Hyperthyroid Disorders

12
Hyperthyroid Disorders
ANTHONY HOLLENBERG AND WILMAR M. WIERSINGA
CHAPTER OUTLINE
Clinical Manifestations of Thyrotoxicosis, 365 Toxic Adenoma, 394
Laboratory Diagnosis, 368 Subclinical Hyperthyroidism, 395
Graves Hyperthyroidism, 369 Induced Hyperthyroidism, 396
Graves Orbitopathy, 380 Amiodarone-Induced Thyrotoxicosis, 396
Graves Dermopathy, 387 Hyperthyroidism Due to Thyrotropin Secretion, 398
Pregnancy and the Thyroid, 387 Tumor Chorionic Gonadotropin-Induced Hyperthyroidism, 398
Inherited Nonimmune Hyperthyroidism, 392 Transient Thyrotoxicosis, 399
Toxic Multinodular Goiter, 392 Other Causes of Thyrotoxicosis With a Low Radioiodine Uptake, 402
KEY POINTS
• H yperthyroidism has a prevalence of 1% to 2% in women and • T he treatment of hyperthyroidism is best initiated with the
0.1% to 0.2% in men. antithyroid drug methimazole; propylthiouracil (PTU) is no
• The most common causes of an overactive thyroid are Graves longer recommended as first-line therapy because of its rare,
disease and toxic multinodular goiter. but occasionally severe, hepatic toxicity. PTU may be useful in
• Graves disease is caused by the development of unique human treating severe hyperthyroidism because of its capacity to block
autoantibodies to the thyroid-stimulating hormone (thyrotro- conversion of thyroxine (T4) to triiodothyronine (T3) by the type
pin, TSH) receptor; these autoantibodies act as TSH receptor 1 deiodinase (D1) in liver, kidney, and Graves thyroid.
agonists. • Methimazole embryopathy is also rare. It may be avoided by the
• Graves orbitopathy (GO) remains one of the most difficult endo- use of PTU in the first trimester as well as for women planning a
crine diseases to treat and requires a multidisciplinary approach. pregnancy while under treatment for hyperthyroidism.
It may occur before, during, or even long after resolution of the • Overtreatment of the pregnant hyperthyroid patient must be
hyperthyroidism. avoided because of the transplacental passage of both PTU
• Toxic thyroid nodules are caused by a constitutive activating and methimazole. Fetal hypothyroidism can impair cognitive
mutation in the TSH receptor. development. Typically the TSH should remain suppressed and
• Subacute thyroiditis secondary to infectious agents is usually the free T4 slightly above normal throughout pregnancy. If pos-
painful, in marked contrast to the transient autoimmune thy- sible, the patient should be followed in concert with a high-risk
roiditis seen in the postpartum period. obstetrician.
T
hese days the terms thyrotoxicosis and hyperthyroidism are the thyroid gland (called thyroiditis), which may be autoimmune,
used interchangeably and refer to the classic or subtle phys- postviral, or drug induced; and extrathyroidal sources of thyroid
iologic manifestations of excessive quantities of the thyroid hormone, most often iatrogenic or self-administered. For most
hormones, which are the characteristics of this condition (Table patients with thyrotoxicosis, the symptoms and signs caused by an
12.1). In addition to overstimulation of the thyroid via the TSH excess of thyroid hormone, whatever the source, lead to medical
receptor and true TSH receptor mutations, other common condi- attention. Others may have surprisingly few symptoms and are
tions causing hyperthyroidism include the passive release of thy- referred because of a suppressed TSH. This chapter begins with a
roid hormones from damaged thyroid follicles; inflammation of brief review of the symptoms and signs of thyrotoxicosis and their
364
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Chapter 12 Hyperthyroid Disorders 365
TABLE 12.1 C
auses of Hyperthyroidism patient (see Chapter 11), has made the more classic and severe
manifestations of long-standing thyrotoxicosis less prevalent. In
I. Excessive TSH-Receptor Stimulation fact, a continued area of some controversy is how aggressively to
Graves disease (TRAb) treat the condition termed subclinical hyperthyroidism, a bio-
Pregnancy-associated transient hyperthyroidism (hCG) chemical diagnosis in which a subnormal serum TSH level is
Trophoblastic disease (hCG) accompanied by normal free thyroid hormone concentrations.
Familial gestational hyperthyroidism (mutant TSH receptor) Nonetheless, the classic presentation is still common, serves to
TSH-producing pituitary adenoma illustrate the pleiotropic physiologic effects of excess thyroid hor-
II. Autonomous Thyroid Hormone Secretion mones, and, if not recognized, can progress to life-threatening
severity despite the fact that hyperthyroidism is a benign condi-
Multinodular toxic goiter (somatic mutations)
Solitary toxic thyroid adenoma (somatic mutation)
tion (accelerated hyperthyroidism). The next sections review the
Congenital activating TSH-receptor mutation (genomic mutation) pathophysiology of the most important manifestations of excess
thyroid hormone.
III. Destruction of Follicles With Release of Hormone
Subacute de Quervain thyroiditis (virus infection)
Painless thyroiditis/postpartum thyroiditis (hashitoxicosis—autoimmune)
Cardiovascular System
Acute thyroiditis (bacterial infection) Alterations in cardiovascular function in the thyrotoxic patient
Drug-induced thyroiditis (amiodarone, interferon-γ) are in part due to increased circulatory demands that result from
IV. Extrathyroidal Sources of Thyroid Hormone the hypermetabolism and the need to dissipate the excess heat
produced.1 At rest, peripheral vascular resistance is decreased, and
Iatrogenic overreplacement with thyroid hormone
Excessive self-administered thyroid medication
cardiac output is increased as a result of an increase first in heart
Food and supplements containing excessive thyroid hormone rate and, with more severe disease, in stroke volume. Thyroid
Functional thyroid cancer metastases hormones in excess also have a direct ionotropic effect on cardiac
Struma ovarii contraction mediated by an increase in the ratio of α-myosin to
β-myosin heavy chain expression. Tachycardia is virtually always
hCG, Human chorionic gonadotropin; TRAb, thyrotropin receptor antibodies; TSH, thyroid- present and is due to a combination of increased sympathetic and
stimulating hormone (thyrotropin).
decreased vagal tone.2 Widening of the pulse pressure is due to
the increase in systolic pressure and decrease in diastolic pressure
caused by reduced resistance.3 The decreased resistance is due to
increased nitric oxide production via the PI3K/AKT signaling
pathophysiologic basis. The appropriate use of the laboratory tests pathway.4 The increased systolic force is often felt by the patient
already described in Chapter 11 is then presented to show how as a palpitation and is evident on inspection or palpation of the
these results can focus the search for a diagnosis. precordium. Because of the diffuse and forceful nature of the
apex beat, the heart may seem enlarged, and echocardiography
Clinical Manifestations of Thyrotoxicosis may show an increased ventricular mass. In addition, the pre-
ejection period is shortened and the ratio of preejection period
One very important clinical clue to the cause of the patient’s to left ventricular ejection time is decreased.3,5 The heart sounds
thyrotoxicosis is the duration of symptoms. Patients with hyper- are enhanced, particularly S1, and a scratchy systolic sound along
thyroidism have generally had manifestations for months before the left sternal border, resembling a pleuropericardial friction
presentation, but because the week-to-week increases in thyroid rub (Means-Lerman scratch), may also be heard. These manifes-
hormones are small, the effects of the disorder may become rather tations abate when a normal metabolic state is restored. Mitral
extreme, while going unnoticed by the patient. In addition, valve prolapse occurs more frequently in Graves or Hashimoto
patients will often attribute the symptoms to other causes; for disease than in the normal population6 and has been suggested as
example, they may ascribe their fatigue to family or work respon- autoimmune in origin.7 Cardiac arrhythmias are almost invari-
sibilities, heat intolerance to the weather, weight loss to an effec- ably supraventricular, especially in younger patients. Between
tive diet, and dyspnea and palpitations to a lack of regular exercise. 2% and 20% of patients with thyrotoxicosis have atrial fibril-
On the other hand, patients with thyrotoxicosis due to thyroiditis lation, and about 15% of patients with otherwise unexplained
can often date the onset of their symptoms precisely, usually to atrial fibrillation are thyrotoxic,1 which may be caused directly
within a month or so of their seeking medical attention, as might by the thyroid hormone excess or by activating autoantibodies to
be expected from the effects of the release of the equivalent of 30 the β1-adrenergic receptors.8,9 In the Framingham cohort, indi-
to 60 days’ supply of thyroid hormone into the circulation over a viduals over age 60 with a suppressed TSH level had a 2.8-fold
few days to weeks. Thus ascertaining the chronology as well as the increased risk of developing atrial fibrillation compared to those
spectrum of symptoms is a critical goal of the interview process. with normal serum TSH values,10 and such a finding has been
Another general characteristic is that the symptoms and signs widely confirmed.11
of thyrotoxicosis are more readily recognized in the younger than The increased cardiovascular cost of a standard workload or
in the older patient. The term masked or apathetic thyrotoxicosis metabolic challenge is adequately met if the thyrotoxic patient is
is used to describe the syndrome sometimes seen in the elderly, not, or has not previously been, in heart failure. Thus in most
which may present as congestive heart failure with arrhythmia patients without underlying heart disease, cardiac competence is
or as unexplained weight loss without the increased appetite and maintained. Mild peripheral edema may occur in the absence of
other typical symptoms and signs of the younger patient. heart failure. Heart failure per se usually, but not always, occurs in
At present, the ready availability of sensitive serum TSH assays, patients with preexisting heart disease and therefore is more typi-
a reliable indicator of excess thyroid hormone in the ambulatory cally seen in the elderly, but it may not be possible to determine
366 SE C T I O N I I I Thyroid
whether underlying heart disease is present until after thyrotoxico- Nervous System
sis is relieved. Atrial fibrillation decreases the efficiency of the car-
diac response to any increased circulatory demand and may play a Alterations in the function of the nervous system in thyrotoxicosis
role in causing cardiac failure.5 Attempts to convert or abate atrial are manifested by nervousness, emotional lability, and hyperkine-
fibrillation to sinus rhythm are not indicated while thyrotoxicosis sia. Fatigue may be due both to muscle weakness and to the insom-
is present, and about 60% of patients revert spontaneously to sinus nia that is commonly present. Emotional lability is common, and
rhythm after treatment, most within 4 months. While thrombo- in rare cases mental disturbance may be severe; manic depressive,
embolism is not frequent in patients under 50 with thyrotoxico- schizoid, or paranoid reactions may emerge. The hyperkinesia of
sis, the decision to anticoagulate should be potentially considered the thyrotoxic patient is characteristic and may manifest to such
in such patients taking into account additional risks for embolic a point that the patient is almost levitating. During the interview
events and risks of therapy.12 Medical or electrical cardioversion the patient shifts positions frequently and movements are quick,
of patients with thyrotoxicosis-induced atrial fibrillation is often jerky, exaggerated, and often purposeless. In children, in whom
successful even after a year has passed.13 such manifestations tend to be more severe, inability to focus may
lead to deterioration in school performance suggesting attention
deficit hyperactivity disorder. There may be a fine tremor of the
Protein, Carbohydrate, and Lipid Metabolism hands, tongue, or lightly closed eyelids. The electroencephalogram
The stimulation of metabolism and heat production is reflected reveals an increase in fast wave activity, and in patients with con-
in increased appetite and heat intolerance but only rarely by vulsive disorders the frequency of seizures is increased.
elevated basal body temperature.14 Despite an increased food
intake, a state of chronic caloric and nutritional inadequacy Muscle
often ensues, depending on the degree of increased metabolism.
Both synthesis and degradation rates of proteins are increased, Weakness and fatigability are usually not accompanied by objec-
the latter to a greater extent than the former, with the result that tive evidence of muscle disease save for the generalized wasting
in severe thyrotoxicosis there is a net decrease in tissue protein associated with weight loss. The weakness is most prominent in
as indicated by loss of weight, muscle wasting, proximal muscle the proximal muscles of the limbs, causing difficulty in climb-
weakness, and even mild hypoalbuminemia. Preexisting diabetes ing stairs or fatigue from minimal exertion such as using a blow
mellitus may be aggravated, one cause being accelerated turnover dryer or lifting an infant. Proximal muscle wasting may be out
of insulin. Both lipogenesis and lipolysis are increased in thyro- of proportion to the overall loss of weight (often referred to as
toxicosis, but the net effect is lipolysis as reflected by an increase thyrotoxic myopathy). In the most severe forms, the myopathy may
in the plasma concentration of free fatty acids and glycerol and involve the more distal muscles of the extremities and the muscles
a decrease in serum cholesterol level; triglyceride levels are usu- of the trunk and face. Although myopathy of ocular muscles is
ally slightly decreased. The enhanced mobilization and oxidation unusual, the disorder may mimic myasthenia gravis or ophthal-
of free fatty acids in response to fasting or catecholamines are mic myasthenia.21–25 Muscular strength returns to normal when
due to enhancement of lipolytic pathways by thyroid hormones, a normal metabolic state is restored, but muscle mass takes longer
including their effects on mitochondrial beta oxidation in the to recover.
liver.14,15 Graves disease occurs in about 3% to 5% of patients with myas-
thenia gravis, and about 1% of the patients with Graves disease
Sympathetic Nervous System and develop myasthenia gravis. Antibodies and T cells specific for the
TSH and acetylcholine receptors are involved in the pathogenesis
Catecholamines of the two diseases.26 Unlike thyrotoxic myopathy, the association
Many of the manifestations of thyrotoxicosis and of sympa- of myasthenia gravis with Graves disease has a distinct female pre-
thetic nervous system activation are similar. Nonetheless, the ponderance. The effect of both thyrotoxicosis and its alleviation
plasma concentrations of epinephrine and norepinephrine, as on the course of myasthenia gravis is variable, but in the majority
well as their urinary excretion and that of their metabolites, are of instances, myasthenia is accentuated during the thyrotoxic state
not increased in patients with thyrotoxicosis, and thyroid hor- and improves when a normal metabolic state is restored. A form
mones exert effects separate from, but similar and additive to, of myasthenia affecting mainly the orbital muscles may also occur
those of the catecholamines. The improvement in cardiac func- more commonly in patients with Graves disease and needs to be
tion in patients with hyperthyroidism by β-adrenergic blockade distinguished from GO by the prominence of bilateral ptosis of a
has led to the concept that there is increased sympathetic tone or variable degree.22
increased cardiac sensitivity to the sympathetic nervous system.16 Periodic paralysis of the hypokalemic type may occur together
Support for the latter are the results in the transgenic mouse in with thyrotoxicosis, and its severity is accentuated by the latter
which overexpression of type 2 deiodinase in the heart increases disorder. The coincidence of the two disorders is particularly com-
myocardial T3 and the cyclic adenosine monophosphate (cAMP) mon in Asian and Latino males.27,28
response to norepinephrine in the cardiac myocytes due to altera-
tions in G proteins.17,18 However, stimulation of the heart by Eyes
thyroid hormones does not require β-adrenergic receptors in
mouse models such that it is likely that β-adrenergic blockade Some retraction of the upper or lower eyelids, or both, evident as
in hyperthyroidism is only influencing part of the disorder. Still the presence of a rim of sclera between either lid and the limbus,
intact thyroid hormone signaling pathways are required for may be seen in all forms of thyrotoxicosis regardless of the under-
adrenergic signaling in white adipocytes leading to lipolysis and lying cause and is responsible for the typical stare of the patient.
for the induction of UCP1 in brown adipocytes by adrenergic Also common is either lid lag, a phenomenon in which the upper
signaling pathways.19,20 lid lags behind the globe when the patient is asked to shift the gaze
slowly downward, or globe lag, which becomes evident when the In such instances the pathologic changes are variable and
eye lags behind the upper lid when the patient looks up. These may include osteitis fibrosa, osteomalacia, or osteoporosis,
ocular manifestations appear to be the result of increased adren- most likely varying with vitamin D status. Urinary excretion
ergic tone. It is important to differentiate these signs, which may of collagen breakdown products (teleopeptides) is increased
occur in all forms of thyrotoxicosis, from those of infiltrative auto- in thyrotoxicosis. Kinetic studies indicate an increase in the
immune orbitopathy, which are associated with Graves disease exchangeable calcium pool and acceleration of both bone resorp-
and are described later. tion and accretion, particularly the former. Thyroid hormone
(T3) has been shown to accelerate activity of the osteoclasts
via its nuclear receptors and helps explain these widespread
Skin and Hair changes.21,24,32 Some data indicate that TSH itself may have
The most characteristic change in the patient with long-standing a local action, which may normally balance thyroid hormone
thyrotoxicosis is the warm, moist feel of the skin that results from action on osteoclasts and enhance osteoblast activity.25,33,34 Such
cutaneous vasodilation and excessive sweating. The elbows may be an action by TSH would be absent in hyperthyroidism, allow-
smooth and pink, the complexion is rosy, and the patient blushes ing accentuation of the thyroid hormone effects. However, not
readily. Palmar erythema may resemble liver palms (palmar ery- all models recapitulate these findings, and taken together it is
thema), and telangiectasia may be present. The hair is fine and likely that excess levels of thyroid hormones have a more pro-
friable, and hair loss may increase. The nails are often soft and found effect on bone mineral density.35 As the thyrotoxicosis is
friable. A characteristic but uncommon finding is Plummer nails, treated, bone density may normalize in many younger patients
onycholysis, typically involving the fourth and fifth fingers. Vit- but not all.36 Postmenopausal women, however, may have an
iligo, another autoimmune disease, is more common in patients accelerated reduction in bone density that requires treatment
with autoimmune thyroid disease. (see Chapter 30). Much controversy has existed over the induc-
tion of decreased bone density by TSH-suppression therapy in
patients with thyroid cancer. Suffice it to say that postmeno-
Respiratory System pausal, but not premenopausal, women given a TSH-suppressive
Dyspnea is common in severe thyrotoxicosis, and several factors may dosage of thyroid hormones are at risk of osteopenia and require
contribute to this condition. Vital capacity is commonly reduced, prophylaxis with calcium and vitamin D or more aggressive
mainly from weakness of the respiratory muscles. During exercise, approaches.37,38 The decision to relax TSH suppression in low-
ventilation is increased out of proportion to the increase in oxygen risk patients may be influenced by their bone status.
uptake, but the diffusing capacity of the lung is normal. Because For all the same reasons, hypercalcemia may occur in patients
of the general increase in oxygen consumption associated with thy- with severe thyrotoxicosis. The total serum calcium concentration
rotoxicosis, patients with chronic lung diseases may experience a is increased in as many as 27% of patients, and the ionized serum
rather severe worsening of the condition if they become thyrotoxic. calcium is elevated in 47%. The concentrations of heat labile
serum alkaline phosphatase and osteocalcin are also frequently
elevated. These findings resemble those of primary hyperparathy-
Alimentary System roidism, but the concentration of parathyroid hormone in serum
An increase in appetite is common but is usually not seen in is low-normal in most. True primary hyperparathyroidism and
patients with mild disease. In more severe disease the increased thyrotoxicosis sometimes coexist. Plasma 25-hydroxycholecalcif-
intake of food is inadequate to meet the increased caloric require- erol levels are decreased in thyrotoxic patients, and this alteration
ments, and weight is lost at a variable rate. More often, the patient could contribute to the decreased intestinal absorption of calcium
reports a gratifying success with a previously frustrated attempt at and osteomalacia noted in some.
weight control. The frequency of bowel movements is increased;
diarrhea, although rare, can also be a problem. The increased gas- Renal Function: Water and Electrolyte
tric emptying and intestinal motility in thyrotoxicosis appear to
be responsible for slight malabsorption of fat, and these functions Metabolism
return to normal when a normal metabolic state has been restored. Thyrotoxicosis produces no symptoms referable to the urinary
Celiac and Graves diseases coexist more commonly than once tract save for mild polyuria, which may lead to nocturia. Never-
thought, and there is an increased prevalence of pernicious anemia. theless renal blood flow, glomerular filtration, and tubular reab-
Hepatic dysfunction occurs, particularly when thyrotoxicosis sorptive and secretory maxima are increased. Total exchangeable
is severe; hypoproteinemia and increases in serum alanine ami- potassium is decreased, possibly due to a decrease in lean body
notransferase (ALT) and bone or liver alkaline phosphatase lev- mass, but electrolytes are normal except when hypokalemic peri-
els may be elevated. Progressive hepatomegaly and jaundice was odic paralysis occurs.
a cause of death prior to the development of successful treatment
for Graves patients likely exacerbated by congestive heart failure. Hematopoietic System
Skeletal System: Calcium and Phosphorus The red blood cells are usually normal, as judged by the usual
indices, but red blood cell mass is increased. The increase in eryth-
Metabolism ropoiesis is due to the direct effect of thyroid hormones on the
Thyrotoxicosis is generally associated with increased excretion erythroid marrow, as patients that harbor mutations in the thyroid
of calcium and phosphorus in urine and stool; with an increase hormone receptor alpha (TRα) have mild anemia secondary to
in bone turnover and a net demineralization of bone, as dem- defects in erythropoiesis.39 A parallel increase in plasma volume
onstrated by routine bone densitometry; and occasionally with also occurs, with the result that the hematocrit is normal in hyper-
pathologic fractures, especially in elderly women.21,23,29–32 thyroid patients.
Approximately 3% of patients with Graves disease have perni- however, the metabolic clearance rate is normal, suggesting that
cious anemia, and a further 3% have antibodies to intrinsic fac- tissue metabolism of the hormone is increased. Conversion rates
tor but normal absorption of vitamin B12. Autoantibodies against of androstenedione to testosterone, estrone, and estradiol and of
gastric parietal cells may also be present in patients with Graves testosterone to dihydrotestosterone are increased.50 The increased
disease, and the requirements for vitamin B12 and folic acid rate of conversion of androgens to estrogenic byproducts may
appear to be increased. The total white blood cell count is often be the mechanism for gynecomastia and erectile dysfunction in
low because of a decrease in the number of neutrophils. The abso- some 10% of thyrotoxic men and one mechanism for menstrual
lute lymphocyte count is normal or increased, leading to a relative irregularities in women. Another likely mechanism for menstrual
lymphocytosis. The numbers of monocytes and eosinophils may changes is the disruption in amplitude and frequency of LH/FSH
also be increased. Splenic enlargement occurs in about 10% of the pulses due to thyroid hormone influences on GnRH signaling.
patients, and thymic enlargement is common in Graves disease.40
The latter may present as a mediastinal mass. Thymic hyperpla- Laboratory Diagnosis
sia is also due to thyrotoxicosis because it is sometimes seen in
patients receiving excess exogenous T4 for suppression.41 The effects of thyrotoxicosis on the major organ systems are the
Platelet levels and the intrinsic clotting mechanism are nor- same regardless of the underlying cause. Their frequency and
mal, but the concentration of factor VIII is often increased and intensity and the other findings with which they are associated
returns to normal when the thyrotoxicosis is treated. Despite this are influenced by the cause of the excess thyroid hormone. To a
increase, there is an enhanced sensitivity to warfarin because of the large extent, the same is true of laboratory test results. However,
accelerated clearance of the vitamin K–dependent clotting factors. the patient with thyrotoxic symptoms will virtually always have
Therefore the dosage of warfarin needs to be reduced in thyrotoxic a serum TSH concentration less than 0.1 mU/L and an elevated
patients.42 This must be kept in mind if initiating anticoagulant serum free T4. In general, serum free T3 is more elevated than is
treatment for atrial fibrillation in older patients.43 Coincidental the free T4, but free T4 is relatively high if thyrotoxicosis is caused
autoimmune thrombocytopenia may also occur. by thyroiditis or intake of levothyroxine.
If the possibility of exogenous thyroid hormone can be elimi-
nated, the primary differential is between excess thyroid hormone
Pituitary and Adrenocortical Function production and excess thyroid hormone release from sick cells,
The thyrotoxic state imposes several challenges on pituitary and as in thyroiditis. Often this differentiation can be made on the
adrenocortical function. The hepatic inactivation of cortisol is accel- basis of the history and physical. Laboratory tests, including an
erated, including enhanced 5α/5β-reductases and 11β hydroxys- increased sedimentation rate and a high serum thyroglobulin
teroid dehydrogenase. As a result of these changes, the disposal of (Tg), may favor thyroiditis, but the most critical differentiating
cortisol is accelerated, but its rate of secretion is also increased, so the test is the radioactive iodine uptake (RAIU), which is elevated or
plasma cortisol concentration remains normal. The concentration inappropriately high-normal given the suppressed serum TSH
of corticosteroid-binding globulin in plasma is also normal. The level with excess thyroid hormone production and very low (<5%)
urinary excretion of free cortisol is normal or slightly increased44 in patients with thyroiditis (Fig. 12.1). However, the RAIU may
(see Chapter 15). Interestingly, thyroid hormone receptors have also be low in a hyperthyroid patient who has recently received an
now been identified in adrenal cortical cells in the mouse. It is not iodine load, usually iodinated contrast for a computed tomogra-
clear if they are also present similarly in humans.45 phy (CT) scan or for angiography. A 24-hour urine iodine mea-
surement can confirm this. Also helpful is measurement of TSH
Reproductive Function
Thyrotoxicosis in early life may cause delayed sexual maturation, TSH<0.01
although physical development is normal and skeletal growth may
be accelerated. Thyrotoxicosis after puberty influences reproduc-
tive function, especially in women. The intermenstrual interval
may be prolonged or shortened, and menstrual flow is initially
diminished and ultimately ceases. Fertility may be reduced, and Radioactive Iodine Uptake
if conception takes place, there is an increased risk of miscarriage (RAIU)
and other complications.46–48 In some patients, menstrual cycles
are predominantly anovulatory with oligomenorrhea, but in most,
ovulation occurs as indicated by a secretory endometrium. In the
former, a subnormal midcycle surge of luteinizing hormone (LH)
may be responsible. In premenopausal women with thyrotoxico- Normal or Increased Absent
sis, basal plasma concentrations of LH and follicle-stimulating Graves Disease Thyroiditis
hormone (FSH) are reportedly normal but may display enhanced hCG Iodine
Hot Nodule Exogenous
responsiveness to gonadotropin-releasing hormone (GnRH).
Multinodular Goiter Struma Ovarii
Thyrotoxicosis, whether spontaneous or induced by exogenous Metastatic Thyroid Carcinoma
hormone, is accompanied by an increase in the concentration of
sex hormone–binding globulin (SHBG) in plasma.49 As a result, • Fig. 12.1 Determination of the cause of hyperthyroidism based on the 123I
uptake in the gland. In the setting of a suppressed thyroid-stimulating hor-
the plasma concentrations of total testosterone, dihydrotestoster- mone (TSH) a normal or increased uptake is indicative of something else
one, and estradiol are increased, but their unbound fractions are driving uptake rather than endogenous TSH. In the absence of uptake the
normal or transiently decreased. The increased binding in plasma gland has either been damaged or an external factor such as exogenous
may be responsible for the decreased metabolic clearance rate of hormone or iodine is playing a role. Rarely, ectopic thyroid hormone pro-
testosterone and dihydrotestosterone. In the case of estradiol, duction may occur. hCG, human chorionic gonadotropin.
receptor antibodies (TSHRAb), which when associated with a TABLE 12.2 Phenotypes of Graves Disease and Their
suppressed TSH is consistent with Graves disease. Estimated Incidence Rates
If the physical examination or thyroid ultrasonography indi-
cates the presence of a nodular thyroid, thyroid scanning may Phenotype % Affected Cases/Million/Year
confirm which nodules are hyperfunctioning. The association All 100 350
of thyrotoxicosis with an elevated TSH is rare and suggests a
TSH-producing pituitary tumor. The possibility of an artifac- Graves hyperthyroidism 90–95 325
tually elevated TSH in a patient with Graves disease should Goiter 50 175
be ruled out by repeating the assay by a different method in
another laboratory (see Chapters 4 and 8). Exceptions to these Graves orbitopathy 30 105
general guidelines are discussed later within the appropriate Severe orbitopathy 5 17
subsection.
Hypo + orbitopathy 5 17
GRAVES DISEASE Graves dermopathy 0.5 4

