism:
maternal aspects
If a subnormal serum TSH concentration is detected
during gestation, hyperthyroidism must be
distinguished from both normal physiology of
pregnancy and gestational thyrotoxicosis because of
the adverse effects of overt hyperthyroidism on the
mother and fetus. Differentiation of Graves' disease
from gestational thyrotoxicosis is supported by the
presence of clinical evidence of autoimmunity, a
typical goiter, and presence of TSH receptor
antibodies (TRAb). TPO-Ab may be present in either
case.
For overt hyperthyroidism due to Graves' disease or
thyroid nodules, antithyroid drug (ATD) therapy
should be either initiated (before pregnancy if
possible, and for those with new diagnoses) or
adjusted (for those with a prior history) to maintain
the maternal thyroid hormone levels for free T4 at or
just above the upper limit of the nonpregnant
reference range, or to maintain total T4 at 1.5 times
the upper limit of the normal reference range or the
free T4 index in the upper limit of the normal
reference range.
Propylthiouracil (PTU), if available, is recommended
as the first-line drug for treatment of
hyperthyroidism during the first trimester of
pregnancy because of the possible association of
methimazole (MMI) with specific congenital
abnormalities that occur during first trimester
organogenesis.
MMI may also be prescribed if PTU is not available or
if a patient cannot tolerate or has an adverse
response to PTU. MMI 10 mg is considered to be
approximately equal to 100–150 mg of PTU.
Recent analyses reported by the U.S. Food and Drug
Administration (FDA) indicate that PTU may rarely be
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associated with severe liver toxicity. For this reason
we recommend that clinicians change treatment of
patients from PTU to MMI after the completion of the
first trimester. Available data indicate that MMI and
PTU are equally efficacious in the treatment of
pregnant women.
Practitioners should use their clinical judgment in
choosing the ATD therapy, including the potential
difficulties involved in switching patients from one
drug to another. If switching from PTU to MMI,
thyroid function should be assessed after 2 wk and
then at 2- to 4-wk intervals. Although liver toxicity
may appear abruptly, it is reasonable to monitor liver
function in pregnant women on PTU every 3–4 wk
and to encourage patients to promptly report any
new symptoms.
Subtotal thyroidectomy may be indicated during
pregnancy as therapy for maternal Graves' disease if:
1) a patient has a severe adverse reaction to ATD
therapy; 2) persistently high doses of ATD are
required (over 30 mg/d of MMI or 450 mg/d of PTU);
or 3) a patient is nonadherent to ATD therapy and
has uncontrolled hyperthyroidism. The optimal
timing of surgery is in the second trimester.
There is no evidence that treatment of subclinical
hyperthyroidism improves pregnancy outcome, and
treatment could potentially adversely affect fetal
outcome.
Management of
maternal
hyperthyroidism:
fetal aspects
Because thyroid receptor antibodies (thyroid
receptor stimulating, binding, or inhibiting
antibodies) freely cross the placenta and can
stimulate the fetal thyroid, these antibodies should
be measured by 22 wk gestational age in mothers
with: 1) current Graves' disease; or 2) a history of
Graves' disease and treatment with 131I or
thyroidectomy before pregnancy; or 3) a previous
neonate with Graves' disease; or 4) previously
elevated TRAb.
Women who have a negative TRAb and do not require
ATD have a very low risk of fetal or neonatal thyroid
dysfunction. 131I should not be given to a woman
who is or may be pregnant. If inadvertently treated,
the patient should be promptly informed of the
radiation danger to the fetus, including thyroid
destruction if treated after the 12th week of
gestation. USPSTF recommendation level: A;
evidence, good.
There are no data for or against recommending
termination of pregnancy after 131I exposure.
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In women with TRAb or thyroid-stimulating Ig
elevated at least 2- to 3-fold the normal level and in
women treated with ATD, maternal free T4 and fetal
thyroid dysfunction should be screened for during
the fetal anatomy ultrasound done in the 18th-22nd
week and repeated every 4–6 wk or as clinically
indicated.
Evidence of fetal thyroid dysfunction could include
thyroid enlargement, growth restriction, hydrops,
presence of goiter, advanced bone age, tachycardia,
or cardiac failure. If fetal hyperthyroidism is
diagnosed and thought to endanger the pregnancy,
treatment using MMI or PTU should be given with
frequent clinical, laboratory, and ultrasound
monitoring.
Umbilical blood sampling should be considered only if
the diagnosis of fetal thyroid disease is not
reasonably certain from the clinical and sonographic
data and the information gained would change the
treatment.
All newborns of mothers with Graves' disease
(except those with negative TRAb and not requiring
ATD) should be evaluated by a medical care provider
for thyroid dysfunction and treated if necessary.
Gestational
hyperemesis and
hyperthyroidism
Thyroid function tests (TSH, total T4, or free T4
index, or free T4) and TRAb should be measured in
patients with hyperemesis gravidarum (5% weight
loss, dehydration, and ketonuria) and clinical
features of hyperthyroidism.
Most women with hyperemesis gravidarum, clinical
hyperthyroidism, suppressed TSH, and elevated
freeT4 do not require ATD treatment.
Clinical judgment should be followed in women who
appear significantly thyrotoxic or who have in
addition serum total T3 values above the reference
range for pregnancy.
Autoimmune thyroid
disease and
Beta-blockers such as metoprolol may be helpful and
may be used with obstetrical agreement. Women
with hyperemesis gravidarum and diagnosed to have
Graves' hyperthyroidism (free T4 above the reference
range or total T4 > 150% of top normal pregnancy
value, TSH < 0.01 μIU/liter, and presence of TRAb)
will require ATD treatment, as clinically necessary.
A positive association exists between the presence of
thyroid antibodies and pregnancy loss. Universal
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miscarriage
screening for antithyroid antibodies, and possible
treatment, cannot be recommended at this time.
As of January 2011, only one randomized
interventional trial has suggested a decrease in the
first trimester miscarriage rate in euthyroid
antibody-positive women, but treatment duration
was very brief before the outcome of interest.
However, because women with elevated anti-TPO
antibodies are at increased risk for progression of
hypothyroidism, if identified such women should be
screened for serum TSH abnormalities before
pregnancy, as well as during the first and second
trimesters of pregnancy.
Thyroid nodules and
cancer
Fine-needle aspiration (FNA) cytology should be
performed for predominantly solid thyroid nodules
larger than 1 cm discovered in pregnancy.
Women with nodules 5 mm to 1 cm in size should be
considered for FNA if they have a high-risk history or
suspicious findings on ultrasound, and women with
complex nodules 1.5 to 2 cm or larger should also
receive an FNA.
During the last weeks of pregnancy, FNA can
reasonably be delayed until after delivery.
Ultrasound-guided FNA is likely to have an advantage
for maximizing adequate sampling.
When nodules discovered in the first or early second
trimester are found to be malignant or highly
suspicious on cytopathological analysis, to exhibit
rapid growth, or to be accompanied by pathological
neck adenopathy, pregnancy need not be interrupted,
but surgery should be offered in the second
trimester.
Women found to have cytology indicative of papillary
cancer or follicular neoplasm without evidence of
advanced disease and who prefer to wait until the
postpartum period for definitive surgery may be
reassured that most well-differentiated thyroid
cancers are slow growing and that delaying surgical
treatment until soon after delivery is unlikely to
change disease-specific survival. It is appropriate to
administer thyroid hormone to achieve a suppressed
but detectable TSH in pregnant women with a
previously treated thyroid cancer, in those with an
FNA positive for or suspicious for cancer, or in those
who elect to delay surgical treatment until
postpartum.