Neonatal hyperthyroidism 0.2 1.0
Graves disease is a multisystem autoimmune disorder character-
ized by TSHRAb. The disease has been described by von Base- Fetal hyperthyroidism 0.1 0.5
dow in Germany, Graves in Ireland, and Parry in the United Acropachy 0.1 0.5
Kingdom, all in the first half of the 19th century and inde-
pendent of each other.51 Hallmarks of the disease were palpita-
tions (hyperthyroidism), goiter, and exophthalmos, called the
Merseburg triad after the hometown of von Basedow (Merse-
burg, Germany). The nature of the disease remained unclear for Goiter is present in about half of patients. Typically the goiter
many years, and cardiac, neurologic, and pituitary origins were is diffuse in nature, with a soft to firm consistency and a smooth
proposed. The autoimmune nature was not recognized before surface. In severe cases, a thrill may be felt, usually over the upper
the late 1950s when Adams reported on the presence of a long- or lower poles where the superior and inferior thyroid arteries,
acting thyroid stimulator (LATS) in serum, different from respectively, enter the thyroid gland; a thrill is accompanied by an
TSH, which turned out to be an antibody capable of stimulat- audible bruit in systole. The presence of a nodule in the setting of
ing the TSH receptor.52,53 Self-infusion of sera from patients Graves disease should raise suspicion of thyroid cancer. Advanc-
with Graves disease caused thyroid stimulation and was the ing age is associated with less severe Graves hyperthyroidism.58,60
first demonstration of the role of TSHRAb in the induction Remarkably symptom-poor hyperthyroidism may occur in elderly
of human hyperthyroidism.54 Another example of the in vivo people, called apathetic thyrotoxicosis. Graves orbitopathy is
effects of TSHRAb is the transplacental passage of maternal present in 26% of patients when Graves hyperthyroidism is diag-
TSHRAb, which may stimulate the fetal thyroid gland and nosed. Thereafter new cases of GO develop in 9%, rendering a
cause fetal/neonatal thyrotoxicosis.55 It is now recognized that total GO frequency of 35% in Graves hyperthyroidism.61 Taking
TSH receptors are not only expressed on thyrocytes but are also into account the severity of the Merseburg triad (as judged from
outside the thyroid gland on fibroblasts, fibrocytes, adipocytes, serum free thyroxine [FT4], thyroid size, and GO signs), 44% of
osteoblasts, osteoclasts, and pituitary folliculostellate cells. It patients have severe Graves disease, 34% moderate disease, and
is likely that immune responses directed against TSH recep- 22% mild disease.62 The phenotypic appearance of Graves disease
tors on orbital fibroblasts and subcutaneous connective tissue is apparently milder than in the past; this may be due to earlier
cells are involved in other expressions of Graves disease, namely diagnosis and treatment, improved iodine nutrition, and a secular
Graves orbitopathy and Graves dermopathy. Besides stimulat- trend to less smoking.
ing TSHRAb there also exist blocking TSHRAb, which are
found in a small minority of patients with autoimmune hypo- Pathology
thyroidism.56 The clinical phenotypes of Graves disease are thus
manifold (Table 12.2). The thyroid gland in Graves hyperthyroidism is typically both
enlarged and uniformly affected, hence often referred to as dif-
fuse toxic goiter. It is extremely rare that the disease process
Graves Hyperthyroidism remains restricted to one lobe.63 Such unilateral Graves hyper-
thyroidism is difficult to reconcile with the systemic nature of
Clinical Presentation thyroid-stimulating immunoglobulins. The follicles are small
Graves hyperthyroidism (GH) is at least four times more common and lined with hyperplastic columnar epithelium and contain
in women than in men. GH is relatively rare in children. Its inci- scant colloid that displays much marginal scalloping and vacu-
dence starts to increase at the age of 13 years and remains rather olization (Fig. 12.2). Papillary projections of the hyperplastic
stable after the age of 30 years. Average age is 47 years. The typi- epithelium extend into the lumina of the follicles. Vascularity
cal patient complains about weight loss despite increased appe- is increased. There is varying heterogeneous infiltration by lym-
tite, heat intolerance, sweating, palpitations, fine finger tremor, phocytes and plasma cells that collect in aggregates and may
nervousness, and loose stools. Duration of symptoms until diag- form infrequent B-cell germinal centers (in contrast to their
nosis is less than 6 months in 61% of patients.57 A positive fam- abundance in Hashimoto disease). In such regions, thyroid
ily history of autoimmune thyroid disease (AITD) is present in epithelial cells express human leukocyte antigen (HLA) class
about 50%.57,58 There is some evidence for genetic anticipation, II antigens (a phenomenon not seen in normal thyroid glands)
which is a younger age of onset in patients with a family history and are large (perhaps due to local stimulation by TSHRAb).
of AITD.57–59 The intrathyroidal lymphocytic population is mixed, consisting
Immunopathogenesis
Autoimmune thyroid diseases can be defined as complex or multi-
factorial diseases in which autoimmune responses to thyroid anti-
gens develop against a particular genetic background, influenced
by exposure to environmental factors. Breakdown of self-tolerance
to thyroid antigens results in thyroid autoimmunity. A number
of complex regulatory mechanisms serve to protect an immune
response directed against self-antigens.64 During development,
immature T cells enter the thymus where they undergo a process
of selection.65 T cells that recognize with high affinity self-pep-
tides expressed on thymic medullary epithelial cells are deleted by
apoptosis, and T cells with moderate affinities leave the thymus
as mature T cells. The full-length thyroid-stimulating hormone
receptor (TSHR) is indeed expressed in the hyperplastic thymus
of Graves hyperthyroid patients.66 Genetic-epigenetic interactions
A involving a noncoding single-nucleotide polymorphism (SNP) in
the TSHR gene that regulates thymic TSHR gene expression may
facilitate escape of TSHR-reactive T cells from central tolerance
in the thymus, thereby triggering Graves disease.67 Central toler-
ance may not eliminate all self-reactive T cells. Control of auto-
reactive T cells in the periphery (e.g., by engagement of cytotoxic
T-lymphocyte–associated protein 4 [CTLA4] resulting in T-cell
anergy) is considered as a secondary or fail-safe mechanism to
prevent autoimmune reactions (peripheral tolerance). Self-anti-
gen presentation in the thymus also generates regulatory T cells
(Treg) that can inhibit in peripheral tissues those self-reactive T
cells that escaped negative selection in the thymus. Besides these
natural Treg there are inducible Treg generated in the periphery
after antigenic stimulation. Treg are characterized by the expression
of CD4, CD25 (the interleukin 2 [IL2] receptor α-chain), and
FOXP3 (the transcription factor forkhead box P3 protein); they
may act on effector CD4+ and CD8+ lymphocytes by cell-to-cell
B contact hampering their activation and proliferation or indirectly
via secretion of IL10 and transforming growth factor-β (TGFβ).
Treg are crucial in maintaining tolerance through the active sup-
pression of self-reactive T-cell activation and expansion. A fourth
subset of T helper cells, induced by IL6, are highly proinflamma-
tory and designated Th17 cells. They generate IL17, exacerbating
autoimmune responses. Thus a balance between Th17 and Treg is
crucial for immune homeostasis. A number of studies now report
a decrease in the number of Treg cells and an increase in Th17 cells
in peripheral blood of Graves patients, in relationship with stimu-
lating TSHRAb and with improvement upon methimazole treat-
ment.65,68–70 Low Treg and high IL17 levels are also found in an
animal model of Graves disease.71 Recent studies have identified
regulatory beta cells (Breg) that contribute to peripheral tolerance
by inhibiting immune reactions to specific self-antigens.72,73
Traditionally Graves disease is viewed as the result of humoral
immunity (hallmark TSHR antibodies) and Hashimoto thyroid-
C itis as the result of cell-mediated immunity (hallmark thyroid per-
oxidase [TPO] antibodies [TPOAb]). However, TPOAb are also
• Fig. 12.2 Histopathologic features of the thyroid gland in Graves hyper- present in about 70% of Graves patients, and TSHR antibodies
thyroidism (B and C) as compared to normal tissue (A). (Courtesy Dr.
Pamela Unger, Mount Sinai Scholl of Medicine, New York.)
may occur in a minority of Hashimoto patients. Actually, humoral
and cellular immune mechanisms are closely connected, and Th1
(interferon gamma [IFNγ]) and Th2 (IL4) subtypes of helper T
besides B cells mostly of T helper 1 (Th1) and Th2 lymphocytes cell responses are involved in both Graves and Hashimoto dis-
and less often Th17 and regulatory T cells. When the patient ease. IgG1 antibodies arise early in the immune response, whereas
is given iodine or antithyroid drugs (ATDs), the thyroid gland IgG4 antibodies (typically Th2 related) arise after prolonged
may undergo involution as TSHRAb decrease. Then hyperplasia immune stimulation. TPOAb and TgAb may comprise IgG1
and vascularity regress, papillary projections recede, and follicles as well as IgG4 classes indicating participation of Th1 and Th2
enlarge and become filled with colloid again. cytokines, respectively. Stimulating TSHRAb are mostly found
in the IgG1 subclass, which is selectively induced by Th1 cells; two subunits, alpha and beta, which are linked by disulfide bonds.
Graves hyperthyroidism is a predominantly Th1-type cytokine The 50-kDa α-subunit is water soluble and heavily glycosylated.
disease.74 Oligoclonality and light chain restriction of stimulat- TSH and TSHRAb bind to the leucine-rich repeat regions of the
ing TSHRAb support their primary role in disease causation.75,76 α-subunit. The 30-kDa β-subunit is water insoluble, contains the
Th1 cells may also induce antibody production through secretion membrane-spanning domain with its three extracellular loops and
of IL10, which in turn activates B cells. B cells may turn into three cytoplasmic loops, and is 70% to 75% homologous with the
plasma cells secreting antibodies. The thyroidal lymphocytic infil- LH/human chorionic gonadotropin (hCG) receptor. The TSHR
trate is a major production site of thyroid autoantibodies. Trans- forms dimers and multimeric complexes on the thyrocyte surface,
plantation of Graves thyroid tissue into mice deficient in both T probably enhancing the stability of the receptor. The holoreceptor
cells and B cells with severe combined immunodeficiency (SCID undergoes cleavage in the hinge region due to breakage of disul-
mice) results in the appearance of human thyroid autoantibodies fide bonds. As a result of this post-translational modification, the
in serum, including TSHRAb.77 Thyroid antibodies can also be extracellular α-subunit is shed. The shed TSHR α-subunit, rather
produced outside the thyroid gland as they may persist after total than the holoreceptor, is apparently the autoantigen in Graves
thyroidectomy. disease.79 Enhanced α-subunit shedding from damaged follicular
cells may be the cause of the increase of serum TSHRAb concen-
TSH Receptor, the Major Autoantigen in Graves trations after radioiodine therapy.80
Stimulating TSHRAb isolated from patients with Graves
Disease hyperthyroidism bind to the TSHR and activate Gαs and Gq
A mice animal model of Graves hyperthyroidism is provided by signaling pathways, thereby inducing thyroid growth, increased
genetic immunization against the TSH receptor, which induces vascularity, and increased production and secretion of thyroid
stimulating TSHRAb and hyperthyroidism.78 The gene encoding hormones.81,82 In contrast, some TSHRAb act as TSH antagonists
the TSH receptor is located on chromosome 14q31. The TSHR and are referred to as blocking TSHRAb; they may occur in some
belongs to the family of G protein–coupled receptors and has patients with autoimmune hypothyroidism but also after treat-
seven transmembrane domains, a large extracellular domain, and ment of Graves hyperthyroidism.56,81 So-called neutral or cleav-
a small intracellular domain (Fig. 12.3). The TSH holoreceptor age region TSHRAb neither block TSH binding nor block TSH
consists of a 100-kDa glycosylated 744–amino acid sequence and action; they do not induce cAMP but have the potential to induce
a 20–amino acid signal peptide. The holoreceptor is cleaved into apoptosis by binding to the hinge region.81
Etiology
A complex interaction between existential factors, genetic vari-
ants, and environmental insults determines susceptibility of sub-
jects to develop Graves disease83 (Fig. 12.4).
Existential Factors
LRD
The strong female preponderance in Graves patients remains
incompletely understood. Among all women with Graves hyper-
thyroidism, the rate of postpartum onset is 7.2%,84 and parity
as a risk factor has received much attention. Women with chil-
dren, compared to childless women, have a relative risk for Graves
Hinge α
GRAVES HYPERTHYROIDISM
ECLs
ENVIRONMENT GENES
• iodine • TSHR
• smoking • Tg
• alcohol
• selenium • HLA
• stress • IL2A
TMD • infections • CD25
• drugs • CD40
• CTLA4
• PTPN22
ICLs β EXISTENTIAL FACTORS