High-risk patients may benefit more than low-risk
patients from a greater degree of TSH suppression.
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The free T4 or total T4 levels should ideally not be
increased above the normal range for pregnancy.
Radioactive iodine (RAI) with 131I should not be
given to women who are breastfeeding or for at least
4 wk after nursing has ceased.
Furthermore, pregnancy should be avoided for 6
months to 1 yr in women with thyroid cancer who
receive therapeutic RAI doses to ensure stability of
thyroid function and confirm remission of thyroid
cancer.
Iodine nutrition
during pregnancy
Women in the childbearing age should have an
average iodine intake of 150 μg/d. As long as
possible before pregnancy and during pregnancy and
breastfeeding, women should increase their daily
iodine intake to 250 μg on average.
Iodine intake during pregnancy and breastfeeding
should not exceed twice the daily recommended
nutrient intake (RNI) for iodine, i.e., 500 μg iodine
per day.
Although not advised as a part of normal clinical
practice, the adequacy of the iodine intake during
pregnancy can be assessed by measuring urinary
iodine concentration (UIC) in a representative cohort
of the population. UIC should ideally range between
150 and 250 μg/liter.
If there is significant concern, the caregiver should
assay TSH and thyroid hormone levels.
To reach the daily recommended nutrient intake for
iodine, multiple means must be considered, tailored
to the iodine intake level in a given population.
Different situations must therefore be distinguished:
1) countries with iodine sufficiency and/or with a
well-established universal salt iodization (USI)
program; 2) countries without a USI program or with
an established USI program where the coverage is
known to be only partial; and 3) remote areas with
no accessible USI program and difficult
socioeconomic conditions. It is recommended that
once-daily prenatal vitamins contain 150–200 μg
iodine and that this be in the form of potassium
iodide or iodate, the content of which is verified to
ensure that all pregnant women taking prenatal
vitamins are protected from iodine deficiency.
Ideally, supplementation should be started before
conception. Preparations containing iron
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supplements should be separated from thyroid
hormone administration by at least 4 h. It is
recommended that breastfeeding women maintain a
daily intake of 250 μg of iodine to ensure that breast
milk provides 100 μg iodine per day to the infant.
Postpartum
thyroiditis
There are insufficient data to recommend screening
of all women for postpartum thyroiditis (PPT).
Women known to be TPO-Ab+ should have TSH
measured at 6–12 wk gestation and at 6 months
postpartum, or as clinically indicated.
Because the prevalence of PPT in women with type 1
diabetes, Graves' disease in remission, and chronic
viral hepatitis is greater than in the general
population, screening by TSH is recommended at 3
and 6 months postpartum. Women with a history of
PPT have a markedly increased risk of developing
permanent primary hypothyroidism in the 5- to 10-yr
period after the episode of PPT. An annual TSH level
should be performed in these women.
Asymptomatic women with PPT who have a TSH
above the reference range but less than 10 mIU/liter
and who are not planning a subsequent pregnancy do
not necessarily require intervention but should, if
untreated, be remonitored in 4–8 wk. When a TSH
above the reference range continues, women should
be treated with levothyroxine. Symptomatic women
and women with a TSH above normal and who are
attempting pregnancy should be treated with
levothyroxine.
There is insufficient evidence to conclude whether an
association exists between postpartum depression
(PPD) and either PPT or thyroid antibody positivity
(in women who did not develop PPT). USPSTF
recommendation level: I; evidence, poor. However,
because hypothyroidism is a potentially reversible
cause of depression, women with PPD should be
screened for hypothyroidism and appropriately
treated.
Screening for
thyroid dysfunction
during pregnancy
Universal screening of healthy women for thyroid
dysfunction before pregnancy is not recommended.
However, caregivers should identify individuals at
“high risk” for thyroid illness on the basis of their
medical history, physical exam, or prior biochemical
data. When such individuals are identified, prenatal
measurement of serum TSH is recommended.
If it is above 2.5 mIU/liter, the test should be
confirmed by repeat assay. Although no randomized
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controlled trials are available to guide a response,
the committee believes it is appropriate to give lowdose T4 treatment to bring TSH below 2.5 mIU/liter.
This treatment can be discontinued if the woman
does not become pregnant or postpartum. All women
considering pregnancy with known thyroid
dysfunction and receiving levothyroxine should be
tested for abnormal TSH concentrations before
pregnancy. If hypothyroidism has been diagnosed
before pregnancy, the recommendation is for
adjustment of the preconception T4 dose to reach
before pregnancy a TSH level not higher than 2.5
mIU/liter.
All women receiving levothyroxine should be verbally
screened prenatally to assess their understanding of
changing levothyroxine requirements after
conception. These women should be counseled to
contact a physician or medical professional
immediately upon a missed menstrual cycle or
suspicion of pregnancy to check their serum TSH
level. An additional recommendation may be to
increase their levothyroxine dose by 30%, which is
often two additional tablets per week (nine tablets
per week), until their serum TSH can be checked.
Universal screening for the presence of anti-TPO
antibodies either before or during pregnancy is not
recommended. However, women with elevated antiTPO antibodies are at increased risk for miscarriage,
preterm delivery, progression of hypothyroidism, and
PPT. Therefore, if identified, such women should be
screened for serum TSH abnormalities before
pregnancy, as well as during the first and second
trimesters of pregnancy. The committee could not
reach agreement with regard to screening
recommendations for all newly pregnant women.
Two versions are therefore presented. Some
members recommended screening of all pregnant
women for serum TSH abnormalities by the ninth
week or at the time of their first visit.
Some members recommended neither for nor against
universal screening of all pregnant women for TSH
abnormalities at the time of their first visit. These
members strongly support aggressive case finding to
identify and test high-risk women for elevated TSH
concentrations by the ninth week or at the time of
their first visit before and during pregnancy, and they
recognize that in some situations ascertainment of
the individual's risk status may not be feasible.
In such cases, and where the local practice
environment is appropriate, testing of all women by
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wk 9 of pregnancy or at the first prenatal visit is
reasonable
If serum TSH is greater than 2.5 mIU/liter at the
time of testing (or > 3.0 mIU/liter in the second
trimester), levothyroxine therapy should be
instituted.
If TSH concentration is 2.5–10 mIU/liter, a starting
levothyroxine dose of 50 μg/d or more is
recommended. Other thyroid preparations (such as
T3) are not recommended.
Women at high risk for PPT in the postpartum
months should be screened via assessment of serum
TSH. These high-risk groups include: 1) women
known to be TPO-Ab+; 2) women with type 1
diabetes; and 3) women with a prior history of PPT.
Screening should occur at 6–12 wk postpartum.
Women with Graves' disease who enter remission
during pregnancy should be screened for recurrence
by TSH assay at 3–6 months.
Subclinical Hypothyroidism
Subclinical hypothyroidism can be defined as a condition with minimal
or absent signs and symptoms but with mildly elevated TSH in the face
of essentially normal fT4 and other values with no recent or ongoing
severe illness. Estimations of frequency of subclinical hypothyroidism
vary and have not been extensively studied, but generally fall within
10-15% of the elderly. Four major studies did look at prevalence rates
of subclinical hypothyroidism. The NHANESIII study indicated the
subclinical hypothyroidism (defined as TSH over 4.5 mIU/mL) could be
found in 4.3% of an unselected U.S. population.66-68
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The Colorado Thyroid Disease Prevalence Study, with a slightly higher
cutoff for TSH of over 5.0 mIU/mL, found 8.5% of self-selected
individuals were determined to have subclinical hypothyroidism.