• female sex
• Fig. 12.3 Structure of the human thyroid-stimulating hormone receptor
• parity
(TSHR). ECLs, extracellular loops; ICLs, small intracellular loops; LRD, leu-
cine-rich domain; TMD, transmembrane domain. The receptor is cleaved, • Fig. 12.4 Venn diagram illustrating how the combination of existential fac-
probably after activation, into α (or A) and β (or B) subunits. The α-subunit tors, genetic variants, and environmental insults may result in susceptibility
is thought to be shed from the cell surface. to Graves hyperthyroidism.
disease of 1.19 (CI 1.14–1.24).85 Fetal microchimerism (persis- present endogenous antigens to immune cells, including those
tence of fetal cells in maternal tissues) may trigger autoimmunity derived from viruses, which are possible triggers for AITD. Note-
through maternal immune responses against foreign fetal anti- worthy is the lack of an association between Graves disease and
gens, but its contribution to the female preponderance appears mutations in the autoimmune regulator gene (AIRE ) expressed
limited.86 At odds with this hypothesis is a recent report that in thymic medullary epithelial cells, resulting in failure to present
fetal microchimerism is more frequent in healthy controls than in self-antigens correctly in the thymus; AIRE mutations cause auto-
Graves disease (64% vs. 33%, p = 0.0004), suggesting a possible immune polyglandular syndrome type 1.96 Polymorphisms in the
protective role.87 More relevant might be the epigenetic phenom- PTPN22 gene encoding lymphoid protein tyrosine phosphatase is
enon of X-chromosome inactivation (XCI): In female cells, one another susceptibility gene, with a gene dose-dependent effect on
of the two X chromosomes is inactivated in early embryonic life. the age of onset of Graves disease.97
Female tissues are thus mosaics of two cell lines, one with the
paternal X and the other with the maternal X chromosome, usu- Environmental Insults
ally in a 50:50 ratio. The consequence of skewed XCI (arbitrarily Iodine
defined as inactivation of the same X chromosome in ≥80% of Iodine-induced thyroid autoimmunity is related to TgAb, and the
cells) might be that self-antigens on one X chromosome are not unmasking of a cryptic epitope on Tg contributes to this rela-
expressed at sufficiently high levels to induce tolerance.88 A meta- tionship in humans.98 Longitudinal epidemiologic studies dem-
analysis confirmed significant skewing of XCI in women with onstrate that iodine fortification in iodine-deficient areas initially
Graves disease (odds ratio 2.54, CI 1.58–4.10).89 FOXP3 is a key lead to a transient increase in the incidence of toxic multinodular
gene in the development of Treg, located on the X chromosome. goiter and Graves hyperthyroidism. In the long term, however,
Polymorphisms in FOXP3 have been linked to Graves disease in there is a decline in the incidence rate of thyrotoxicosis, mainly
some but not all studies. due to fewer cases of toxic multinodular goiter but also—although
to a lesser extent—to fewer cases of Graves disease.99,100
Genetic Variants
Twin studies suggest that 79% of the liability to develop Graves Smoking
disease is attributable to genetic factors.90 Identified susceptibility Smoking is a well-established risk factor for Graves disease.101 The
genes for Graves disease include thyroid-specific genes (TSHR, Tg) odds ratio for Graves hyperthyroidism is 3.30 (CI 2.09–5.22) in
and genes involved in the regulation of immune responses (HLA, current smokers when compared with never smokers. The risk dis-
CD25, CD40, CTLA4, and PTPN22).91 These genes together appears a few years after cessation of smoking.
probably do not explain more than about 10% of the heritabil-
ity of Graves disease92; it follows there must be many more still Alcohol
undetected genetic loci, each contributing a little. The TSHR gene Moderate alcohol consumption is associated with a considerable
is most tightly associated with Graves disease, but the functional reduction in the risk of Graves hyperthyroidism. Odds ratios
consequences of SNPs in the unusual large intron 1 are not clear.93 are 1.73 (CI 1.17–2.56) for 0 units/week, 1.00 for 1 to 2 units/
They could give rise to RNA splice variants, increasing the level week (reference), 0.56 (0.39–0.79) for 3 to 10 units/week, 0.37
of autoantigenic TSHR α-subunits. Alternatively, SNP carriers (0.21–0.65) for 11 to 20 units/week, and 0.22 (0.08–0.60) for
may have fewer thymic TSHR transcripts, decreasing central tol- 21+ units/week.83,102 No interaction was found with type of alco-
erance to TSHR. Multiple SNPs in the thyroglobulin gene are hol (wine vs beer), smoking habits, gender, or iodine intake.
linked to both Graves and Hashimoto disease.91 Possible interac-
tions between HLA-DRβ1 and thyroglobulin variants have been Selenium
described in Graves disease, which would result in more effec- As evident from population-based studies in China, low selenium
tive presentation of disease-associated thyroglobulin-SNP allelles intake might be a risk factor for autoimmune thyroiditis and
to T cells.94 The immunoregulatory genes HLA, CD25, CD40, hypothyroidism, but not for Graves hyperthyroidism.103
CTLA4, and PTPN22 are all involved in the immunologic syn-
apse, in which antigenic peptides complexed in HLA molecules are Stress
presented by antigen-presenting cells (APCs; macrophages, den- Stressful life events have already been implicated in the early
dritic cells, but also B cells) to T-cell receptors (TCRs) on T cells. descriptions of Graves hyperthyroidism.51 Numerous reports on
Formation of the trimolecular complex (HLA, antigenic peptide, exposure to severe emotional stress prior to the onset of Graves
TCR) activates CD4+ T cells via expression of the interleukin 2 disease support a causal relationship,104 but prospective studies on
receptor (IL2Rα; CD25 is a marker for the IL2R α-chain) and by this issue are lacking.83
inducing co-stimulation via induction of CD40 ligand on T cells,
which binds to constitutively expressed CD40 on APCs. CTLA4 Infections
is finally induced, which should terminate the immune response. Similarity between different antigens can lead to specificity cross-
Polymorphisms in these genes may functionally hinder the proper over (molecular mimicry). Antigenic similarity between bacteria/
development of central and peripheral tolerance and alter T-cell viruses and human proteins is common. The best studied example
interactions with APCs in the immunologic synapse.91 They is infection with Yersinia enterocolitica (YE). IgG from Graves
confer susceptibility for AITD but also for other autoimmune patients inhibit TSH binding to outer membranes of YE, and
diseases, explaining the co-occurrence of various autoimmune dis- conversely IgG from patients with YE infection inhibit binding of
eases.83 Odds ratios of individual loci for AITD are rather low TSH to thyroid membranes. There is cross-reactivity between YE
(<2.0), but slightly higher for HLA (2.0–4.0). HLA-C, an HLA outer membrane proteins and epitopes of TSHR antibodies.105
class I molecule, is stronger associated with Graves disease than Despite this clear evidence of molecular mimicry, epidemiologic
HLA class II molecules (HLA-DRB1, DQA1, and DQB1), at studies have not detected an association between YE infection and
least in Caucasians.95 This is interesting as HLA class I molecules AITD.106 A local insult (whether trauma or infection) may cause
an inflammatory infiltrate and production of cytokines in the thy- TABLE 12.3 Assays of Thyroid-Stimulating Hormone
roid gland, which may induce HLA class II expression; this may Receptor Antibodies: Nomenclature and
facilitate presentation of thyroid antigens and activation of local Indications
autoreactive thyroid-specific T cells in susceptible individuals.107
A number of infections (e.g., with enteroviruses, Helicobacter Nomenclature of TSHRAb Assays
pylori, reoviruses) have been implicated in Graves disease, but TBII (TSH binding inhibitory Measurement of inhibition of labelled
conclusive evidence for their involvement has not been obtained. immunoglobulins) TSH (or labelled thyroid-stimulating
The exception is hepatitis C virus (HCV), which seems the only monoclonal antibody) binding to
infectious agent that is clearly associated with an increased risk recombinant TSHR by serum
for autoimmune thyroiditis.108 HCV can infect human thyrocytes antibodies
resulting in production of proinflammatory cytokines, which may TSAb or TSI (thyroid- Measurement of cAMP production by
enhance the autoimmune response.109 stimulating thyroid cell lines transfected with
antibodies) TSHR
Drugs
TBAb (thyroid-blocking Measurement of inhibition of cAMP
Interferon-α has direct cytotoxic effects on thyrocytes but can also antibodies) production after TSH-mediated
provoke destructive bystander immune responses. Treatment of stimulation of thyroid cells or
hepatitis C with interferon-α and ribavirin combination therapy TSHR-transfected cells
is associated with development of a suppressed TSH in 10.4%,
due to Graves disease in 0.8%, and to destructive thyroiditis in Indications for Assay of TSHRAb
9.6%.110 Exogenous estrogens such as oral contraceptives are asso- Diagnosis Graves hyperthyroidism
ciated with a lower risk of Graves hyperthyroidism.111,112 Graves orbitopathy and Graves
Graves hyperthyroidism may occur during periods of lymphocyte dermopathy
recovery after induced lymphopenia, known as the immune recon- Fetal and neonatal thyrotoxicosis
stitution syndrome. It is observed after bone marrow or hematopoi- Treatment Chance of remission of hyperthyroidism
etic stem cell transplantation,113 during highly active antiretroviral at baseline, and during treatment
therapy (HAART) for human immunodeficiency virus (HIV) infec- with antithyroid drugs.
tion in 3%,114 and during alemtuzumab therapy for multiple sclero-
cAMP, Cyclic adenosine monophosphate; TSH, thyroid-stimulating hormone; TSHR, thyroid-
sis in 30%.115 Alemtuzumab is a humanized anti-CD52 monoclonal stimulating hormone receptor; TSHRAb, thyroid-stimulating hormone receptor antibodies.
antibody, inducing a rapid and prolonged depletion of lymphocytes
from the circulation, resulting in a profound immunosuppression
followed by an immune reconstitution phase. Median onset of
Graves hyperthyroidism is 17 months (range 2–107 months) fol- are very high (97% and 98%, respectively).120 In contrast, cell-based
lowing last dose of alemtuzumab.116 Graves hyperthyroidism in bioassays are able to differentiate between stimulating TSHRAb
this context frequently requires definitive or prolonged ATD treat- (TSAb or TSI) and blocking TSHRAb (TBAb).121,122
ment. Furthermore, fluctuating thyroid status and high frequency of Large variation exists in the use of diagnostic imaging. A recent
TSHRAb-positive hypothyroidism suggest switches between block- study in France among hyperthyroid patients indicated thyroid
ing and stimulating TSHRAb in these patients. ultrasonography was done in 94% and isotope scanning in 40%.123
Immune checkpoint inhibitors are emerging as a new class of European Thyroid Association (ETA) guidelines recommend
anticancer drugs associated with frequent thyroidal side effects. Ipi- ultrasonography (comprising grey scale analysis and color flow or
limumab is a monoclonal antibody against CTLA4 that blocks an power Doppler examination) as the preferred imaging procedure
inhibitory signal to T cells, thereby prolonging a stimulated immune for the diagnosis of Graves hyperthyroidism.124 Graves hyperthy-
response against tumor cells.117 Nivolumab and pembrolizumab are roidism is typically characterized by diffuse thyroid enlargement,
antibodies against programmed death protein 1 (PD1), which is hypoechogenicity, and increased vascularity. The latter can be used
upregulated on activated T cells. By interrupting PD1 binding to its to differentiate between thyrotoxicosis due to Graves disease and
ligand PDL1, effector T-cell activity increases in the tumor micro- destructive thyroiditis (as in subacute thyroiditis, amiodarone-
environment.117 Treatment with these checkpoint inhibitors may induced thyrotoxicosis type 2). Typical ultrasound patterns com-
result in subclinical hyperthyroidism due to destructive thyroiditis bined with positive TSHRAb may obviate the need for thyroid
and, rarely, in Graves hyperthyroidism.117–119 scintigraphy. ETA guidelines suggest scintigraphy when thyroid
nodularity coexists with hyperthyroidism and prior to 131I ther-
apy. The few patients in whom no TSHRAb are detected (TBII
Diagnosis and Differential Diagnosis <2 U/L) have biochemically less severe Graves hyperthyroidism
When the syndromal diagnosis of thyrotoxicosis has been established compared to TSHRAb-positive patients125; however, familial
by the finding of a suppressed serum TSH and an increased serum nonautoimmune hyperthyroidism due to germline TSHR activat-
FT4 and/or FT3, a nosologic diagnosis should be reached: Which ing mutations is present in 4.5% of such patients.126
disease entity causes hyperthyroidism? If Graves orbitopathy is pres-
ent, it is quite evident Graves hyperthyroidism is present. Otherwise Natural History and Prognosis
the presence of TSH receptor antibodies (TSHRAb) in serum con-
firms Graves disease. Most current assays use a competitive binding Knowledge about the natural history of Graves hyperthyroidism
methodology, measuring TSH-binding inhibitory immunoglobu- is limited because nowadays almost no patient escapes therapeutic
lins (TBII) (Table 12.3). These binding assays do not discriminate intervention. Case histories from the older literature and cumu-
between stimulating and blocking TSHRAb. Nevertheless, their sen- lative experience with the outcome of ATDs, however, allow us
sitivity and specificity for the diagnosis of Graves hyperthyroidism to hypothesize that patients with Graves hyperthyroidism can be
divided into three groups, each with a different natural history: (1) TABLE 12.4 A
dverse Events of Antithyroid Drugs
patients who have a prolonged continuous episode of hyperthy-
roidism that never goes into remission (∼10%), (2) patients who Common (1–5%) Skin rash
follow a relapsing and remitting course over many years (∼50%), Urticaria
and (3) patients who have a single episode of hyperthyroidism fol- Arthralgia, polyarthritis
lowed by permanent remission (∼40%). Patients who are in remis- Transient mild leukopenia
sion after a course of ATDs have a low prevalence of TSHRAb Rare (0.2–1%) Gastrointestinal
(<30%) and a much higher prevalence of TPOAb (∼80%). Long- Abnormal smell and taste
term follow-up studies of patients in remission indicate devel- Agranulocytosis
opment of subclinical hypothyroidism in about 20% and overt Very rare (<0.1%) Aplastic anemia (PTU, CBZ)
hypothyroidism in about 6%, associated with either blocking Thrombocytopenia (PTU, CBZ)
TSHRAb or TPOAb.127–129 Vasculitis, lupus-like, ANCA+ve (PTU)
A series of population-based studies in Denmark have provided Hepatitis (PTU)
evidence that Graves hyperthyroidism (but also toxic nodular goi- Hypoglycemia (anti-insulin antibod-
ter) is associated with increased all-cause mortality (hazard ratio ies) (PTU)
1.42, CI 1.25–1.60) due to cardiovascular and lung diseases.130 Cholestatic jaundice (CBZ, MMI)
Excess mortality is related to cumulative periods of low serum ANCA+ve, Antineutrophil cytoplasmic antibody positive; CBZ, carbimazole; PTU, propylthio-
TSH.131 Hyperthyroid patients treated with radioactive iodine uracil; MMI, methimazole.
remain at a higher risk of cardiovascular diseases compared to Adapted from Strieder TG, Prummel MF, Tijssen JG, et al. Risk factors for and prevalence of
patients treated with thyroidectomy, but hypothyroidism during thyroid disorders in a cross-sectional study among healthy female relatives of patients with
follow-up predicts better cardiovascular outcome.132 autoimmune thyroid disease. Clin Endocrinol. 2003;59:396–401.