In the Framingham study, 5.8% of women over 60 years and 2.3% of
men had TSH levels of over 10 mIU/mL. In this population, 39% also
had subnormal T4. Finally, the British Whickham study indicated that
9.3% of women and 1.2% of men had TSH levels of over 10mIU/mL.
Treatment is controversial, with many clinicians recommending
watchful waiting, while others suggest watchful waiting with
intervention in specific groups of patients — those with elevated TSH
(4-10 mIU/mL) along with symptoms that cannot be otherwise
explained and whose symptom significantly affect their quality of life.
The American Thyroid Association recently produced clinical guidelines
for the treatment and management of hypothyroidism in adults. The
general clinical issue and recommendations are highlighted in the table
below.67
ATA Recommendations for the Treatment of Hypothyroidism in Adults
When should antithyroid antibodies be
measured?
Anti–thyroid peroxidase antibody (TPOAb)
measurements should be considered when
evaluating patients with subclinical
hypothyroidism
TPOAb measurement should be considered in
order to identify autoimmune thyroiditis when
nodular thyroid disease is suspected to be due to
autoimmune thyroid disease
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TPOAb measurement should be considered when
evaluating patients with recurrent miscarriage,
with or without infertility.
Measurement of TSHRAbs using a sensitive assay
should be considered in hypothyroid pregnant
patients with a history of Graves’ disease who
were treated with radioactive iodine or
thyroidectomy prior to pregnancy.
This should be initially done either at 20–26
weeks of gestation or during the first trimester
and if they are elevated again at 20–26 weeks of
gestation.
What is the role of
clinical scoring
systems in the
diagnosis of patients
with hypothyroidism?
Clinical scoring systems should not be used to
diagnose hypothyroidism.
What is the role of
diagnostic tests apart
from serum thyroid
hormone levels and
TSH in the evaluation
of patients with
hypothyroidism?
Tests such as clinical assessment of reflex
relaxation time, cholesterol, and muscle enzymes
should not be used to diagnose hypothyroidism
What are the
preferred thyroid
hormone
measurements in
addition to TSH in the
assessment of
patients with
hypothyroidism?
Apart from pregnancy, assessment of serum free
T4 should be done instead of total T4 in the
evaluation of hypothyroidism.
An assessment of serum free T4 includes a free T4
index or free T4 estimate and direct immunoassay
of free T4 without physical separation using antiT4 antibody.
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Assessment of serum free T4, in addition to TSH,
should be considered when monitoring Lthyroxine therapy.
In pregnancy, the measurement of total T4 or a
free T4 index, in addition to TSH, should be done
to assess thyroid status. Because of the wide
variation in the results of different free T4 assays,
direct immunoassay measurement of free T4
should only be employed when method-specific
and trimester-specific reference ranges for serum
free T4 are available.
Serum total T3 or assessment of serum free T3
should not be done to diagnose hypothyroidism.
TSH measurements in hospitalized patients should
be done only if there is an index of suspicion for
thyroid dysfunction.
In patients with central hypothyroidism,
assessment of free T4 or free T4 index, not TSH,
should be done to diagnose and guide treatment
of hypothyroidism.
When should TSH
levels be measured in
patients being treated
for hypothyroidism?
Patients being treated for established
hypothyroidism should have serum TSH
measurements done at 4–8 weeks after initiating
treatment or after a change in dose.
Once an adequate replacement dose has been
determined, periodic TSH measurements should
be done after 6 months and then at 12-month
intervals, or more frequently if the clinical
situation dictates otherwise.
What should be
considered the upper
limit of the normal
range of TSH values?
The reference range of a given laboratory should
determine the upper limit of normal for a third
generation TSH assay. The normal TSH reference
range changes with age. If an age-based upper
limit of normal for a third generation TSH assay is
not available in an iodine sufficient area, an upper
limit of normal of 4.12 should be considered.
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In pregnancy, the upper limit of the normal range
should be based on trimester-specific ranges for
that laboratory. If trimester-specific reference
ranges for TSH are not available in the laboratory,
the following upper normal reference ranges are
recommended: first trimester, 2.5 mIU/L; second
trimester, 3.0 mIU/L; third trimester, 3.5 mIU/L.
Which patients with
TSH levels above a
given laboratory’s
reference range
should be considered
for treatment with Lthyroxine?
Patients whose serum TSH levels exceed 10
mIU/L are at increased risk for heart failure and
cardiovascular mortality, and should be
considered for treatment with L-thyroxine.
Treatment based on individual factors for patients
with TSH levels between the upper limit of a given
laboratory’s reference range and 10 mIU/L should
be considered particularly if patients have
symptoms suggestive of hypothyroidism, positive
TPOAb or evidence of atherosclerotic
cardiovascular disease, heart failure, or associated
risk factors for these diseases.
In patients with
hypothyroidism being
treated with Lthyroxine, what
should the target TSH
ranges be?
In patients with hypothyroidism who are not
pregnant, the target range should be the normal
range of a third generation TSH assay. If an upper
limit of normal for a third generation TSH assay is
not available, in iodine-sufficient areas an upper
limit of normal of 4.12 mIU/L should be
considered and if a lower limit of normal is not
available, 0.45 mIU/L should be considered.
In patients with
hypothyroidism being
treated with Lthyroxine who are
pregnant, what should
the target TSH ranges
be?
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In patients with hypothyroidism who are
pregnant, the target range for TSH should be
based on trimester-specific ranges for that
laboratory. If trimester-specific reference ranges
are not available in the laboratory, the following
upper-normal reference ranges are recommended:
first trimester, 2.5 mIU/L; second trimester, 3.0
mIU/L; and third trimester, 3.5 mIU/L.
Which patients with
normal serum TSH
levels should be
considered for
treatment with Lthyroxine?
Treatment with L-thyroxine should be considered
in women of childbearing age with serum TSH
levels between 2.5 mIU/L and the upper limit of
normal for a given laboratory’s reference range if
they are in the first trimester of pregnancy or
planning a pregnancy including assisted
reproduction in the immediate future.
Treatment with L-thyroxine should be considered
in women in the second trimester of pregnancy
with serum TSH levels between 3.0 mIU/L and the
upper limit of normal for a given laboratory’s
reference range, and in women in the third
trimester of pregnancy with serum TSH levels
between 3.5 mIU/L and the upper limit of normal
for a given laboratory’s reference range.
Treatment with L-thyroxine should be considered
in women of childbearing age with normal serum
TSH levels when they are pregnant or planning a
pregnancy, including assisted reproduction in the
immediate future, if they have or have had
positive levels of serum TPOAb, particularly when
there is a history of miscarriage or past history of
hypothyroidism.
Women with positive levels of serum TPOAb or
with a TSH greater than 2.5 mIU/L who are not
being treated with L-thyroxine should be
monitored every 4 weeks in the first 20 weeks of
pregnancy for the development of hypothyroidism.
For patients who are
pregnant, or planning
pregnancy, or with
other characteristics,
should be screened for
hypothyroidism?
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Universal screening is not recommended for
patients who are pregnant or are planning
pregnancy, including assisted reproduction.
‘‘Aggressive case finding,’’ rather than universal
screening, should be considered for patients who
are planning pregnancy.
Screening for hypothyroidism should be
considered in patients over age 60.