Treatment
Recent guidelines and reviews give detailed information on
the management of Graves hyperthyroidism.124,133,134 Treat- to radioiodine therapy blunts the increase in TSHRAb usually seen
ment of hyperthyroidism in the presence of Graves orbitopa- after 131I.137 The unresolved question, however, is whether the
thy is discussed in the section on Graves orbitopathy. There are effects are caused directly by the action of the drug on the immune
three treatment options (ATDs, thyroidectomy, and radioactive system or indirectly by restoration of the euthyroid state.
iodine) that are effective in restoring euthyroidism. It should be
realized, however, that a causal therapy of Graves disease directed Adverse Effects (Table 12.4)
against the underlying abnormal immune responses is not yet Minor cutaneous reactions such as skin rash and urticaria usually
available. can be managed by antihistamine therapy without stopping the
drug. The lesions may resolve spontaneously or after switching
to another ATD. Prescribing the alternative drug is not recom-
Antithyroid Drugs: Thionamides mended in the case of serious allergic reactions.124,138
Mechanism of Action Agranulocytosis (<500 neutrophils/mm3) is a serious side effect,
The major agents for treating thyrotoxicosis are drugs of the thion- with an incidence of 0.28% in the first 3 months of therapy.139
amide class: carbimazole (CBZ), methimazole (MMI), and PTU. Risk factors are older age, higher doses of ATD, and the pres-
CBZ is rapidly decarboxylated in the liver to the active substance ence of particular HLA-B and HLA-DRB1 alleles or rare NOX3
MMI. Equivalent doses are 40 mg CBZ, 30 mg MMI, and 400 genetic variants.140–142 The onset of agranulocytosis is rather
mg PTU. Each of these agents inhibits the function of thyroid per- abrupt, accompanied by fever and sore throat.138 When therapy
oxidase, thereby reducing oxidation and organification of thyroid with ATD is begun, the patient should be instructed to discon-
iodide, iodotyrosine coupling, and thyroid hormone biosynthesis. tinue the drug and to notify the physician immediately should
In addition, large doses of PTU, but not methimazole, impair the these symptoms develop. This precaution is more important than
conversion of T4 to T3 by D1 in the thyroid and peripheral tis- the frequent measurement of white blood cell counts because
sues.135 Consequently large doses of PTU may provide more rapid agranulocytosis may develop within 1 to 2 days. Neither the
alleviation of very severe thyrotoxicosis. American Thyroid Association (ATA) nor the ETA recommend
The plasma half-life of MMI is about 6 hours, whereas that routine monitoring of white blood cells during ATD therapy. If
of PTU is about 1.5 hours. Both drugs are accumulated by the agranulocytosis occurs, the drug should be discontinued immedi-
thyroid gland. Whereas the daily amount of MMI can be given ately and the patient treated with antibiotics as appropriate. Gran-
in one dose, the daily amount of PTU should be divided in three ulocyte colony-stimulating factor may speed the recovery that
doses with each given every 8 hours. In patients with severe hyper- invariably takes place. Lymphocytes of patients who have devel-
thyroidism, splitting the daily dose of MMI might sometimes be oped agranulocytosis while taking PTU undergo blast transforma-
required. Single daily dosing improves compliance and should be tion when exposed in vitro to PTU or methimazole; consequently,
used whenever possible. Thionamides cross the placenta and can thionamides should not be given again. Granulocytopenia occurs
inhibit fetal thyroid function. during ATD therapy and is sometimes a forerunner of agranulo-
MMI and PTU may also have immunosuppressive effects.136 cytosis, but it can also be a manifestation of thyrotoxicosis itself.
In vitro MMI reduces HLA-DR expression on thyroid cells, either Although rare, PTU has been associated with fulminant
directly or indirectly via inhibiting IFNγ. In vivo, MMI decreases hepatic necrosis, and it is the third most common cause of drug-
the number of intrathyroidal activated T cells and the concentra- related liver failure, accounting for 10% of all drug-related liver
tion of serum TSHRAb (but not of nonthyroid antibodies such as transplants. Children are at a higher risk than adults.143 Fortu-
parietal cell antibodies). MMI, but not glucocorticoids, given prior nately, stopping PTU results in recovery in most cases. This
PTU-associated liver failure may occur at any time during therapy, (or 30–40 mg CBZ). Normal FT4 and T3 concentrations are
so routine monitoring of liver function may not be helpful.138 usually reached after 4 to 6 weeks, which should be followed
Because of this well-known rare but serious PTU side effect of by tapering the MMI dose toward a maintenance dose of about
hepatic failure, sometimes requiring liver transplantation, in June 5 to 10 mg MMI, which keeps the patient euthyroid. In the
2009 the Food and Drug Administration (FDA) issued an advisory block-and-replace regimen one starts with the same high ini-
that PTU should not be used as a first-line agent in hyperthyroid- tial dose of MMI, then adds LT4 when the patient has become
ism.144 The use of PTU should be restricted to the first trimester euthyroid under continuation of the high initial MMI dose.
of pregnancy (see later), to thyroid storm, and to patients who In the rare patient given PTU, the high starting PTU dose is
experience minor side effects of MMI and are unable or unwilling 300 to 400 mg daily divided in three to four doses, whereas
to undergo 131I therapy or thyroidectomy. MMI is associated in the maintenance dose is about 50 to 100 mg daily. The advan-
a dose-dependent manner with an increased risk for hepatitis and tage of the titration method is the use of lower doses of MMI
cholestasis.145 There are no reported cases of liver transplantation and thereby slightly fewer side effects; the disadvantage is the
attributed to MMI toxicity. need for more frequent blood sampling to adjust the MMI dose
and larger fluctuations between hypothyroidism and hyperthy-
Practical Use roidism. The advantages of the block-and-replace regimen are
Guidelines agree MMI (CBZ) should be used in virtually every fewer blood samples and more stable thyroid function during
nonpregnant patient who chooses ATD therapy.124,134 Guide- ATD therapy; the disadvantages are the higher MMI dose and
lines also recommend that patients should be informed of side slightly more side effects. The two methods have never been
effects of ATD and the necessity of informing the physician compared in a randomized clinical trial. The recurrence rate of
promptly if they should develop jaundice, light-colored stools, Graves hyperthyroidism is similar between both regimens. In
dark urine, fever, or pharyngitis. Preferably this information many patients, serum TSH may remain suppressed for a long
should be in writing. Prior to ATD therapy it is suggested to time despite already normalized serum FT4 and T3 concentra-
obtain a baseline complete blood count, including white blood tions.146 This phenomenon has been linked to the presence of
cell count with differential, and a liver profile, including bili- still high serum concentrations of stimulating TSHRAb, which
rubin and transaminases. Restoration of the euthyroid state via binding to TSH receptors in pituitary folliculostellate cells
by ATD can be done according to the titration method or the downregulate TSH release.147
block-and-replace regimen. In the titration method one starts MMI is administered for 12 to 18 months and then discon-
with a relatively high single daily dose of 20 to 30 mg MMI tinued to see if the disease has gone into remission. Remission
TABLE 12.5 Predictive Scores for the Risk of Recurrent Graves Hyperthyroidism After 1-Year Treatment With
Antithyroid Drugs
GREAT SCORE
Items (Assessed Before GREAT Score
Starting Therapy) Range 0–6 Risk Class Recurrences
Age (yr) ≥40 0 Class I (score 0–1) 16%
<40 +1
Class II (score 2–3) 44%
FT4 (pmol/L) <40 0 Class III (score 4–6) 68%
≥40 +1
TBII (U/L) <6 0
6–19.9 +1
≥20 +2
Goiter sizea gr. 0–I 0
gr. II–III +2
GREAT+ SCORE
GREAT+ Score
Items Added Range 0–10 Risk Class Recurrences
PTPN22 C/C wild type 0 Class I+ (score 0–2) 4%
C/T +1
Class II+ (score 3–4) 21%
HLA nr.b 0 0
1–2 +2 Class III+ (score 5–6) 49%
3 (LD) +3 Class IV+ (score 7–10) 84%
aGoiter size: grade 0, thyroid not or distinctly palpable but usually not visible; grade I, thyroid easily palpable and visible with head in normal or raised position; grade II, thyroid easily visible with the head
in a normal position; grade III, goiter visible at a distance.
bNumber of HLA subtypes (DQB1-02, DQA1-05, DRB1-03) present.
FT4, Free thyroxine; HLA, human leukocyte antigen; LD, linkage disequilibrium; TBII, thyroid-stimulating hormone–binding inhibitory immunoglobulins.
Modified from Vos XG, Endert E, Zwinderman AH, et al. Predicting the risk of recurrence before the start of antithyroid drug therapy in patients with Graves’ hyperthyroidism. J Clin Endocrinol Metab.
2016;101:1381–1389.

rate is between 40% and 60%; it is not influenced very much by patients. Combining a number of independent risk factors led
dose or duration of ATD therapy. Most recurrences occur in the to a predictive score composed of age, FT4, TBII, and goiter
first year after stopping ATD. Exposure to stressful life events size (by inspection and palpation), called the GREAT score
and daily hassles after withdrawal of ATD increase the risk of (Graves Recurrent Events After Therapy) (Table 12.5).151 The
recurrent hyperthyroidism.104,148 It is recommended to check clinical relevance is that the GREAT score provides a reasonable
thyroid function annually to detect late recurrences or develop- prediction of recurrence risk after a course of ATDs based on
ment of hypothyroidism. Recurrences should be treated with just four items, readily available before the start of treatment
radioiodine or surgery. About one-third of patients experience (Fig. 12.5). It might allow for discussions with the patient of
a lasting remission. whether the treatment option of ATDs is optimal for them. If
Chances of remission increase if during ATD therapy goiter the recurrence risk is low, ATD might be a good choice; if the
size and/or TSHRAb decrease and TSH has become normal. It recurrence risk is rather high, surgery or radioiodine could be
has been recommended to measure TSHRAb just prior to stop- a better option. The GREAT score has been validated in an
ping ATD. If TSHRAb have disappeared, chances of remission are independent study.152 Adding the results of specific genotypes
high. If TSHRAb can still be detected, one may consider prolong- provides the GREAT score with even better prediction. It can
ing ATD therapy because chances of remission are low. A major be foreseen that such predictive scores will be of great value in
advantage of a more prolonged therapy is that nearly all patients personalized medicine.
remain euthyroid as long as therapy is given, even if the dose of
the drug is low. Other Drugs Used in Hyperthyroidism
Predicting who will experience relapsing hyperthyroidism Beta-Adrenoceptor Blocking Agents. Thyroid hormone excess
after stopping ATD has proven to be difficult. A change from increases sensitivity of the sympathetic nervous system to catechol-
stimulating to blocking TSHRAb might play a role, as well as amines. Drugs that block the response to catecholamines at the
many other factors.149 A systematic review and meta-analysis of receptor site (e.g., propranolol) ameliorate some of the manifesta-
7595 patients, of whom 48.7% relapsed, identified a significant tions of thyrotoxicosis and are often used as adjuncts in manage-
association with relapse of the following items, all assessed before ment. Beta blockers rapidly improve complaints of tremulousness,
starting treatment with ATD: smoking, thyroid size (either by palpitations, excessive sweating, and eyelid retraction. Beta block-
sonography or by inspection and palpation), orbitopathy, FT4, ers are recommended in all patients with symptomatic thyrotoxi-
FT3, and TBII.150 These risk factors by themselves, however, cosis, especially in elderly patients and patients with resting heart
have not sufficient power for accurate prediction in individual rates in excess of 90 beats per minute or coexistent cardiovascular
100
80
68% Class III
Recurrence rate (%)
60
44% Class II
40
20 16% Class I
A 0 6 12 18 24
100
84% Class IV+
80
Recurrence rate (%)
60
49% Class III+
40
21% Class II+