“Aggressive case finding’’ should be considered in
those at increased risk for hypothyroidism.
How should patients
with hypothyroidism
be treated and
monitored?
Patients with hypothyroidism should be treated
with L-thyroxine monotherapy.
The evidence does not support using L-thyroxine
and L-triiodothyronine combinations to treat
hypothyroidism.
L-thyroxine and L-triiodothyronine combinations
should not be administered to pregnant women or
those planning pregnancy.
There is no evidence to support using desiccated
thyroid hormone in preference to L-thyroxine
monotherapy in the treatment of hypothyroidism
and therefore desiccated thyroid hormone should
not be used for the treatment of hypothyroidism.
3,5,3’-triiodothyroacetic acid (TRIAC; tiratricol)
should not be used to treat primary and central
hypothyroidism due to suggestions of harm in the
literature.
Patients resuming L-thyroxine therapy after
interruption (less than 6 weeks) and without an
intercurrent cardiac event or marked weight loss
may resume their previously employed full
replacement doses.
When initiating therapy in young healthy adults
with overt hypothyroidism, beginning treatment
with full replacement doses should be considered.
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When initiating therapy in patients older than 50–
60 years with overt hypothyroidism, without
evidence of coronary heart disease, an L-thyroxine
dose of 50 lg daily should be considered.
In patients with subclinical hypothyroidism, initial
L-thyroxine dosing is generally lower than what is
required in the treatment of overt hypothyroidism.
A daily dose of 25–75 lg should be considered,
depending on the degree of TSH elevation. Further
adjustments should be guided by clinical response
and follow-up laboratory determinations including
TSH values.
Treatment with glucocorticoids in patients with
combined adrenal insufficiency and
hypothyroidism should precede treatment with Lthyroxine.
L-thyroxine should be taken with water
consistently 30–60 minutes before breakfast or at
bedtime 4 hours after the last meal. It should be
stored properly per product insert and not taken
with substances or medications that interfere with
its absorption.
In patients with central hypothyroidism,
assessments of serum free T4 should guide
therapy and targeted to exceed the mid-normal
range value for the assay being used.
In patients with hypothyroidism being treated
with L-thyroxine who are pregnant, serum TSH
should be promptly measured after conception
and L-thyroxine dosage adjusted, with a goal TSH
of less than 2.5 mIU/L during the first trimester.
In patients with hypothyroidism being treated
with L-thyroxine who are pregnant, the goal TSH
during the second trimester should be less than 3
mIU/L and during the third trimester should be
less than 3.5 mIU/L.
Maternal serum TSH (and total T4) should be
monitored every 4 weeks during the first half of
pregnancy and at least once between 26 and 32
weeks gestation and L-thyroxine dosages adjusted
as indicated.
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In patients receiving L-thyroxine treatment for
hypothyroidism, serum TSH should be remeasured
within 4–8 weeks of initiation of treatment with
drugs that decrease the bioavailability or alter the
metabolic disposition of the L-thyroxine dose.
Apart from pregnant patients being treated with
L-thyroxine for hypothyroidism, the evidence does
not support targeting specific TSH values within
the normal reference range.
When should
endocrinologists be
involved in the care of
patients with
hypothyroidism?
Physicians who are not endocrinologists, but who
are familiar with the diagnosis and treatment of
hypothyroidism should be able to care for most
patients with primary hypothyroidism.
However, patients with hypothyroidism who fall
into the following categories should be seen in
consultation with an endocrinologist.
These categories are (i) children and infants,
(ii) patients in whom it is difficult to render and
maintain a euthyroid state, (iii) pregnancy, (iv)
women planning conception, (v) cardiac disease,
(vi) presence of goiter, nodule, or other structural
changes in the thyroid gland, (vii) presence of
other endocrine disease such as adrenal and
pituitary disorders, (viii) unusual constellation of
thyroid function test results, and (ix) unusual
causes of hypothyroidism such as those induced
by agents that interfere with absorption of Lthyroxine, impact thyroid gland hormone
production or secretion, affect the hypothalamic–
pituitary–thyroid axis (directly or indirectly),
increase clearance, or peripherally impact
metabolism.
Which patients should
not be treated with
thyroid hormone?
Thyroid hormones should not be used to treat
symptoms suggestive of hypothyroidism without
biochemical confirmation of the diagnosis.
Thyroid hormones should not be used to treat
obesity in euthyroid patients.
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There is insufficient evidence to support using
thyroid hormones to treat depression in euthyroid
patients.
What is the role of
iodine
supplementation,
dietary supplements,
and nutraceuticals in
the treatment of
hypothyroidism?
Iodine supplementation, including kelp or other
iodine containing functional foods, should not be
used in the management of hypothyroidism in
iodine-sufficient areas.
Iodine supplementation in the form of kelp or
other seaweed-based products should not be used
to treat iodine deficiency in pregnant women.
Selenium should not be used to prevent or treat
hypothyroidism.
Patients taking dietary supplements and
nutraceuticals for hypothyroidism should be
advised that commercially available thyroidenhancing products are not a remedy for
hypothyroidism and should be counseled about
the potential side effects of various preparations
particularly those containing iodine or
sympathomimetic amines as well as those marked
as ‘‘thyroid support’’ since they could be
adulterated with L-thyroxine or Ltriiodothyronine.
Congenital Hypothyroidism
Congenital hypothyroidism (formerly termed cretinism) is the
inadequate production of thyroid hormone in newborns. It can occur
because of iodine deficiency, anatomic defects, rarely by maternal
anti-thyroid antibodies or an inborn error in thyroid metabolism. Signs
and symptoms are not always evident at birth but can include:
decreased activity, poor feeding and weight gain, small stature or poor
growth, jaundice, decreased stooling or constipation, hypotonia, large
anterior fontanelle, hoarse cry, coarse facial features, macroglossia,
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large fontanelles, umbilical hernia, mottled, cool and dry skin,
developmental delay, pallor, myxedema and goiter.79-82
Diagnosis is confirmed through lab tests indicated low levels of thyroid
hormone and elevated levels of TSH (defined under the American
Academy of Pediatrics as a TSH> 20mIU). Treatment is with
levothyroxine with many infants achieving normal growth and
development, particularly if diagnosis is made within the first 10 days
and normal levels of T4 are achieved within the first 2-3 months of life.
Congenital hypothyroidism should be considered an endocrine
emergency according to a recent study presented at the 86th annual
meeting of the American Thyroid Association. In the presentation,
about 50% of children identified as having congenital hypothyroidism
had a delayed diagnosis and about the same percentage were
inadequately treated.79-82
Myxedema and Hypothyroidism
The term myxedema may be confusing because it is used to describe
dermatologic changes seen in hypothyroidism and, in Graves’ disease,
in hyperthyroidism. Myxedema coma, however, is a life-threatening
condition resulting from severe hypothyroidism that is either untreated
or poorly treated. It can be precipitated by trauma such as infection,
heart failure, physical injury, cardiovascular disease, pregnancy or
drug therapy.