20
4% Class I+
0
B 0 6 12 18 24
Time of follow-up after withdrawal of antithyroid drugs (months)
• Fig. 12.5 Kaplan-Meier curves for recurrent Graves hyperthyroidism after a 1-year course of antithyroid
drugs according to risk classes I to III of the GREAT score (A) and risk classes I+ to IV+ of the GREAT+
score (B). (Redrawn from Vos XG, Endert E, Zwinderman AH, et al. Predicting the risk of recurrence before
the start of antithyroid drug therapy in patients with Graves’ hyperthyroidism. J Clin Endocrinol Metab.
2016;101:1381–1389.)
disease.124,134 Beta blockers are most useful in the interval before iodide (SSKI) or approximately 1 drop of Lugol solution; many
the response to thionamides or radioiodine therapy occurs. Pro- physicians, however, prescribe 5 to 10 drops of one of these
pranolol, in addition to its action as a β-adrenoreceptor antago- agents three times daily. Although it is advisable to administer
nist, also inhibits 5′-deiodination resulting in a decrease of plasma amounts larger than the suggested minimal effective dose, huge
T3 and an increase of plasma reverse T3.153 Plasma T3 decreases quantities of iodine are more likely to produce adverse reactions.
by 20% at a daily dose of 80 mg propranolol (four 20-mg doses) We recommend the use of a maximum 2 to 3 drops of SSKI
and by 30% at 160 mg propranolol (four 40-mg doses). Beta twice daily. Adverse reactions to iodine are unusual and in general
blockers without membrane-stabilizing activity do not decrease not serious. They include rash, which may be acneiform; drug
plasma T3, but the clinical response to β-blockers is independent fever; sialadenitis; conjunctivitis and rhinitis; vasculitis; and a leu-
of the decrease in T3. The largest experience is with propranolol, kemoid eosinophilic granulocytosis. Sialadenitis may respond to
but the drug can be contraindicated (e.g., in asthma and chronic reduction of dosage and the addition of lemon/lime candies to
obstructive pulmonary disease). Longer acting drugs with relative increase salivary flow; in the case of the other reactions, iodine
β1 selectivity might then be preferred, such as atenolol (25–100 should be stopped.
mg once or twice daily) and metoprolol (25–50 mg twice or three Lithium. Lithium carbonate inhibits thyroid hormone secre-
times daily).124 tion, but unlike iodine it does not interfere with the accumu-
Perchlorate. Perchlorate inhibits thyroid iodide transport lation of radioiodine. Lithium, 300 to 450 mg every 8 hours,
and has been used in the past to treat Graves hyperthyroidism. is used only to provide temporary control of thyrotoxicosis in
Although it was effective in restoring euthyroidism and decreasing patients who are allergic to both thionamides and iodide.159
TSHRAb, it is no longer used in view of its side effects (except in Another short-term use for lithium has been as an adjunct to
amiodarone-induced thyrotoxicosis type 1).154,155 radioiodine therapy because the drug slows the release of iodine
Iodine. Iodine is now rarely used as a sole therapy. The mecha- from the thyroid.160
nism of action of iodine in relieving thyrotoxicosis differs from Selenium. Selenium levels were higher in patients in remission
that of the thionamides. Although quantities of iodine in excess and correlated inversely to TSHRAb.161 Therefore it was hypoth-
of several milligrams can acutely inhibit organic binding (acute esized that selenium supplementation might increase remission
Wolff-Chaikoff effect), this transient phenomenon probably does rate. Addition of 300 μg sodium selenite daily to methimazole
not contribute to the therapeutic effect. Instead, the major action did not, however, increase remission rate in a placebo-controlled
of iodine is to inhibit hormone release. Administration of iodine trial.162
increases glandular stores of organic iodine, but the beneficial Cholecystographic Agents. The oral iodine-containing cho-
effect of iodine is evident more quickly than the effects of even lecystographic contrast agent sodium ipodate causes a prompt
large doses of agents that inhibit hormone synthesis. In patients decrease in serum T4 and serum T3 in Graves hyperthyroidism.
with Graves disease, iodine acutely retards the rate of secretion After a course of 500 mg sodium ipodate daily for 5 days, plasma
of T4, an effect that is rapidly lost when iodine is withdrawn. T3 is normalized in all patients, allowing uneventful thyroidec-
These features of iodine action provide both disadvantages and tomy on day 5.163 However, supplies of such agents are generally
advantages. The enrichment of glandular organic iodine stores no longer available.
that occurs when this agent is given alone may retard the clini- Cholestyramine. Thyroxine is metabolized in the liver to gluc-
cal response to subsequently administered thionamides, and the uronides and sulfates that enter the enterohepatic circulation.
decrease in RAIU produced by iodine prevents the use of radio- Cholestyramine interferes with the enterohepatic cycle, thereby
iodine as treatment for several weeks. Furthermore, if iodine is acting as an effective and well-tolerated adjunctive therapy in
withdrawn, resumption of accelerated release of hormone from patients with resistant Graves hyperthyroidism.164,165 It can pro-
an enriched glandular hormone pool may exacerbate the disorder. duce a rapid and complete decline in thyroid hormone levels.
Another reason for not using iodine alone is that the therapeu- Immunosuppressive Drugs. Because of the autoimmune
tic response on occasion is either incomplete or absent. Even if nature of Graves disease, additional use of immunosuppressive
initially effective, iodine treatment may lose its effect with time. agents might improve outcomes. A systematic review identi-
This phenomenon, termed iodine escape, should not be confused fied seven randomized or controlled trials in which the effect of
with the escape from the acute Wolff-Chaikoff effect.156 Never- addition of glucocorticoids or rituximab to standard treatment
theless, the rapid slowing of hormone release by iodine makes was compared to standard treatment alone.166 Relapse rate was
it more effective than the thionamide drugs when prompt relief much lower in the intervention group with immunosuppressive
of thyrotoxicosis is mandatory. Therefore, aside from its use in drugs (24%) than in the control group (59%), with a risk ratio
preparation for thyroid surgery, iodine is useful mainly in patients of 0.55 (CI 0.41–0.75, p < 0.001). However, the study has several
with actual or impending thyrotoxic crisis, severe thyrocardiac limitations, such as small sample sizes and moderate to high risk
disease, or acute surgical emergencies. If iodine is used in these of bias.
circumstances, it should be administered with large doses of a Future Developments. It is foreseen that novel treatment
thionamide. modalities for Graves hyperthyroidism will become available in the
Recent studies suggest a potential role for iodine in patients next decade. There may be causal therapies directed against stimu-
who have adverse reactions to ATD or contraindications for radio- lating TSHRAb, the immediate cause of Graves disease. Examples
iodine or surgery.157,158 Sometimes iodine is used as a beneficial are antigen-specific immunotherapy with tolerogenic peptides of
adjunct to ATD: 38 mg potassium iodide (KI) + 15 mg MMI the TSH receptor, monoclonal TSH receptor–blocking antibod-
resulted in better control of hyperthyroidism and fewer adverse ies, and low-molecular-weight TSH receptor antagonists.167,168
reactions than 30 mg MMI alone.158 Thyroidectomy. Thyroidectomy has a high cure rate for Graves
The lowest dose of iodine required for control of thyrotoxi- hyperthyroidism. Total thyroidectomy has a nearly 0% risk of
cosis is approximately 6 mg daily. Six milligrams of iodine are recurrence, whereas subtotal thyroidectomy may have an 8%
present in one-eighth of a drop of saturated solution of potassium chance of persistent or recurrent hyperthyroidism at 5 years.124,134
Near-total or total thyroidectomy is therefore the procedure of solution is used by less than 40% of thyroidologists in Europe.172
choice. It is recommended to refer the patient to a high-volume In exceptional circumstances, when it is not possible to render a
thyroid surgeon. Average complication rates, length of hospital patient euthyroid prior to thyroidectomy, the patient should be
stay, and cost are reduced when the operation is performed by adequately treated with KI and β-blockers (eventually also with
a surgeon who conducts many thyroidectomies. Surgeons who glucocorticoids and cholestyramine) in the immediate preopera-
perform more than 25 thyroid surgeries per year have superior tive period.134 Lastly, checking for calcium and 25-hydroxy vita-
outcomes compared to surgeons who perform fewer.169 Compli- min D preoperatively is recommended. Preoperative vitamin D
cation rates are on average 51% higher when surgery is performed deficiency is a risk factor for postoperative hypocalcemia. Supple-
by low-volume surgeons.134 menting calcitriol for a brief period preoperatively helps to reduce
Complications. In the hands of high-volume thyroid surgeons postoperative hypocalcemia.124,134
the rate of permanent hypoparathyroidism is less than 2% and After thyroidectomy, ATDs are stopped immediately and
that of permanent recurrent laryngeal nerve injury is less than 1%. β-blockers should be weaned. Serum calcium with or without
Bleeding into the operative site necessitating reoperation occurs parathyroid hormone (PTH) levels can be measured and oral
in 0.3% to 0.7%; it is the most serious postoperative complica- calcium and calcitriol supplementation be given based on these
tion, which can rapidly produce death by asphyxia and requires results; alternatively, prophylactic calcium with or without cal-
immediate evacuation of the blood and ligation of the bleeding citriol is prescribed empirically. l-Thyroxine should be started at
vessel. Even with subtotal surgery, the recurrent laryngeal nerve a daily dose appropriate for the patient’s weight (1.6 μg/kg) and
can be damaged. If such damage is unilateral, it causes dysphonia serum TSH measured 6 weeks postoperatively.134
that usually improves in a few weeks but may leave the patient
slightly hoarse. Intraoperative recurrent laryngeal nerve moni- Radioactive Iodine
toring does not necessarily improve long-term outcomes. Hypo- Radioactive iodine (RAI) has been used since 1941. Prospective
parathyroidism can be either transient or permanent. Transient trials in this area are few, leaving many questions.173 The cellular
hypoparathyroidism results from inadvertent removal of some effect of the ionizing radiation leads to cell death and thereby to a
parathyroids and/or impairment of blood supply to those that decrease in thyroid function and a reduction in thyroid size. One
remain. Depending on the severity of these insults, symptoms year after 131I therapy, thyroid size is mostly normalized, hyper-
and signs of hypocalcemia appear, usually within 1 to 7 days after thyroidism has disappeared in 50% to 90% of patients, and hypo-
surgery. Severe hypoparathyroidism should be treated with intra- thyroidism has developed in up to 50% of patients directly related
venous calcium gluconate. Milder cases can be treated with oral to the thyroid RAI dose.173 This is followed by a yearly hypothy-
calcium carbonate and cholecalciferol, although the active form of roidism rate of 3% to 5%, largely independent of RAI dose.124 A
vitamin D (calcitriol) is more effective and preferred in most cases. seminal question thus arises: What is the goal of 131I therapy in
However, the hypocalcemia that occurs immediately after surgery Graves hyperthyroidism? Is it to get rid of hyperthyroidism and
for thyrotoxicosis may not be due to transient hypoparathyroid- restore euthyroidism? That has proven to be an elusive goal, as even
ism because it occurs more frequently in the Graves patient than meticulous calculation of a seemingly appropriate 131I dose does
after surgery for other thyroid disorders. Instead it may be due not prevent a high incidence of post-radioiodine hypothyroidism.
to “hungry bones” because of the demineralization of bone that The ATA therefore recommends the following: “Sufficient activ-
occurs in hyperthyroidism. This begins to be reversed after cure of ity of RAI should be administered in a single application, typi-
the hyperthyroid state and may contribute to the modest elevation cally a mean dose of 10–15 mCi (370–555 MBq), to render the
in alkaline phosphatase during recovery unless the patients have patient with Graves disease hypothyroid.”134 It means that cure
been rendered euthyroid for some time prior to surgery. Many of one disease (hyperthyroidism) is exchanged for the creation
surgeons who fear that they have caused damage to the parathy- of another disease (hypothyroidism). ETA guidelines agree: “No
roid glands at total thyroidectomy may reimplant the apparent dose calculation can secure long-term euthyroidism and it is fully
parathyroid tissue into local muscles. acceptable to offer a fixed dose of RAI.”124 Therefore many have
Preparation for Surgery. If surgery is chosen, patients should given up meticulous dose calculation and offer fixed activities of,
be rendered euthyroid prior to the procedure with ATD pretreat- for example, 185, 370, or 555 MBq, depending on thyroid size.
ment, with or without β-adrenergic blockade. These agents do An increased mortality rate has been reported in hyperthyroid
not improve the hyperplasia and hypervascularity of the gland in patients treated with RAI.174 This was not observed in patients
the short term. Iodine, however, is reported to cause a decrease rendered hypothyroid, and these findings support the practice of
in height of the follicular cells, enlargement of follicles with treating hyperthyroidism with doses of radioiodine sufficient to
retention of colloid, and reduction of hypervascularity. Hence induce overt hypothyroidism.
the recommendation to give a KI-containing preparation in the There has been concern that RAI therapy might produce can-
immediate preoperative period should be made.124,134 SSKI 2 to 3 cer. A hypothetical 0.8% lifetime cancer risk attributable to a
drops twice daily might be initiated 7 to 10 days before surgery to 15-mCi 131I dose at the age of 20 years has been calculated. This
decrease thyroid blood flow and vascularity and hence intraopera- is only a small increase in baseline cancer risk, and most studies
tive blood loss during thyroidectomy. During this period a preex- have found no significant increase in the prevalence of thyroid
isting bruit or thrill may decrease in intensity or disappear entirely, cancer or secondary malignancies in adult patients treated with
and the gland may become firm. However, little clinical evidence RAI. Also the frequency of genetic damage in the offspring of
exists that postoperative outcomes are any different following a patients treated earlier with radioiodine does not appear to be
course of iodine.170 A recent prospective controlled trial observed increased. In view of the lack of evidence of serious toxicity from
that preoperative use of KI decreased gland vascularity but not RAI in doses generally used for treating adults with hyperthyroid-
the overall difficulty of thyroidectomy; however, KI was associated ism, the age limit for the use of RAI has been lowered progres-
with less transient hypoparathyroidism and transient hoarseness, sively from the initial lower limit of 40 years to age 10 or younger.
suggesting KI improves the safety of thyroidectomy.171 KI or Lugol However, in a 5-year-old child the theoretical lifetime cancer risk
70 TABLE 12.6 Advantages and Disadvantages

s-TRAb (% inhibition of 125-I TSH binding)
60
of Treatment Options for Graves
Hyperthyroidism
50 Treatment Option Advantages Disadvantages
40 Antithyroid drugs Chance of permanent Side effects of ATDs
remission (∼35%) Long duration (12–18
30 months)
Radioiodine
High recurrence risk
20 Surgery
Radioactive iodine Simplicity Risk of orbitopathy
10 Low recurrence risk Lifelong LT4 needed
Medication Possible small increase
0 in cancer risk
0 1 2 3 4 5 Thyroidectomy Rapidity Low but unavoidable
Years Almost no morbidity
recurrences Lifelong LT4 needed
• Fig. 12.6 Course of TSH receptor antibodies after treatment of Graves
hyperthyroidism with antithyroid drugs, thyroidectomy, or radioactive ATDs, Antithyroid drugs; LT4, l-thyroxine.
iodine. (Redrawn from Leimberg P, Wallen G, Tallstedt L, et al. TSH-
receptor autoimmunity in Graves’ disease after therapy with anti-thyroid
drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur
J Endocrinol. 2008;158:69–75.)
should be paused around 1 week before and after 131I therapy to
avoid decreasing RAI efficacy.124,134 A pregnancy test should be
after 15 mCi 131I is 4%, so in very young children ATDs should obtained within 48 hours prior to RAI treatment in any woman
be considered. The use of RAI in reproductive-age women also with childbearing potential. Pregnancy and breastfeeding consti-
remains unpopular, and RAI is contraindicated during pregnancy. tute absolute contraindications to RAI therapy.
Fetuses exposed to 131I after 10 weeks of gestation may be born The physician administering RAI should provide written
athyreotic. In addition, 131I should not be administered for at advice concerning radiation safety precautions following treat-
least 8 weeks after cessation of lactation because it is concentrated ment.124,134 National differences in radiation regulations have
in breast milk. considerable impact on the way RAI therapy is given in different
Complications of RAI Therapy. The early induction of euthy- countries (e.g., in the criteria for hospitalization). Attempts have
roidism and later the development of hypothyroidism are both been made to standardize the radiation delivered to the thyroid
consequences of radiation-induced destruction of thyroid paren- gland by varying the dose of radioiodine according to the size of
chyma. With large doses of RAI a tender radiation thyroiditis may the gland, the uptake of 131I, and its subsequent rate of release
develop within the first week of treatment, as evidenced by epi- (dosimetry). However, no data support an advantage of dosimetry
thelial swelling and necrosis, disruption of follicular architecture, over a fixed-dose regimen. Most clinics have redefined the goal
edema, and infiltration with mononuclear cells. Resolution of the of RAI therapy from making patients euthyroid to ablating the
acute phase is followed by fibrosis, vascular narrowing, and fur- thyroid with a permanent need for thyroid hormone replacement.
ther lymphocytic infiltration. Radiation thyroiditis may lead to an A dose of 20 mCi alleviates hyperthyroidism in almost all patients
exacerbation of thyrotoxicosis 10 to 14 days after RAI is admin- and results in approximately 90% hypothyroidism.
istered. The effect of RAI on other tissues that concentrate iodide After RAI therapy, patients are seen at intervals of 4 to 6 weeks
(e.g., the salivary glands, the gastric glands, and the breasts) is not for 6 months, and FT4 and TSH levels are monitored. However,
likely to be a problem with the relatively low doses prescribed for TSH is not a reliable guide as to when to begin levothyroxine
Graves hyperthyroidism. replacement therapy, as it can remain suppressed for a consid-
RAI therapy is associated with development or worsening of erable period of time even after the FT4 falls below normal. To
Graves orbitopathy in about 15% of cases compared to ATDs avoid overt hypothyroidism, levothyroxine replacement therapy
or thyroidectomy, as evident from three randomized clinical may be initiated when the FT4 reaches the lower portion of the
trials.175–177 This effect is presumably related to the substan- reference range. The starting dose should be relatively low to avoid
tial increase in serum TSHRAb after RAI therapy, whereas in overtreatment given that the residual thyroid function will not
contrast TSHRAb decrease after thyroidectomy or upon treat- be subject to feedback regulation. When hyperthyroidism persists
ment with ATD.80 Five years later the level of TSHRAb is still after 6 months, retreatment with RAI is suggested, generally with
higher after RAI than after ATD or surgery (Fig. 12.6). Thus the about 1.5 times the initial dose of 131I. Conception should be
presence of Graves orbitopathy may influence which treatment postponed until at least 6 months after RAI therapy, both in males
modality is chosen for hyperthyroidism (see section on Graves and females.124
orbitopathy).
Preparation for 131I Therapy. Because 131I therapy can cause a Choice of Therapy
transient exacerbation of hyperthyroidism, β-blockers should be Advantages and disadvantages of each of the three treatment modal-
considered even in asymptomatic patients who are at increased ities are listed in Table 12.6. Weighing the pros and cons of each
risk for complications due to worsening of hyperthyroidism (i.e., treatment by patients varies greatly. Clinical conditions leading to
elderly patients and patients with comorbidities). In addition to a preferred therapy are summarized in Table 12.7. Patients with
β-adrenergic blockade, pretreatment with MMI should also be high likelihood of remission are ideal candidates for ATD therapy;
considered in patients at increased risk for complications. ATD application of the GREAT score might identify such patients.151
TABLE 12.7 Clinical Conditions That Favor a Graves’ disease:

Treatment choice by year
Particular Treatment Modality for
80
Graves Hyperthyroidism Thionamides
Condition ATD RAI Surgery 70 Radioiodine
Percentage of patients treated (%)

High chance of remission + Surgery
60
Active Graves orbitopathy +
50
Elderly with comorbidities + +
Increased surgical risk + + 40
Liver disease + 30
Major adverse reactions ATD +
20
Hypokalemic periodic paralysis +
10
Pulmonary hypertension or +
congestive heart failure
0
Previous neck surgery or irradiation + 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Recurrent hyperthyroidism + + • Fig. 12.7 Antithyroid
drugs have become the most common treatment
modality for Graves hyperthyroidism in the last decade in the United
Malignancy suspected + States. (Redrawn from Brito JP, Schilz S, Singh Ospina N, et al. Antithyroid
Large thyroid nodules + drugs—the most common treatment for Graves’ disease in the United
States: a nationwide population-based study. Thyroid. 2016;26:1144–
Coexistent hyperparathyroidism + 1145.)
ATD, Antithyroid drug; RAI, radioactive iodine

Modified from Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association
guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxi- surgery in 2%.172 In contrast, the first-line treatment in North
cosis. Thyroid. 2016;26:1343–1421. America had been RAI in the vast majority of cases in the 20th
century. Recently this has changed dramatically; as of 2014, ATD
also is the preferred treatment option in the United States, fol-
lowed by RAI and then surgery179 (Fig. 12.7).
ATD might also be preferred in patients with active Graves orbi-
topathy. Contraindications are major adverse reactions to ATD. Graves Orbitopathy
RAI therapy is preferred in patients with contraindications for
ATD or surgery, in case of recurrences after ATD, and in patients Graves orbitopathy is also known as Graves ophthalmopathy,
with hypokalemic periodic paralysis, pulmonary hypertension, or thyroid-associated ophthalmopathy (TAO), and thyroid eye
congestive heart failure. Contraindications for RAI are pregnancy disease (TED). It is one of the phenotypes of Graves disease.
or planning pregnancy within 6 months, lactation, and suspicion Graves hyperthyroidism is present in about 90% of GO patients,
of thyroid cancer. Thyroidectomy might be preferred in women whereas 5% to 10% of GO patients are euthyroid or hypothyroid
planning pregnancy within 6 months, in large or compressive goi- (Fig. 12.8).180
ters (>80 g), when thyroid malignancy is suspected, and in case
of coexisting hyperparathyroidism. Thyroidectomy is best avoided
in the first and third trimesters of pregnancy and in patients with
Clinical Presentation
increased surgical risk and substantial comorbidity. Long-term Most patients initially notice a change in appearance. There is
follow-up of patients randomized to receive one of the three treat- redness in the eyes or lids and swelling or feeling of fullness in
ment options did not disclose differences in perceived quality-of- the upper eyelids and/or bags under the eyes.181 The most com-
life between treatments.178 mon presenting sign is eyelid swelling, followed by eyelid lagging
The choice of the most appropriate treatment in a particular behind eyeball movement on downgaze (von Graefe sign). Early
patient thus depends on a multitude of factors, including per- symptoms are a gritty sensation in the eyes, light sensitivity (pho-
sonal ones such as emotional attitudes, economic considerations, tophobia), and excess tearing. With ongoing disease, upper eyelid
and family issues. It is obvious that a satisfactory choice can only retraction occurs in most patients. Exophthalmos (also referred to
be made in close consultation with the patient. One approach is as proptosis) develops in about 60% of patients. These patients are
to start with ATD in all patients. This would be useful also in more likely to show incomplete eyelid closure (lagophthalmos);
patients who opt later for RAI or surgery. The patient will become many such patients, especially those with a wide palpebral fis-
euthyroid in 4 to 6 weeks, and this period can be used to discuss sure, will show punctate inferior corneal staining with fluorescein.
with the patient what the optimal treatment option would be. Patients may complain about retrobulbar pressure and blurred
This approach allows the establishment of a workable physician- vision. Extraocular muscle involvement may result in aberrant
patient relationship, which is especially important in addressing position of the globe or, in extreme cases, fixation of the globe.
anxieties about the use of radioiodine. More common is limitation of eye muscle movements in cer-
First-line treatment of uncomplicated Graves hyperthyroid- tain directions of gaze, especially in upward gaze. This may cause
ism in Europe is with ATD in 84%, with RAI in 14%, and with diplopia (double vision), occurring in about 50% of patients.
A B
• Fig. 12.8 Patient with Graves orbitopathy. Note the typical bilateral rather symmetrical eye disease with
periorbital swelling, stare, and exophthalmos (A), subsequently corrected by orbital decompression sur-
gery (B). (Courtesy Dr. Jack Rootman, University of British Columbia, Vancouver, BC, Canada.)
Diplopia will not occur if the vision of one eye is very low (such hyperthyroidism.61,185 When Graves hyperthyroidism is diag-
as in amblyopia) or if the impairment of muscle motility is strictly nosed, 74% have no GO, but 13% in this group will develop
symmetrical. Impairment of elevation and of abduction are most GO (mild in 10% and moderate to severe in 3%) during subse-
common, related to swollen inferior and medial rectus muscles, quent ATD therapy (Fig. 12.9). Mild GO at the time of diagnos-
respectively, whereas impairment of depression and adduction are ing hyperthyroidism disappears spontaneously in 58% of these
less frequent. Corneal ulceration nowadays is rare. It develops only cases.61 Thus GO is diagnosed at the same time as Graves hyper-
when normal corneal protection is lost.181 This may happen in thyroidism in about 75% of GO patients, whereas GO is diag-
patients with lagophthalmos in whom the cornea remains visible nosed later in about 25%.186 In a few patients GO onset is before
when the eyelids are closed. Sight loss due to optic nerve involve- that of Graves hyperthyroidism.
ment (referred to as dysthyroid optic neuropathy [DON]) occurs There seems to be a secular trend to a lower incidence of
in about 5%. Patients with DON may complain about decrease of GO.187 Earlier diagnosis and treatment of hyperthyroidism, iden-
visual acuity, loss of color vision, visual field defects, and blurred tification of risks conferred by 131I therapy and postradioiodine
vision.182 Visual blurring may disappear after blinking (caused by hypothyroidism, and focus on the detrimental effects of smoking
alteration of the tear film on the surface of the cornea due to lacri- have likely contributed to this decline.183,186
mation or dry eyes) or after closing one eye (caused by eye muscle
imbalance). Visual blurring that persists is of concern as it may Pathology
indicate DON.
The average age of presentation is 49 years, a few years after the The pathologic anatomy of GO orbits is characterized by enlarge-
average age of presenting with Graves hyperthyroidism. Female ment of the extraocular muscles and the retrobulbar fat/connec-
preponderance is obvious, but GO is more severe in males and tive tissue compartment. The increased volumes of muscles and
the elderly. GO is a typical bilateral and rather symmetrical eye fat are attributed to an increase of the ground substance consisting
disease. Unilateral GO, however, occurs in about 10% of all GO of collagen and glycosaminoglycans (GAGs). GAGs (mainly hyal-
patients. There is good evidence that the GO presentation is uronate) are very hydrophilic and thus attract much water, result-
changing. Upon referral, GO patients in 2012 had less severe and ing in edematous swelling. The ground substance accumulates in
less active disease than in 2000.183 the endomysial space between muscle fibers. The number of mus-
cle fibers is not increased, and there is no damage to the muscle
cells except in very advanced cases. The number of fibroblasts is
Epidemiology increased in the endomysial space and in the fat/connective tissue
In the general Swedish population the incidence rate of Graves compartment. The orbital fibroblasts (OFs) are responsible for the
hyperthyroidism is 210 per million per year, and the incidence excessive production of GAGs. A subset of OFs may differentiate
rate of GO is 42 per million per year.184 It means 20% of patients into mature adipocytes thereby adding to the volume expansion.
with Graves hyperthyroidism also develop GO, which is mild in OFs have been recognized as the target of the autoimmune attack
15% and more severe in 5%. The data are in good agreement in GO.
with studies from Denmark and Italy, reporting that moderate- The increased muscle and fat volumes within the confined
to-severe GO occurs in about 5% of all patients with Graves space of the bony orbit allow a mechanistic explanation of the
100 No GO at baseline (n = 194)
80
Percent of Patients
60
40
20
100 Prevalence of GO 0
Absent Mild Moderate-
to-severe
80
B GO after 18 months
Percent of Patients
60 87% 10% 3%
40
100 Mild GO at baseline (n = 43)
20
80
Percent of Patients
0
Absent Mild Moderate- Sight-
A to-severe threatening 60
74% 20% 5.8% 0.3%

40
20
0
Absent Mild Moderate-
to-severe
C GO after 18 months
58% 40% 2%
• Fig. 12.9 (A) Prevalence of Graves orbitopathy (GO) in patients with newly diagnosed Graves hyperthy-
roidism and during subsequent treatment with antithyroid drugs in those with initially absent GO (B) or mild
GO (C). (Modified from Tanda ML, Piantanida E, Liparulo L, et al. Prevalence of natural history of Graves’
orbitopathy in a large series of patients with newly diagnosed Graves’ hyperthyroidism seen in a single
center. J Clin Endocrinol Metab. 2013;98:1443–1449.)
eye changes. The swollen retrobulbar tissues will impair venous (known as apical crowding), close to the entrance of the optic
drainage of eyelids and conjunctiva, resulting in eyelid edema nerve in the optic canal, may compress the optic nerve, resulting
and chemosis. Eyelid swelling can also be caused by herniation of in DON.
retrobulbar fat through openings in the orbital septum. Increased
retrobulbar pressure will push the globe forward, resulting in
Immunopathogenesis
exophthalmos. Upper eyelid retraction and proptosis contrib-
ute to overexposure of the cornea, which may become dry and Microscopy reveals orbital lymphocytic infiltration, edema, and
inflamed. The enlargement of extraocular muscles impairs muscle fibrosis. The lymphocytic infiltration is often focal and consists of T
relaxation, not the ability for muscle contraction. For instance, helper cells, cytotoxic T cells, many macrophages, and a few B cells.
impairment of elevation is caused by insufficient relaxation of the The infiltrating immunocompetent cells produce cytokines capable
rectus inferior muscle, which may cause diplopia when gazing of remodeling orbital tissues. The cytokine profile in the early stages of
up. Marked swelling of rectus muscles in the apex of the orbit GO is predominantly that of Th1 cells, whereas cytokines are mostly
TSH receptor
antibodies
TSH receptor IGF-1
Gαs
Gαq IGF-1
Orbital fibroblast PLC

AC IGF 1 receptor
P13K IRS-1/2
cAMP
mTOR
Akt
Hyaluronic acid (HA)

Adipogenesis synthesis
HA
Orbital adipocytes
Expanded orbital muscles

and adipose tissue
• Fig. 12.10 Role of the thyroid-stimulating hormone (TSH) receptor in the immunopathogenesis of Graves
orbitopathy. Ligation of the TSH receptor on orbital fibroblasts with stimulating TSH receptor antibodies results
in activation of the adenylyl/cyclic adenosine monophosphate (cAMP) pathway and the phosphoinositide
3-kinase (PI3K)/Akt signaling cascade. It induces hyaluronic acid production by the orbital fibroblasts, with a
subset exhibiting enhanced adipogenesis. (From Iyer S, Bahn RS. Immunopathogenesis of Graves’ ophthal-
mopathy: the role of the TSH receptor. Best Pract Res Clin Endocrinol Metab. 2012;26:281–289.)
derived from Th2 cells in patients with a duration of GO for more and both activity and severity of GO.191 Genetic immunization
than 2 years.188 The data suggest GO is primarily a T-cell–mediated against the TSH receptor (but not against the IGF1 receptor) also
disease. The cytokines induce expression of immunomodulatory pro- gives rise to a fair although not perfect animal model of GO.192,193
teins on endothelial cells and fibroblasts, including HLA-DR, heat The IGF1 receptor (IGF1R) has been proposed as another
shock protein 72, and several adhesion molecules. Cytokine-activated major autoantigen in GO. IGF1Rs are indeed overexpressed in
OF synthesize IL16 and RANTES (regulated on activation, normal OF of GO patients. Graves IgG can induce hyaluronan produc-
T cell expressed and secreted, also known as CCL5) attracting more tion in OF, effects that can be attenuated by IGF1R-blocking anti-
T cells to the orbit. Macrophages present antigen to T cells; activated body.194 Stimulating IGF1R autoantibodies (IGF1RAb) thus have
T cells may bind to OF, inducing hyaluronan synthesis, cytokines, been postulated and have been found in 10% of GO samples and
COX2, and PGE2. OF are considered the target (and effector) cells in 10% of control samples; however, the IGF1RAb failed to stim-
of the autoimmune attack in GO. Retrobulbar T cells of GO patients ulate IGF1R autophosphorylation but instead inhibited IGF1-
recognize autologous OF (but not eye muscle extract) and proliferate induced signaling.195 These data do not support the hypothesis
in response to proteins from autologous OF (but not from orbital that IGF1RAb contribute to GO pathogenesis. Immunoglobulins
myoblasts); conversely, OF proliferate in response to autologous T of GO patients stimulate Akt in OF as well as in cells expressing
cells dependent on MHC class II and CD40/CD40L signaling.189 TSHR and IGF1R; knockdown of IGF1R causes a 65% decrease
The TSH receptor is presently viewed as the major autoanti- in IGF1-stimulated Akt but has no effect on GO-Ig stimulation
gen in GO. OF express full-length functional TSH receptors; the of Akt.196 GO immunoglobulins thus do not activate the IGF1R,
expression is more abundant in active than in inactive GO and is and there is no evidence of stimulating IGF1R antibodies (Fig.
directly related to IL1β levels.190 Graves immunoglobulins as well as 12.10).197 The implication is that TSHRAb stimulate Akt via
monoclonal TSHR-stimulating antibodies recognize TSHR on OF the PI3K pathway. The therapeutic effect of teprotumumab, an
as evident from increased cAMP and hyaluronan production in cell IGF1R-blocking monoclonal antibody, in GO thus could be
cultures of OF exposed to these agents. OF not expressing THY1 explained at least in part by decreasing Akt, thereby also impairing
(present in orbital fat but not in extraocular muscles) may under the effects of TSHR signaling via the PI3K pathway.198
the influence of IL1 or PPARγ agonists differentiate into mature Whereas postreceptor signaling pathways of TSHR and IGF1R
adipocytes, associated with increased TSHR expression. The role of partly overlap, it has further been suggested that TSHR and
TSHR is underscored by a direct relationship between TSHRAb IGF1R form a physical and functional complex in OF199,200 and
that GO immunoglobulins exert their action via TSHR/IGF1R 100

crosstalk rather than direct binding to IGF1R.201 A subset of OF
75 Immunosuppression
are CD34+, and they might be derived from circulating CD34+
fibrocytes, which unexpectedly express relatively high levels of % 50
TSH receptors.202 The relevance of these findings is subject of
active research. 25
0
Genetics and Environment A Time
No differences are found in the frequency of known susceptibil- 100

ity genes for Graves disease between patients with Graves hyper-
thyroidism and Graves orbitopathy. The genetic makeup in both 75 Immunosuppression
phenotypes seems largely the same.203 Smoking is a risk factor for
% 50
GO, as in Graves hyperthyroidism, but the odds ratio is much
higher (OR 4.40, CI 2.88–6.73).101 The risk is dose dependent 25
and decreases in ex-smokers. Exposure of OF in vitro to cigarette
smoke extract dose-dependently increases hyaluronan production 0
B Time
and adipogenesis.204
Exposure to ionizing radiation in the form of RAI therapy
is associated with a relative risk for progression of GO of 4.23 red = severity blue = activity
(CI 2.04–8.77) when compared to ATD.205 The immediate and
substantial rise of TSHRAb after 131I therapy might be causally • Fig. 12.11 Natural history of Graves orbitopathy, as reflected by a curve
describing disease severity (red continuous line) and a curve describ-
connected to the worsening of GO.80 Risk factors for develop-
ing disease activity (blue discontinuous line) over time. Intervention with
ing GO in Graves hyperthyroidism were evaluated in a large immunosuppressive agents at peak activity is likely to result in modi-
longitudinal cohort study from Australia.206 The odds of GO fication of the natural course (gain reflected by the red stippled area)
increased by 17% for each decade increase in the age of onset (A), whereas late intervention when the disease has become inactive, is
of Graves hyperthyroidism and by 7% for each year increase unlikely to modify the natural course (B). (Modified from Wiersinga WM.
in the duration of Graves hyperthyroidism. Smoking increased Advances in medical therapy of thyroid-associated ophthalmopathy.
the odds for GO to 2.22 for current smokers and 2.07 for ex- Orbit. 1996;15:177–186.)
smokers compared with never smokers. The odds for GO were
86% less in patients using ATD than those not (OR 0.14, CI
0.06–0.34). Risk factors for the development of GO in Graves
hyperthyroid patients treated for 18 months with ATD were stage of the disease characterized by fibrosis, with immunosup-
current smoking, mild conjunctival redness or mild eyelid swell- pression less likely to be effective. The time interval between onset
ing, duration of hyperthyroid symptoms, and TBII.186 These of GO and reaching the late inactive stage of the disease varies
items, assessed before starting ATD, can be combined in a quan- considerably between patients, from several months to several
titative manner in a predictive score (called PREDIGO), which years. Assessment of GO activity may thus influence the treat-
is better in predicting those patients who will not develop GO ment plan. The prognosis of GO has improved substantially in
than who will. Another longitudinal study used a large data- the last few decades, thanks to earlier diagnosis and treatment,
base of a US managed care network.207 Of Graves hyperthyroid more attention to risk factors, and better organization of care.
patients, 8.8% developed GO; surgical thyroidectomy alone or Nowadays it is the rare patient who becomes blind as a result of
in combination with medical therapy was associated with a 74% GO. But the sequelae of GO are substantial: 45% of patients are
decreased hazard for GO (HR 0.26, CI 0.12–0.51) compared restricted in their daily activities, 36% are on sick leave, 28% are
with RAI therapy alone.207 Statin use also decreased the risk disabled, 5% went into early retirement, and 3% lost their jobs,
of GO (HR 0.60, CI 0.37–0.93), an unexpected and hard-to- all because of GO.211
understand finding.
Diagnosis and Differential Diagnosis
Natural History and Prognosis Diagnosis of GO can be very easy in the case of a bilateral sym-
GO has a tendency to spontaneous improvement. Early studies metric ophthalmopathy in a patient with Graves hyperthyroidism.
from Rundle in the 1940s and 1950s about the natural history Diagnosis can be difficult in euthyroid or hypothyroid patients
of GO describe the initial development of upper eyelid retrac- presenting with eye changes; in euthyroid or hypothyroid GO
tion, exophthalmos, and restricted eye muscle motility, followed patients, GO is milder and more often asymmetric.180 Unilateral
by spontaneous but incomplete recovery.208 Thus in about 60% GO occurs in about 10% of all GO patients, whereas GO is the
of patients some eye changes persist. In GO patients who did most prevalent cause of unilateral exophthalmos. Schematically,
not require immediate treatment, a 1-year follow-up revealed GO is diagnosed along three avenues: ocular symptoms and signs,
substantial improvement in 22%, slight improvement in 42%, thyroid autoimmunity, and orbital imaging.
no change in 22%, and worsening in 14%.209 The available data
suggest there is initially an active stage of the disease character- Ocular Symptoms and Signs
ized by inflammatory edema and lymphocytic infiltration; immu- It should be realized that none of the symptoms and signs is spe-
nosuppression given in this stage is likely to improve GO (Fig. cific for GO. Guidelines recommend to assess severity and activity
12.11).210 The early active stage is followed by a late inactive of the disease in every patient.134,212 GO severity is assessed using
TABLE 12.8 Clinical Assessment of the Patient With