Myxedema coma (in which the patient may not actually be comatose)
has 25-65% mortality. There is currently no set of criteria by which to
diagnose myxedema coma. Characteristics include:68
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
An altered mental state

Hypothermia

A precipitating factor or traumatic event

Reduced T4/T3 levels

Increased TSH (which may be decreased or normal in secondary
hypothyroidism—see below)
However, a recent study indicated that few patients diagnosed with
myxedema coma presented with all the features. The authors
recommended the following screening tool based on a review of the
literature:68
Proposed Classification for Myxedema coma
Criterion
Glasgow Coma
Scale
Score
Total Scores are added, resulting in 3
categories: Most likely, likely and unlikely for
Myxedema coma
0-10
11-13
4
3
Total
Score
Category
14
15
2
0
8-10
Most
Likely
Treatment for
myxedema coma:
airway management,
cardiac monitoring,
thyroid hormone
replacement,
glucocorticoids,
supportive measures
2
1
1
5-7
Likely
Treat if no other causes
can be found
1
1
<5
Unlikely
Consider other possible
causes. i.e.,
hypothermia,
hypoventilation
syndromes, septic
shock
TSH
> 30mU/L
15-30mU/L
Low fT4 (<
0.6ng/dL)
Hypothermia
(<95oF)
Bradycardia
(<60bpm)
Precipitating
event/trauma
1
Recommendation
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Thyroxine-binding Globulin Deficiency
Thyroxine-binding globulin deficiency can be recognized by low to
normal total T4 levels along with a normal TSH and with no clinical
signs or symptoms of any thyroid disorder. The condition is considered
non-harmful.3,70-71
Thyroxine circulates by reversibly with high avidity but low capacity
primarily to thyroxine-binding globulin (TBG). Minor amounts of
thyroxine may also be bound by prealbumin (transthyretin) and
albumin. TBG may be low due to gene defects — the gene for TBG is
found on the X-chromosome (Xq22) and is a member of the serine
protease inhibitor superfamily — TBG does not, however, have
protease activity.
TBG deficiency can also be acquired due to hyperthyroidism, kidney
disease such as nephrotic syndrome or chronic renal failure, chronic
liver disease, Cushing Syndrome, severe systemic illness or it may be
drug-induced.
Disorders Associated with Autoimmune Hypothyroidism
While it is not yet clear why, an autoimmune disease places patients at
a higher risk for a second or more autoimmune disease including
distinct genetic syndromes comprising multiple autoimmune
endocrinopathies (MAE). There are three types of MAE known, also
known as polyglandular autoimmune (PGA) syndromes and
autoimmune polyendocrine syndromes (APS). These are multiple
endocrine deficiencies (insufficiencies).3,70-71
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Type I MAE is also known as autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED) or as Whitaker syndrome
and was first described in the 1940s. Type I MAE is characterized by
the presence of inflammatory infiltrates and three main types of
autoantibodies receptor molecules, hormones and cytokines,
particularly IFN-Ω and IFN-α. There does not appear to be an
association with HLA. Type I MAE is associated with
hypoparathyroidism, Addison’s disease and mucocutaneous
candidiasis.
Autoimmune thyroiditis is found in approximately 10-15% of cases of
Type I MAE. In addition, Type I MAE is associated with increased risk
of Type I diabetes, primary hypogonadism, autoimmune hepatitis,
pernicious anemia and ovarian failure. The mucocandidiasis occurs
first, usually in patients under the age of 5. This is followed within 5
years by hypoparathyroidism. The last to appear is Addison’s disease
before the age of 15. Type I MAE is rare in the US but found more
frequently in Europe in populations of Finns, Sardinians, and Iranian
Jews.
Other cases have been described in populations of northern Italy and
Britain, Norway and Germany. Most cases appear to be transmitted as
an autosomal recessive trait with no gender preferences.
Type II MAE (also known as Schmidt’s Syndrome) is the most common
of the multiple autoimmune endocrinopathies. It occurs with Addison’s
disease and autoimmune thyroid disease (usually Hashimoto’s
thyroiditis) and/or Type I diabetes.
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Myasthenia gravis, celiac disease and hypogonadism are also
commonly found in these patients. Type II MAE generally occurs in
adulthood during the 3rd and 4th decades. Frequency is approximated
0.0014-0.0020%. Type II MAE appears to be triggered by an
environmental factor. The disorder is 3-4 times more common in
women than men. Symptoms depend on which endocrinopathy is the
first to appear.
Secondary and Tertiary Hypothyroidism
Secondary (central) hypothyroidism is extremely rare — even rarer is
a specific deficiency of TSH as it is more common to find multiple
pituitary hormone deficiencies, as for example, a result of a sellar
meningioma or primary empty sella syndrome.3,72,73 The TSH and TRH
stimulation tests are used to distinguish primary, secondary and
tertiary (hypothalamic) hypothyroidism.
In primary hypothyroidism, exogenous TSH will not increase the
production of thyroid hormone. In secondary hypothyroidism, TSH will
induce an increase in the production of thyroid hormone. In tertiary
hypothyroidism where the hypothalamus is not releasing TRH, patients
will show a delayed and an exaggerated response to TRH stimulation.
Prolactin levels are used as a control for the thyroid hormone
response.
Summary
The thyroid gland is critical to health and wellness and while the basic
functions have been well understood for decades, there is still much to
understand. One of the greatest achievements in preventive medicine
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has been the significant decline in congenital hypothyroidism, yet more
can be done. Understanding the functions, biosynthesis and
metabolism of thyroid hormones has increased dramatically, yet there
is still much that is not known.
Preventive measures are in their infancy, yet it is clear that
maintaining overall health, eating a nutritious diet, rational
supplementation and screening for thyroid diseases all play an
important role in either prevention or early detection. Considering the
use of combination T4/T3 may be the first step in personalized
medicine as can adjusting the hormone replacement dose based on
the personal response of the individual patient rather than basing the
dosage solely on biochemical parameters. Clinicians informed about
the varied diagnostic tests and learning about the varied types of
thyroid diseases and treatments will be better able to identify the
needed course of care earlier on when an issue of thyroid disease and
metabolic disturbances become evident.
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1. The thyroid gland has been called the “Master Gland”
because it
a. produces parathormone.
b. is a member of the hormone-responsive nuclear transcription
factors superfamily.
c. is active in virtually every cell of the body.
d. plays a vital role in controlling calcium and phosphate levels.
2. True or False: Embryologically, the developing thyroid forms
the floor of the pharynx, around the base of the tongue,
descending the neck to its adult location.
a. True
b. False
3. The thyroid is supplied by the superior and inferior thyroid
arteries, and on rare occasions, there is an additional artery
known as the
a.
b.
c.
d.
innominate artery.
subclavian artery.
deep artery.
thyroidea ima.
4. Thyroid hormone is
a. required for normal human growth and development.
b. required for the regulation of metabolism in infants and
adolescents.
c. mostly active during the neonatal and pre-adolescent periods.
d. primarily used for the production of iodine.
5. Thyroid hormone ____________ begins with the
organification of iodide to iodine and then condensed onto
tyrosine residues found on thyroglobulin protein.
a.
b.
c.
d.
absorption
secretion
synthesis
conversion
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6. The main function of the thyroid gland is to produce the
thyroid hormones, known as
a.
b.
c.
d.
thyroxine (T4) and triiodothyrodine (T3).
prohormones.
parathyrin and polypeptide.
deiodinase D1 and D2.
7. An important control point for thyroid hormone biosynthesis
is _______________ by three different deiodinases.
a.
b.
c.
d.
feedback control
de-iodination
metabolism
dysgenesis
8. True or False: The parathyroid glands are part of the thyroid
gland located in the colloid-filled center of the gland.
a. True
b. False
9. The deiodinase D1 is
a. critical for the control by feedback inhibition of thyroid
hormone synthesis.
b. significant in the pituitary.
c. stimulated by selenium deficiency.
d. found at high levels in the liver, kidney and in the thyroid
gland.
10. The _________________ detects T3 levels produced by
the action of the D2 deiodinase.
a.
b.
c.
d.
hypothalamus
pituitary
thymus
thyroid
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11. Which of the following is an adipocyte hormone that
regulates appetite by inhibiting both food intake and
increasing energy expenditure?
a.
b.
c.
d.
D2 deiodinase
Pituitary hormone
Thyrotropin
Leptin
12. Parafollicular cells (C cells) secrete calcitonin, which has
the effect of
a.
b.
c.
d.
producing T3 thyroid hormones.
increasing the serum calcium levels in the body.
decreasing the serum calcium levels in the body.
increase sodium levels in the body.
13. Triiodothyrodine (T3) is the active hormone in the thyroid
a.
b.
c.
d.
and it has a longer half-life than T4.
while T4 has a longer half-life than T3.
and it converts to T4 in most tissue.
that serves as a prohormone.
14. The nuclear thyroid receptor (nTR) isoforms α and the β
provide the primary action of triiodothyrodine (T3) and
they undergo __________________ modification.
a.
b.
c.
d.
posttranslational
transcendental
transcriptional
pre-elongation
15. True or False: Resting energy expenditure is highly
sensitive to changes in thyroid hormone levels and the
BMR correlates with both lean body mass and with the
levels of thyroid hormone.
a. True
b. False
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16. A thyroid hormone defect more commonly seen is a
reduced T3 binding and irreversible interactions with
corepressors and it may be clinically manifested by goiter
and
a.
b.
c.
d.
elevated cholesterol.
abnormal TSH.
chronic constipation.
euthyroid, with possible tachycardia.
17. Significant reductions in basal metabolic rate (BMR) can
result in
a.
b.
c.
d.
hypercalcemia and weight loss.
weight loss and undernutrition.
weight gain and obesity.
hypoxia and diabetes.
18. ___________________ can be defined as the regulated
production of heat in response to environmental changes in
temperature and diet.
a.
b.
c.
d.
Adaptive thermogenesis
Adaptive dysgenesis
Posttranslational modification
Posttranslational synthesis
19. True or False: Brown adipose tissue (BAT) is important
only in neonates—and hibernating animals.
a. True
b. False
20. The primary sites of action regarding cholesterol and lipid
metabolism are
a.
b.
c.
d.
thyroid and pituitary glands.
hypothalamus and parathyroid glands.
the liver and brown adipose tissue (BAT).
the pituitary gland and white adipose tissue (WAT).
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21. Patients with hypothyroidism may exhibit the following
clinical condition:
a.
b.
c.
d.
hypolipidemia.
weight loss.
increased risk of non-alcoholic fatty liver disease (NAFLD).
increased hepatic lipid oxidation.
22. Simple nontoxic goiter is a non-inflammatory or nonneoplastic hypertrophy of the thyroid that
a.
b.
c.
d.
is often cancerous with an enlarged thyroid.
may appear diffusely or as nodules.
always appears as diffuse goiter.
is synonymous with Graves’ disease.
23. Goiter is about 4 times more common
a.
b.
c.
d.
in women than it is in men.
in non-pregnant women.
in individuals under age 40, compared to those over 40.
in adults consuming dairy products, compared to those
avoiding dairy products.
24. True or False: With simple nontoxic goiter, thyroid function
often remains normal except in cases of severe iodine
deficiency.
a. True
b. False
25. Which of the following is NOT considered a cause of goiter?
a.
b.
c.
d.
Iodine deficiency
Consuming large amounts of broccoli
Consuming dairy products
Iodine supplements
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26. Patients with hyperthyroid disease may exhibit the
following clinical condition:
a.
b.
c.
d.
increased total cholesterol
weight gain with an increased risk of obesity.
increased risk of non-alcoholic fatty liver disease (NAFLD).
increased basal metabolic rate.
27. Table salt has been iodized since the 1920s to prevent
endemic goiter and
a.
b.
c.
d.
cretinism.
obesity.
hyperthyroid disease.
hepatic lipid oxidation.
28. Graves’ disease is
a.
b.
c.
d.
an autoimmune disorder.
more common in women.
more common with increasing age.
All of the above
29. ________________ is a life-threatening condition
resulting from severe hypothyroidism that is either
untreated or poorly treated, can be precipitated by trauma
such as infection, heart failure, physical injury,
cardiovascular disease, pregnancy or drug therapy.
a.
b.
c.
d.
Plummer’s disease
Thyroiditis
Diffuse goiter
Myxedema coma
30. True or False: Surgery is overall the most successful
treatment for Graves’ disease, but patients must take
replacement hormone for the rest of their lives.
a. True
b. False
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31. When should TSH levels be measured in patients being
treated for hypothyroidism?
a.
b.
c.
d.
4–8 weeks after initiating treatment
At 12-month intervals
Before initiating treatment
At 6-month intervals
32. Thyroid storm is a severe and often sudden form of
a.
b.
c.
d.
hypothyroidism.
a myxedema coma.
hyperthyroidism.
non-alcoholic fatty liver disease (NAFLD).
33. Thyroid storm may be life-threatening, commonly because
of
a. significantly higher than normal TSH.
b. cardiovascular effects such as tachycardia, arrhythmias or
cardiovascular collapse.
c. inflammation of the thyroid gland.
d. apoptosis and parenchymal destruction.
34. True or False: Partial thyroidectomy is most commonly
recommended as partial thyroidectomy has significantly
better outcomes than total thyroidectomy.
a. True
b. False
35. Thyroid orbitopathy is an autoimmune inflammatory
disorder that occurs in 90% of patients with
a.
b.
c.
d.
Diffuse goiter.
Graves’ disease.
Plummer’s disease.
Thyroiditis.
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36. The mitochondria in BAT have very high numbers of
mitochondria containing UCP-1 that when activated
stimulates
a.
b.
c.
d.
the respiratory chain.
the shiver response.
tremors.
glycolysis.
37. ______________ is a significant factor in thyroid
orbitopathy.
a.
b.
c.
d.
Apoptosis
Parenchymal destruction
Plummer’s disease
Oxidative stress
38. True or False: There is currently no set of criteria by which
to diagnose myxedema coma.
a. True
b. False
39. Approximately ___ of patients with Graves’ disease will
experience some ophthalmopathy.
a.
b.
c.
d.
25%
half
60%
10%
40. ______________________________ is often first-line
treatment of Graves’ disease.
a.
b.
c.
d.
β-adrenergic blockade
Corticosteroid therapy
Radioactive ablation of the thyroid
Acetaminophen for cooling
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41. Radioactive ablation is also contraindicated in patients who
are suspected of having
a.
b.
c.
d.
toxic adenomas.
thyroid cancer.
toxic multinodular goiter.
Graves’ disease.
42. True or False: Surgery is an important part of the
multimodal treatment plan for patients with thyroid storm.
a. True
b. False
43. In the context of testing for thyroid disease, women who
are planning a pregnancy should
a.
b.
c.
d.
be universally screened.
use the ‘‘aggressive case finding” approach.
be tested for medullary thyroid cancer (MTC).
have a genetic test performed.
44. Thyroxine-binding globulin deficiency can be recognized by
low to normal total T4 levels along
a.
b.
c.
d.
harmful symptoms of thyroid disorder.
with clinical signs or symptoms of thyroid disorder.
with a normal TSH.
multinodular goiter.