Graves Orbitopathy
SEVERITY MEASURES (USING THE MNEMONIC NO SPECS)
NO SPECS Class Item Method
0. No signs or symp-
toms
1. Only signs, no Lid aperture With ruler in midline
symptoms in mm
2. Soft tissue Eyelid and Inspection, color
A B
involvement conjunctiva picturesa • Fig. 12.12 Axial
(A) and coronal (B) CT scans of a patient with Graves
swelling and orbitopathy demonstrating generalized enlargement of all extraocular
redness muscles, expansion of the orbital fat, and marked bilateral proptosis.
3. Proptosis Exophthalmos Hertel in mm
4. Extraocular muscle Eye muscle motility Impaired elevation, mm above upper normal limit, inconstant or constant diplopia,
involvement Diplopia abduction mild punctuate keratopathy, and normal optic nerve status), and
Subjective gradingb very severe sight-threatening GO (corneal breakdown, or DON).
5. Corneal Keratitis, ulcer Fluoresceine Upper normal limits of proptosis are 23/24 mm in African Ameri-
involvement cans, 19/21 mm in whites, and 16/17 mm in Asians (female/male
values, respectively). Disease activity is best assessed by the clinical
6. Sight loss due Dysthyroid optic Visual acuity, color
to optic nerve neuropathy vision, visual
activity score (CAS), based on the classic signs of inflammation (see
involvement (DON) fields, optic disc Table 12.8).213 GO is likely to be inactive at CAS values below 3
and active at CAS values of 3 or greater.
ACTIVITY MEASURES (USING THE CLINICAL
ACTIVITY SCORE [CAS]) Thyroid Autoimmunity
Inflammatory Besides assay of TSH and FT4 to determine thyroid function, assay
Sign Item Score of TPOAb and TSHRAb are useful to assess whether thyroid auto-
immunity is present. This is especially relevant in euthyroid and
Pain Spontaneous retrobulbar pain 1 hypothyroid cases. Knowledge of the level of TSHRAb would any-
Pain on up gaze, side gaze, or down 1 way be useful in view of their direct relationship with disease activ-
gaze
ity and severity and their prognostic value for the course of GO.214
Redness Redness of the eyelids 1
Redness of the conjunctiva 1 Orbital Imaging
Swelling Swelling of the eyelids 1
Orbital imaging is not always necessary. It is indicated in patients
Swelling of the caruncle and/or plica 1 with suspected DON (to look for apical crowding of enlarged
Chemosis 1 muscles), in euthyroid or hypothyroid GO, and in unilateral GO
to exclude alternative diagnoses. Orbital imaging is performed by
Maximum CAS score (assessed momently) 7 CT or magnetic resonance imaging (MRI). Orbital CT scanning
Impaired func- Increase in proptosis ≥2 mm in 1–3 1 is indicated before surgical orbital decompression to have a close
tion months 1 look at the bony orbit (Fig. 12.12). GO activity might be assessed
Decrease of ≥8⁰ in eye muscle motil- 1 by MRI provided sophisticated programs are installed measuring
ity in any direction in 1–3 months T2-weighted relaxation time and/or short tau inversion recovery
Decrease in visual acuity of more than sequence. The most frequent diseases mimicking GO are orbital
one line on the Snellen chart (using myositis, caroticocavernous fistula, non-Hodgkin lymphoma,
pinhole) in 1–3 months
orbital meningioma, and IgG4-related orbital disease.215
Maximum CAS score (assessed over time) 10
aColor atlas in Dickinson AJ, Perros P. Controversies in the clinical evaluation of active thyroid- Treatment
associated orbitopathy: use of a detailed protocol with comparative photographs for objective
assessment. Clin Endocrinol (Oxf). 2001;55:283–303.
Specific guidelines for the management of Graves orbitopathy are
bIntermittentdiplopia = at awakening or when tired; inconstant diplopia = at extremes of
available.212 Recommendations are divided into three groups, deal-
gaze; constant diplopia = in primary or reading position. ing with general measures, thyroid treatment, and eye treatment.
General Measures
It is recommended that GO patients—except the mildest cases—
the mnemonic NOSPECS (Table 12.8). Three degrees of severity should be referred to combined thyroid-eye clinics or specialized
are distinguished: mild GO (characterized by lid retraction <2 mm, centers providing endocrinologic and ophthalmologic expertise.
mild soft tissue involvement, proptosis <3 mm above upper normal A multidisciplinary approach is likely to improve outcomes.216 A
limit, absent or intermittent diplopia, absent corneal exposure, and patient-focused approach to the treatment is also advocated, which
normal optic nerve status), moderate-to-severe GO (lid retraction encompasses the effects of the disease and its treatment on quality
≥2 mm, moderate to severe soft tissue involvement, proptosis ≥3 of life (QoL) and psychosocial well-being. Use of the GO-QoL, a
All patients with GO
• Restore euthyroidism
• Urge smoking cessation
• Local measures
• Refer to specialists except for
mildest cases
Mild Moderate to severe Sight threatening (DON)
i.v. GCs
Wait and see i.v. GCs if QoL is Active Inactive Poor response
Selenium severely impaired (2 weeks)
Stable and Progression i.v. GCs Inactive Prompt

inactive (1st choice) decompression
Still active
Stable and
inactive
Rehabilitative surgery i.v. GCs

(if needed)
• Fig. 12.13 Algorithm for the management of patients with Graves orbitopathy. (Redrawn from Bartalena
L, Baldeschi L, Boboridis K, et al. The 2016 European Thyroid Association/European Group on Graves
Orbitopathy guidelines for the management of Graves’ orbitopathy. Eur Thyroid J. 2016;5:9–26.)
disease-specific QoL questionnaire and well-validated tool, is rec- toxin A injections to possibly provide temporary control of eyelid
ommended in routine clinical practice and is available in several retraction.
languages (www.eugogo.eu).212,217 It consists of eight questions
about visual functioning and eight questions about appearance. Thyroid Treatment
It may serve as the primary outcome measure in clinical trials. Euthyroidism should be promptly restored and maintained.
Treatment should not only work from the physician’s perspective Antithyroid drugs or thyroidectomy is preferred as neither mod-
but also help from the patient’s perspective. It can also be useful in ifies the natural history of GO, whereas ample evidence indi-
daily clinical practice to facilitate discussion with the patient on cates 131I therapy carries a risk of developing or worsening of
the most disturbing features and to identify patients in need of GO. The risk can be reduced by concomitant oral prednisone
further counseling. Counseling may reduce anxiety, provide reas- in a daily dose of 0.3 to 0.5 mg/kg for 3 months. This steroid
surance, and help in developing better coping strategies. prophylaxis should be considered in high-risk patients (i.e., in
Smokers should be urged to refrain from smoking, and specialized smokers, in active GO, and when TSHRAb are high). Lower
smoking cessation programs or clinics should be offered. The success doses (0.2 mg/kg prednisone for 6 weeks) can be used in low-
rate of quitting smoking is rather low, but success rate could be some- risk patients. Patients with inactive GO can safely receive RAI
what higher in GO because many patients are very much concerned without steroid cover as long as post-radioiodine hypothyroidism
about their appearance. Patients should be confronted with the evi- is avoided.218,219 Some experts prefer very long-term ATD treat-
dence that (a) smokers have more severe GO, (b) smokers are more ment until GO has become inactive and no further treatment
likely to have progression of GO after 131I therapy, and (c) smoking of GO is required; if a relapse of Graves hyperthyroidism occurs
delays or worsens the outcome of immunosuppressive treatment. after discontinuation of ATD, it can be safely managed with RAI
Simple measures that may be helpful in any stage of the dis- without flare-up of GO.218
ease are (1) artificial tears to reduce surface symptoms and protect
the epithelium, (2) sunglasses to reduce photophobia but also to Eye Treatment
comfort patients who are self-conscious of their appearance, (3) Management depends on severity and activity of GO (Fig.
lubricant ointments to protect from exposure keratopathy dur- 12.13).212 Mild GO is best managed by a wait-and-see policy or
ing sleep, (4) prisms to improve diplopia, and (5) botulinum selenium. Spontaneous improvement is to be expected in about
one-third of cases. Intervention with a 6-month course of sele- a monoclonal antibody inhibitor of IGF1 receptors. In a placebo-
nium (100 μg sodium selenite twice daily) improves QoL and eye controlled RCT it had great efficacy in reducing CAS, reducing
manifestations (in 61% vs 36% in placebo) and prevents progres- exophthalmos, and improving diplopia and GO-QoL scores.228
sion to more severe GO (which occurred in 7% vs 26% in the Its potential to reduce exophthalmos is remarkable, and in this
placebo group).220 These results were obtained in European coun- respect the drug could be superior to IVMP. However, to displace
tries in which selenium intake is relatively low. It is not known IVMP as first-line treatment, teprotumumab should be compared
if selenium supplementation is also effective in areas with suffi- to IVMP in a RCT.
cient selenium intake. Steroids could be considered if the QoL is Very severe GO, DON requires urgent intervention. It is recom-
severely impaired. mended to start with IVMP: 1 g IV on 3 consecutive days in the
Active moderate-to-severe GO qualifies for immunosuppres- first week, followed by 1 g IV on 3 consecutive days in the second
sion. Steroids are considered as first-line treatment; they are rather week. If visual functions improve by the end of the second week,
effective in reducing swelling and redness of eyelids and conjunc- continue with oral prednisone; if not, then urgent surgical decom-
tiva and in improving diplopia, less so in reducing exophthalmos. pression is indicated.229
Intravenous methylprednisolone pulses (IVMP) rather than oral Inactive GO indicates rehabilitative surgery can be done when
prednisone are recommended because IVMP have greater effi- GO has reached this state. If surgery is performed while the dis-
cacy than oral prednisone (74% vs 51%) and fewer side effects ease is still active, results might be lost because of ongoing dis-
(56% vs 81%).212 A dose-finding study indicated a cumulative ease. Most orbital surgeons require stable eye disease for 6 months
dose of 4.5 g IVMP is appropriate for most patients, administered before surgery. Rehabilitative surgery includes orbital decompres-
as 500 mg IV once weekly for 6 weeks followed by 250 mg IV sion, eye muscle surgery, and eyelid surgery and should be carried
once weekly for another 6 weeks.221 Higher doses (750 mg once out in this sequence if several procedures are needed.
weekly for 6 weeks followed by 500 mg once weekly for another 6
weeks for a cumulative dose of 7.5 g) are slightly more effective at Graves Dermopathy
the expense of more side effects and should be reserved for worst
cases. IVMP have been associated with significant cardiovascular Graves dermopathy is also known as pretibial myxedema or local
or cerebrovascular morbidity and hepatic toxicity if administered myxedema. It is a rather rare phenotype of Graves disease occur-
in high single doses of 1000 mg or more, in cumulative doses of ring almost always in the presence of Graves orbitopathy and asso-
more than 8 g, and/or as repeat infusions on consecutive days. It ciated with very high levels of TSHRAb. Thus the typical patient
is therefore recommended that cumulative doses of IVMP should with Graves dermopathy has also Graves orbitopathy and Graves
not exceed 8 g and that IVMP should not be given in patients hyperthyroidism (sometimes also thyroid acropachy), constitut-
with recent viral hepatitis, significant hepatic dysfunction, and ing the most severe expression of Graves disease. The skin lesion
severe cardiovascular morbidity or psychiatric disorders.212 Severe consists usually of nonpitting edema with violet discoloration,
hypertension, inadequately managed diabetes, and glaucoma are induration, and prominent hair follicles, giving the appearance
other contraindications. IVMP therapy should be monitored and texture of an orange peel (peau d’orange).230 Other forms are
by regular measurements of blood pressure, blood glucose, and plaques, nodules, and elephantiasis (Fig. 12.14). Its predilection
liver function tests. Efficacy of IVMP can be slightly enhanced site is the pretibial area (hence the name pretibial myxedema), but
by coadministration of mycophenolate (one 360-mg tablet twice it has been observed at other sites also exposed to local mechani-
daily for 24 weeks).222 cal pressure.231 Local trauma may provoke Graves dermopathy as
Patients who do not or partially respond to IVMP and patients well. Its pathogenesis looks similar to that of Graves orbitopathy,
in whom GO flares up after discontinuation of IVMP may require which likewise develops in a confined space with increased local
a second-line therapy. Shared decision making is recommended pressure. Dermal fibroblasts seem the target of the autoimmune
to select one of the available treatment options: low-dose oral attack. There is an upregulated expression of TSH receptors on
prednisone + either cyclosporine or retrobulbar irradiation (usu- dermal fibroblasts, which also produce cytokine-induced gly-
ally 20 Gy fractionated in 10 daily doses of 2 Gy over a 2-week cosaminoglycans. Treatment is not always required. Spontane-
period), repeat IVMP, or rituximab (RTX; 1 g twice at a 2-week ous regression occurs in the long term. If treatment is necessary
interval). RTX is an anti-CD20 monoclonal antibody that effec- because of functional or cosmetic complaints, nighttime occlusive
tively causes B-cell depletion. Open studies report a remarkable dressings with 0.05% to 0.1% triamcinolone acetonide in a cream
improvement in CAS and GO severity.223 Side effects occur in base might be helpful as well as compressive bandages or stock-
about 30%; notable is the risk of the cytokine-release syndrome ings. Treatment of GO with glucocorticoids or biologics may also
with the development of DON. RTX has been tested in two ran- cause regression of Graves dermopathy.
domized clinical trials. One compared RTX with placebo: CAS
decreased similarly in both treatment arms, and RTX was not
better than placebo.224 The other compared RTX with IVMP Pregnancy and the Thyroid
(cumulative dose 7.5 g). The decrease in CAS was greater in the Human Chorionic Gonadotropin
RTX group than in the placebo group, and RTX was judged to be
slightly better than IVMP.225 Sample size in both trials was very hCG is a glycoprotein heterodimer composed of an α-subunit that
modest, and some differences in patient characteristics and trial is common to all glycoprotein hormones (TSH, LH, and FSH) and
execution have been noted.226 Nevertheless, it remains difficult to a specific β-subunit that allows for biologic specificity. Despite this
reconcile the difference in outcomes. It seems too early to accept separate structure hCG can bind to and stimulate the hTSHR,232–
RTX as an alternative for IVMP but also too early to dismiss RTX 234 with an in vitro potency of about 1 U hCG = 0.7 μU of human
as a disease-modifying drug. The same holds true for tocilizumab, TSH, depending on its carbohydrate content. In high concentra-
a monoclonal antibody directed against the IL6 receptor. It had tions as found in hyperemesis gravidarum, multiple gestation, or
good efficacy in GO patients refractory to IVMP in an open study, molar pregnancy hCG will cause hyperthyroidism characterized by
but the drug has not been tested in a RCT.227 Teprotumumab is a diffuse goiter, elevated free T4, and a suppressed TSH.
A B
• Fig. 12.14 (A) Chronic pretibial myxedema in a patient with Graves disease and orbitopathy. The lesions
are firm and nonpitting, with a clear edge to feel. (B) Here the chronic myxedema has continued to spread
to the foot, causing severe disfiguration and immobility. (A, Courtesy Dr. Andrew Werner, Mount Sinai
School of Medicine, New York, NY.)
Transient Gestational Thyrotoxicosis serious medical complications for both the mother and the infant
In the late first trimester of normal pregnancy in humans there if it should persist.47,48,243–245 More commonly, a woman under
is often a physiologic mild transient gestational thyrotoxicosis treatment for hyperthyroidism becomes pregnant. Whatever the
or hyperthyroidism.235,236 An exaggeration of this physiologic sequence, pregnancy complicates the diagnosis and treatment of
increase in thyroid stimulation in the first trimester may also be hyperthyroidism in Graves disease and influences its severity and
seen in some women and is associated with high levels of hCG course.
(100,000–200,000 U/L), such as those found in twin pregnan-
cies, and is often accompanied by hyperemesis.237–239 In most Influence of Pregnancy on the Immune System
patients, the condition is self-limited and the risk of birth defects The development of pregnancy and the growth of the placenta
warrants against the use of antithyroid drugs in early pregnancy. have profound influences on the immune system, as discussed
It may be difficult to separate this syndrome from early Graves earlier. The overall suppression of autoimmune responses, which
disease, and a TSHRAb test may be helpful.240 occurs in pregnancy and is mediated by a variety of placental fac-
tors, is designed to allow the fetus with its 50% paternal antigens
Abnormal Responses to Human Chorionic Gonadotropin to survive immune assault.246,247 These changes promote mater-
A few patients have been reported with an inherited variant of nal-fetal tolerance, but the increased role of the regulatory T cells
gestational thyrotoxicosis in which a mutation in the TSHR gene and their suppression of maternal responses to the fetus appears
resulted in a receptor protein with an increase in its responsive- to be predominant and long lived.248,249 It has been shown that
ness to hCG.241 Such patients develop hyperthyroidism with each a major shift in such T-cell control reduces the effectiveness of all
pregnancy due to even physiologic serum hCG concentrations. inflammatory T cells.
Similarly, the use of gonadotropins in in vitro fertilization and
indirectly the use of GnRH agonists have been associated with Thyroid Antibodies in Pregnant Patients With Graves
cases of thyroid dysfunction.242 Disease
The hallmark of the immune effects initiated by the placenta
Graves Disease During Pregnancy and the is the fall in thyroid autoantibody secretion—TPOAb, TgAb,
and TSHRAbs—that is seen in almost all patients as pregnancy
Postpartum Period progresses.250,251 This is now considered secondary to enhanced
Although seen more regularly in clinical practice, a truly overac- regulatory T-cell activity252 and precedes a rapid increase in
tive thyroid gland is uncommon in established pregnancy, affect- autoantibody levels after the immunosuppression is lost in
ing approximately 0.2% of women. This low rate is because the postpartum period. Assays for TSHRAbs in the serum of
pregnancy tends to suppress autoimmune responses during preg- pregnant women with Graves disease may be of clinical value
nancy, and Graves disease, an autoimmune disorder, is the most in selected cases because a failure of this immunosuppression
common cause of thyrotoxicosis in young women. Furthermore, may indicate potential fetal problems.55,253 Because maternal
although thyrotoxicosis has a variety of negative influences on fer- antibodies cross the placenta, there is a correlation between the
tility itself, it is also associated with increased pregnancy loss and maternal level of stimulatory TSHRAbs and the development
of fetal thyrotoxicosis. Fortunately fetal and neonatal thyrotoxi- 6