45. Congenital hypothyroidism is the inadequate production of
thyroid hormone in newborns, caused
a.
b.
c.
d.
by iodine deficiency.
in most cases, by maternal anti-thyroid antibodies.
by an umbilical hernia.
by multinodular goiter.
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CORRECT ANSWERS:
1. The thyroid gland has been called the “Master Gland”
because it
c. is active in virtually every cell of the body.
“The thyroid gland has been called the Master Gland because it
is active in virtually every cell of the body, regulating cellular
respiration, energy expenditure, overall metabolism, growth
and development of cells and tissues.”
2. True or False: Embryologically, the developing thyroid forms
the floor of the pharynx, around the base of the tongue,
descending the neck to its adult location.
a. True
“Embryologically, the developing thyroid forms the floor of the
pharynx, around the base of the tongue, descending the neck
in the adult.”
3. The thyroid is supplied by the superior and inferior thyroid
arteries, and on rare occasions, there is an additional artery
known as the
d. thyroidea ima.
“The superior and inferior thyroid arteries supply the thyroid.
Relatively rarely, there is an additional artery, the thyroidea
ima that originates from the aortic arch or the innominate
artery, entering the gland at the inferior border of the
isthmus.”
4. Thyroid hormone is
a. required for normal human growth and development.
“The main function of the thyroid gland is to produce the
thyroid hormones, thyroxine (T4) and triiodothyrodine (T3).
Thyroid hormone is required for both normal growth and
development as well as for the regulation of metabolism in the
adult.”
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5. Thyroid hormone ____________ begins with the
organification of iodide to iodine and then condensed onto
tyrosine residues found on thyroglobulin protein.
c. synthesis
“Thyroid hormone synthesis begins with the conversion
(organification) of iodide to iodine and condensed onto tyrosine
residues found on thyroglobulin.”
6. The main function of the thyroid gland is to produce the
thyroid hormones, known as
a. thyroxine (T4) and triiodothyrodine (T3).
““The main function of the thyroid gland is to produce the
thyroid hormones, thyroxine (T4) and triiodothyrodine (T3).”
7. An important control point for thyroid hormone biosynthesis
is _______________ by three different deiodinases.
b. de-iodination
“De-iodination by three different deiodinases, D1, D2 and D3,
found in different levels in various tissues, including the liver,
is an important control point for thyroid hormone
biosynthesis.”
8. True or False: The parathyroid glands are part of the thyroid
gland located in the colloid-filled center of the gland.
b. False
“The parathyroid glands are 4 small glands usually located at
the posterior portions of the thyroid and which produce
parathyroid hormone (PTH) and play a vital role in controlling
calcium and phosphate levels. The parathyroid glands share
blood supply, lymphatic drainage and venous supply with the
thyroid.”
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9. The deiodinase D1 is
d. found at high levels in the liver, kidney and in the thyroid
gland.
“The deiodinases are peroxidases. D1 is not significant in the
pituitary, so is not believed to be critical for the control by
feedback inhibition of thyroid hormone synthesis. D1 is found
at high levels in the liver, kidney and in the thyroid gland itself
and is expressed on the cellular membrane in these tissues.”
10. The _________________ detects T3 levels produced by
the action of the D2 deiodinase.
a. hypothalamus
”The hypothalamus detects T3 levels produced by the action of
the D2 deiodinase.”
11. Which of the following is an adipocyte hormone that
regulates appetite by inhibiting both food intake and
increasing energy expenditure?
d. Leptin
“Leptin is an adipocyte hormone that acts as a signal from
adipose tissue to the brain, regulating appetite by inhibiting
both food intake and increasing energy expenditure.…”
12. Parafollicular cells (C cells) secrete calcitonin, which has
the effect of
c. decreasing the serum calcium levels in the body.
“Parafollicular cells (C cells) secrete calcitonin in response to
hypercalcemia, causing a decrease in serum calcium levels.”
13. Triiodothyrodine (T3) is the active hormone in the thyroid
b. while T4 has a longer half-life than T3.
“Triiodothyrodine (T3) is the active form of hormone while T4
has a longer half-life than T3. Thyroxine (T4) is converted to
T3 in most tissues, thus serving as a prohormone.”
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14. The nuclear thyroid receptor (nTR) isoforms α and the β
provide the primary action of triiodothyrodine (T3) and
they undergo __________________ modification.
a. posttranslational
“Triiodothyrodine (T3) action is primarily exerted through its
nuclear thyroid receptor (nTR) isoform. There are two primary
isoforms of the nTR — the α and the β isoforms. Both isoforms
undergo posttranslational modification.”
15. True or False: Resting energy expenditure is highly
sensitive to changes in thyroid hormone levels and the
BMR correlates with both lean body mass and with the
levels of thyroid hormone.
a. True
“Resting energy expenditure is highly sensitive to changes in
thyroid hormone levels and the BMR correlates with both lean
body mass and with the levels of thyroid hormone.”
16. A thyroid hormone defect more commonly seen is a
reduced T3 binding and irreversible interactions with
corepressors and it may be clinically manifested by goiter
and
d. euthyroid, with possible tachycardia.
“Defect: This is more commonly seen. Reduced T3 binding and
irreversible interactions with corepressors… Clinical: Goiter,
enhanced metabolic rates, hyperphagia. Generally euthyroid,
with possible tachycardia. Possible, short stature, impaired
hearing, bone defects, ADHD.”
17. Significant reductions in basal metabolic rate (BMR) can
result in
c. weight gain and obesity.
“The basal metabolic rate or BMR is the main source of energy
outlay — significant reductions in BMR can result in weight gain
and obesity while increases in BMR can result in weight loss
and undernutrition.”
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18. ___________________ can be defined as the regulated
production of heat in response to environmental changes in
temperature and diet.
a. Adaptive thermogenesis
“Facultative or adaptive thermogenesis can be defined as the
regulated production of heat in response to environmental
changes in temperature and diet.”
19. True or False: Brown adipose tissue (BAT) is important
only in neonates and hibernating animals.
b. False
“In humans, there is both visceral and subcutaneous BAT and
until recently, was considered important only in neonates —
and hibernating animals. However, it is becoming clear that in
the adult, BAT thermogenesis has important functions as well,
mainly to generate classical non-shiver related heat.”
20. The primary sites of action regarding cholesterol and lipid
metabolism are
c. the liver and brown adipose tissue (BAT).
“The primary sites of action regarding cholesterol and lipid
metabolism are the liver and BAT.”
21. Patients with hypothyroidism may exhibit the following
clinical condition:
c. increased risk of non-alcoholic fatty liver disease (NAFLD).
“Clinically, these effects can be seen in patients with
hypothyroidism: … Increased risk of non-alcoholic fatty liver
disease (NAFLD). In patients with hyperthyroid disease:
Increased basal metabolic rate; Weight loss; Decreased total
cholesterol; Decreased triglyceride levels; Increased hepatic
lipid oxidation; Hyperglycemia and worsening glycemic control
in Type 2 diabetes patients.”
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22. Simple nontoxic goiter is a non-inflammatory or nonneoplastic hypertrophy of the thyroid that
b. may appear diffusely or as nodules.
“Simple nontoxic goiter is a non-inflammatory or nonneoplastic hypertrophy of the thyroid that may appear diffusely
or as nodules.”
23. Goiter is about 4 times more common
a. in women than it is in men.
“Goiter is about 4 times more common in women than in men,
increasing risk is associated with age. Nodules are also less
frequent in men, but have a greater tendency to be malignant,
when found.”
24. True or False: With simple nontoxic goiter, thyroid function
often remains normal except in cases of severe iodine
deficiency.
a. True
“Thyroid function often remains normal except in cases of
severe iodine deficiency.”
25. Which of the following is NOT considered a cause of goiter?
c. Consuming dairy products
“Table salt has been iodized since the 1920s to prevent
cretinism and endemic goiter…. The use of table salt has been
discouraged in the U.S., and around the world to control
hypertension. It is believed that other foods contain sufficient
iodine. However, in some populations such as in children with
food restrictions or adults avoiding dairy productsi intake of
iodine may not be adequate.”
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26. Patients with hyperthyroid disease may exhibit the
following clinical condition:
d. increased basal metabolic rate.
“In patients with hyperthyroid disease: Increased basal
metabolic rate; Weight loss; Decreased total cholesterol;
Decreased triglyceride levels; Increased hepatic lipid oxidation;
Hyperglycemia and worsening glycemic control in Type 2
diabetes patients.”
27. Table salt has been iodized since the 1920s to prevent
endemic goiter and
a. cretinism.
“Table salt has been iodized since the 1920s to prevent
cretinism and endemic goiter.”
28. Graves’ disease is
a.
b.
c.
d.
an autoimmune disorder.
more common in women.
more common with increasing age.
All of the above [correct answer]
“Graves’ disease is an autoimmune disorder. As with many if
not most autoimmune disorders, it is more common in
women and more common with increasing age.”
29. ________________ is a life-threatening condition
resulting from severe hypothyroidism that is either
untreated or poorly treated, can be precipitated by trauma
such as infection, heart failure, physical injury,
cardiovascular disease, pregnancy or drug therapy.
d. Myxedema coma
“The term myxedema may be confusing because it is used to
describe dermatologic changes seen in hypothyroidism and, in
Graves’ disease, in hyperthyroidism. Myxedema coma,
however, is a life-threatening condition resulting from severe
hypothyroidism that is either untreated or poorly treated. It
can be precipitated by trauma such as infection, heart failure,
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physical injury, cardiovascular disease, pregnancy or drug
therapy.”
30. True or False: Surgery is overall the most successful
treatment for Graves’ disease, but patients must take
replacement hormone for the rest of their lives.
a. True
“Surgery is overall the most successful treatment for Graves’
disease, but patients must take replacement hormone for the
rest of their lives.”
31. When should TSH levels be measured in patients being
treated for hypothyroidism?
a. 4–8 weeks after initiating treatment
“Patients being treated for established hypothyroidism should
have serum TSH measurements done at 4–8 weeks after
initiating treatment or after a change in dose. Once an
adequate replacement dose has been determined, periodic TSH
measurements should be done after 6 months and then at 12month intervals, or more frequently if the clinical situation
dictates otherwise.”
32. Thyroid storm is a severe and often sudden form of
c. hyperthyroidism.
“Thyroid storm is a severe and often sudden form of
hyperthyroidism – it may result from untreated or inadequately
treated Graves’ disease, multinodular goiter, solitary nodules
or ingestion of excess thyroid hormone, either as levothyroxine
or as a glandular preparation.”
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33. Thyroid storm may be life-threatening, commonly because
of
b. cardiovascular effects such as tachycardia, arrhythmias or
cardiovascular collapse.
“Thyroid storm may be life-threatening, commonly because of
cardiovascular effects such as tachycardia, arrhythmias or
cardiovascular collapse.”
34. True or False: Partial thyroidectomy is most commonly
recommended as partial thyroidectomy has significantly
better outcomes than total thyroidectomy.
b. False
“Total thyroidectomy is most commonly recommended as total
thyroidectomy has significantly better outcomes than partial
thyroidectomy.”
35. Thyroid orbitopathy is an autoimmune inflammatory
disorder that occurs in 90% of patients with
b. Graves’ disease.
“Thyroid orbitopathy is an autoimmune inflammatory disorder
that occurs (90%) in patients with Graves’ disease.”
36. The mitochondria in BAT have very high numbers of
mitochondria containing UCP-1 that when activated
stimulates
a. the respiratory chain.
“The mitochondria in BAT have very high numbers of
mitochondria containing UCP-1 that when activated stimulates
the respiratory chain.”
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37. ______________ is a significant factor in thyroid
orbitopathy.
d. Oxidative stress
“Oxidative stress is also a significant factor in thyroid
orbitopathy.”
38. True or False: There is currently no set of criteria by which
to diagnose myxedema coma.
a. True
“There is currently no set of criteria by which to diagnose
myxedema coma.”
39. Approximately ___ of patients with Graves’ disease will
experience some ophthalmopathy.
a. 25%
“Approximately 25% of patients with Graves’ disease will
experience some ophthalmopathy.”
40. ______________________________ is often first-line
treatment of Graves’ disease.
c. Radioactive ablation of the thyroid
“Radioactive ablation of the thyroid is a safe, effective and
often first-line treatment of Graves’ disease, toxic adenomas
and toxic multinodular goiter.”
41. Radioactive ablation is also contraindicated in patients who
are suspected of having
b. thyroid cancer.
“Radioactive ablation of the thyroid is a safe, effective and
often first-line treatment of Graves’ disease, toxic adenomas
and toxic multinodular goiter. Contraindications include
pregnancy, lactation, intention to get pregnant and the inability
to comply with safety recommendations. Radioactive ablation
is also contraindicated in patients who are suspected of having
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thyroid cancer. The treatment may worsen or cause
orbitopathy, but this is controversial.”
42. True or False: Surgery is an important part of the
multimodal treatment plan for patients with thyroid storm.
b. False
“A multimodality treatment approach to patients with thyroid
storm should be used. Multimodality treatment includes βadrenergic blockade, ATD therapy, inorganic iodide,
corticosteroid therapy, cooling with acetaminophen and cooling
blankets, volume resuscitation, nutritional support, and
respiratory care and monitoring in an intensive care unit, as
appropriate for an individual patient.”
43. In the context of testing for thyroid disease, women who
are planning a pregnancy should
b. use the ‘‘aggressive case finding” approach.
“Screening for thyroid Universal screening is not recommended
for patients who are pregnant or are planning pregnancy,
including assisted reproduction. ‘‘Aggressive case finding,’
rather than universal screening, should be considered for
patients who are planning pregnancy. Screening for
hypothyroidism should be considered in patients over age 60.
‘Aggressive case finding’ should be considered in those at
increased risk for hypothyroidism.”
44. Thyroxine-binding globulin deficiency can be recognized by
low to normal total T4 levels along
c. with a normal TSH.
“Thyroxine-binding globulin deficiency can be recognized by
low to normal total T4 levels along with a normal TSH and with
no clinical signs or symptoms of any thyroid disorder. The
condition is considered non-harmful.”
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45. Congenital hypothyroidism is the inadequate production of
thyroid hormone in newborns, caused
a. by iodine deficiency.
“Congenital hypothyroidism (formerly termed cretinism) is the
inadequate production of thyroid hormone in newborns. It can
occur because of iodine deficiency, anatomic defects, rarely by
maternal anti-thyroid antibodies or an inborn error in thyroid
metabolism. Signs and symptoms are not always evident at
birth but can include: decreased activity, poor feeding and
weight gain, small stature or poor growth, jaundice, decreased
stooling or constipation, hypotonia, large anterior fontanelle,
hoarse cry, coarse facial features, macroglossia, large
fontanelles, umbilical hernia, mottled, cool and dry skin,
developmental delay, pallor, myxedema and goiter.”
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