cosis occurs in only 1% of infants of mothers with Graves dis- 5.5 97.5th 50th 2.5th
5
ease, and high levels of TSHRAbs, usually greater than three 4.5 90th 10th
times the upper normal limit, are correlated with fetal thyroid 4
stimulation.254,255 Pregnant women at risk for failure to sup-
TSH mu/mL
3.5
press thyroid autoantibodies include those with more severe 3
2.5
hyperthyroidism and those with significant GO or infiltrative 2
dermopathy. In addition, the prior treatment of the mother, 1.5
especially with radioiodine, may not always be accompanied 1
by a sufficient reduction in TRAbs. Thus the fetus of a treated 0.5
0
patient with Graves disease may still be at risk for development 0.5
of fetal or neonatal thyrotoxicosis, and the mother may need
6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 39 40
antithyroid drug treatment and the fetus monitored by umbilic
Weeks
cord blood testing and ultrasonography.256
• Fig. 12.15 Gestation age-specific thyroid-stimulating hormone nomo-
Differential Diagnosis gram derived from 13,599 singleton and 132 twin pregnancies. Different
When mild thyrotoxicosis is present during early pregnancy, it percentiles are shown by colored lines. (From Dashe JS, Casey BM, Wells
CE, et al. Thyroid-stimulating hormone in singleton and twin pregnancy:
may be due to gestational thyrotoxicosis secondary to hCG stimu-
importance of gestational age-specific reference ranges. Obstet Gynecol.
lation of the thyroid gland (see later).257,258 When it is more severe 2005;106:753–757.)
it is usually due to Graves disease because toxic multinodular goi-
ters and hot nodules are uncommon in this age group.
Diagnosis TABLE 12.9 Complications of Hyperthyroidism in

Pregnancy
Pregnancy and hyperthyroidism are both accompanied by thyroid
stimulation, a hyperdynamic circulation, and hypermetabolism. Increased and recurrent pregnancy loss
In pregnancy, serum TBG levels are increased by estrogen-induced Preterm delivery
changes in glycosylation, which increases TBG production and Preeclampsia
lengthens its half-life, and thus in both conditions the total serum Fetal growth restriction
Fetal thyroid hyperfunction or hypofunction caused by TRAb
T4 and T3 levels are elevated so that the upper limit of the normal
Fetal goiter from excessive antithyroid drug treatment
range during second and third trimesters of gestation is about 1.5 Neonatal thyrotoxicosis
times the upper nonpregnant reference limit.254 However, serum Increased perinatal and maternal mortality risk
free T4 levels, as measured by both analog and equilibrium dialy- Potential for decreased IQ of offspring because of excessive use of
sis methodologies, may actually decrease as pregnancy progresses antithyroid drugs
and the normal third trimester reference range for a given assay is
significantly less than its nonpregnant reference range.236 Serum IQ, Intelligence quotient; TRAb, thyrotropin receptor antibodies.
TSH levels also tend to decrease in early pregnancy and up to 15%
of women can have TSH levels below the normal limit.235 The
95th percentile confidence interval lower limits for serum TSH
levels are 0.06 mU/L, 0.3 mU/L, and 0.3 mU/L, respectively, for effect on the newborn. This assay is especially useful in pregnant
the first, second, and third trimesters. Nevertheless, each labora- women who previously received ablative therapy for Graves hyper-
tory needs to establish its own normal ranges for thyroid testing thyroidism and who still have high levels of TSHRAb.
in pregnancy.259,260
Biochemically, the diagnosis of thyrotoxicosis is confirmed Antithyroid Drugs in Pregnancy
when the serum TSH level is below the trimester-specific lower Medical therapy is the usual method of choice in pregnancy.
limit and the total or free T4 levels are above the normative range Because of the usual improvement in the disease, the dosage of
for pregnancy (Fig. 12.15). Detection of TSHRAbs can confirm antithyroid drug required to control the disease in the later phases
the diagnosis of Graves disease, which may or may not be obvious of pregnancy is generally much less than that required in the same
from the clinical history and examination. patient were she not pregnant. Overtreatment of the hyperthyroid
pregnant woman remains a common but avoidable clinical prob-
Treatment During Pregnancy lem with potentially severe consequences for the fetus. Thus the
Hyperthyroidism in pregnancy is associated with a variety of com- clinician should prefer mild undertreatment to the risk of hypo-
plications for mother and child (Table 12.9). Although mild hyperthyroidism.256,261–263 Therefore it is imperative for the clinician to
thyroidism in pregnancy does not lead to a significant increase in understand the therapeutic targets for titrating antithyroid drug
risk for mother or fetus, severe thyrotoxicosis can lead to many dosages during pregnancy.264
complications and endanger the life of the mother and fetus. Fur- Certain aspects of placental physiology are relevant to the use of
thermore, the management of hyperthyroidism during pregnancy antithyroid drugs. PTU and methimazole readily and rapidly cross
can be an even greater problem than its diagnosis. Graves disease the placenta equally well and are concentrated in the fetal thyroid.
can worsen in the first trimester, but the subsequent trimesters In excess quantity these agents can cause goitrous hypothyroidism
have an attenuating influence on the hyperthyroid state because of in the fetus.265 Maternal T4 crosses the placenta (as evidenced by
the immunosuppression associated with pregnancy. Pregnancy is infants born with significant circulating serum T4 concentrations
also one of the few clinical situations in which an assay of the bio- despite congenital hypothyroidism) and is the major source of fetal
logic activity of the TSHRAbs is helpful in predicting its potential thyroid hormone prior to the complete functional development of
population risk of giving birth to a child who has a birth defect

diagnosed before the age of 2 years.273 However, PTU also is terato-
genic,274,275 and the use of PTU is also associated with birth defects
(estimated to be around 1 in 40 exposed).272 These abnormalities
tend to be milder than with methimazole-associated defects and
include preauricular sinuses and cysts and urinary abnormalities.276
The period of risk when these drugs may be teratogenic is
especially weeks 6 to 10 of pregnancy.277 Accordingly, to reduce
the risk of birth defects, withdrawal of antithyroid medication
in patients who are considered in remission of Graves disease or
an unavoidable shift from methimazole to PTU has to take place
very early in pregnancy. Additionally, the lowest possible dose
of an antithyroid drug must be used.278 The risk of birth defects
has to be balanced against the risk of abnormal maternal thyroid
function in early pregnancy. It is therefore wise to recommend to
young women who receive antithyroid drugs for Graves disease
that they test for pregnancy just a few days after a missing men-
struation and immediately contact their physician to plan future
A B therapy or withdrawal of medication. No firm international con-
sensus has yet been reached on how to minimize the risk of birth
• Fig. 12.16 Examples of methimazole embryopathy. (A) Dysmorphic astig- defects from antithyroid drug use in early pregnancy.
matism. (B) Aplasia cutis. (From Bowman P, Osborne NJ, Sturley R, et al.
Carbimazole embryopathy: implications for the choice of antithyroid drugs Caring for the Pregnant Patient
in pregnancy. QJM. 2012;105:189–193.) The therapeutic target for a pregnant Graves patient is a healthy
infant. In the second half of pregnancy both the untreated preg-
the hypothalamic-pituitary axis in the fetus at around 20 weeks nant woman with hyperthyroidism caused by Graves disease and
of gestation. Furthermore, the transplacental passage of maternal her fetus will be thyrotoxic because TSHRAb passes the placenta
TSHRAbs in the latter half of pregnancy can result in fetal thyroid and stimulates the fetal thyroid. Antithyroid drugs given to the
stimulation. Therefore the fetal thyroid is subject to the same fac- mother also pass through the placenta and thus treat both the
tors that influence maternal thyroid hormone production. maternal and the fetal hyperthyroidism. However, the drugs may
Previously, the antithyroid drug of choice throughout pregnancy overtreat the fetus compared with the mother, and accordingly
in the United States was PTU, but because of the rare yet serious the aim of therapy is to keep the mother in a state of subclinical
side effect of PTU-induced hepatic failure, in June 2009 the FDA hyperthyroidism analogous to the normal gestational physiol-
issued an advisory that PTU should be reserved for the first trimester ogy of the first trimester.264 This is associated with the lowest
of pregnancy while organogenesis is occurring144 (see later). Subse- impact on fetal thyroid function and the highest rate of normal
quently, methimazole could be prescribed. One must keep in mind neonatal thyroid hormone levels.279 The maternal serum free T4
that the therapeutic antithyroid potency ratio of methimazole to level should be maintained at or just above the upper normal
PTU is around 20:1. Thus a patient who requires only 50 mg of nonpregnant range, and no attempt should be made to normal-
PTU in the first trimester may be given 2.5 mg methimazole, and ize the serum TSH concentration. Indeed, a normal TSH during
she may not even require a thionamide during the latter part of preg- drug therapy is an indication that the dose of drug should be
nancy. Of course, the best practice is to ensure definitive treatment reduced.280 The clinical status of the patient is an important indi-
prior to pregnancy so that antithyroid drugs are not needed at all. cation for treatment or increases in dosage. A modest tachycardia
is a physiologic response to the increased metabolic demands of
Danger of Antithyroid Drugs in Pregnancy pregnancy, and pulse rates of 90 to 100 beats/minute are well
The first report of birth defects after maternal use of antithyroid tolerated without evidence of myocardial decompensation dur-
drugs was a brief letter reporting on congenital scalp skin defects ing delivery. The natural amelioration of Graves disease in the
after the use of methimazole.266,267 Subsequently, several case third trimester should be kept in mind, and repeated attempts
reports confirmed the association, and other types of defects were should be made to reduce or discontinue the thionamide as the
described as well.268 Such defects included a specific combina- delivery date approaches to avoid TSH-induced fetal/newborn
tion of facial features, and the condition was termed methimazole/ goiter, which may cause asphyxia (Fig. 12.17). The serum TSH
carbimazole embryopathy. Because PTU was not at first associated concentration should be monitored monthly—more to avoid
with such birth defects, guidelines have been proposed that recom- inadvertent overtreatment rather than as the target for normal-
mend the use of PTU in the first trimester and to consider shifting ization. Because thionamides, but not thyroid hormone given to
from methimazole to PTU in women planning a pregnancy.269,270 the mother, pass the placenta rather freely, a block-and-replace
Recent larger studies have since expanded our knowledge on strategy may induce severe fetal hypothyroidism and goiter, and
methimazole-associated birth defects.271,272 Apart from aplasia it is in general not appropriate in the pregnant patient. The rare
cutis, defects are seen in the abdominal wall (gastroschisis, ompha- exception is a pregnant woman who was previously given ablative
locele), gut (esophageal atresia), upper airways (choanal atresia), therapy for Graves disease but who still produces TSHRAb that
urinary system, heart (ventricular septum defect), and eye (Fig. leads to isolated fetal hyperthyroidism.
12.16). Around 1 in 30 women exposed to methimazole or car- All pregnant patients with significant Graves disease should
bimazole in early pregnancy will give birth to children with defects be managed in close cooperation with obstetricians experienced
associated with this therapy. This is in addition to the 5% general with modern techniques for monitoring the fetus for intrauterine
pregnancy if possible. Nevertheless, if antithyroid drug require-

ments are very high or cannot be used, surgery may be indicated.
Iodide can be given for 7 to 10 days to aid in patient prepara-
tion with large and highly vascular thyroid glands. Importantly,
thyroid surgery may cure the hyperthyroidism of the mother, but
TRAb will not disappear immediately. Thus the fetal thyroid may
still be stimulated, and withdrawal of antithyroid drugs from the
pregnant woman may lead to isolated fetal hyperthyroidism, espe-
cially in mothers with high levels of TSHRAb.286
Consequences of Overtreatment
The influence of maternal hypothyroidism on fetal brain develop-
ment and the subsequently reduced IQ of the children of hypo-
thyroid mothers are discussed in Chapter 13. Needless to say, the
overuse of antithyroid drugs in pregnancy may lead to the same
consequences. There is considerable evidence that many pregnant
patients with Graves disease were overtreated in the past as far as
• Fig. 12.17 Sagittal view of a fetus at 23.9 weeks showing a large goiter the fetus is concerned, as evidenced by transiently elevated serum
(arrow) preventing neck flexion. (From Mayor-Lynn KA, Rohrs JH III, Cruz TSH levels on newborn screening tests.287 This is another reason
AC, et al. Antenatal diagnosis and treatment of a dyshormonogenetic fetal why one should accept patients being slightly hyperthyroid rather
goiter. J Ultrasound Med. 2009;28:67–71.) than slightly hypothyroid.
thyroid dysfunction. These techniques normally include fetal Graves Disease in the Postpartum Period
heart rate monitoring and ultrasonographic assessment of fetal Changes in the Immune Response in the Postpartum Period
growth rate. With advanced ultrasonography it is usually possible As discussed earlier, pregnancy induces a variety of immune
to examine the fetus for the presence of goiter. Fetal goiter can changes that are responses to placental influences and the paternal
develop both from the stimulatory effect of maternal TSHRAb foreign antigens and that are designed to prevent rejection of the
passing through the placenta and secondary to antithyroid drugs foreign fetus. These changes include enhanced regulatory T-cell
given to the mother. Occasionally, cordocentesis with fetal thyroid influences and a T-cell shift from Th1 to Th2, resulting in an over-
function testing may be appropriate. The amount of fetal monitor- all decrease in all autoimmune responses as evidenced by marked
ing necessary can be judged based on the degree of hyperthyroid- decreases in thyroid autoantibodies.251 Following delivery, these
ism present, which is indicative of the potency of TRAb present immune changes are slowly lost and a return to normal is observed
and also by the increase in circulating TRAb levels in mothers but only after a period of exacerbated autoimmune reactivity in
previously treated for Graves. A recent systematic review dem- which large increases in T-cell and autoantibody activity occur. It
onstrated that values of TRAb of over 3.7 times the upper limit is at this time—4 to 12 months postpartum—that new-onset or
of normal could be associated with fetal thyrotoxicosis.281 This recurrent thyrotoxicosis is seen. Such thyroid dysfunction may be
is consistent with the American Thyroid Association guidelines transient or permanent.
where fetal monitoring is recommended in mothers who have
TSHRAb levels greater than three times the upper limit of normal Transient Postpartum Thyroiditis
at any time during pregnancy.235 Transient postpartum thyroiditis remains the most common form
of hyperthyroidism in the postpartum period and usually precedes
Iodide and Beta Blockers a period of hypothyroidism.288 The transient thyrotoxicosis is due
Obviously therapeutic radioiodine is contraindicated in preg- to thyroid cell destruction and may occur in approximately 5% to
nancy, although no harm has been found after diagnostic doses of 10% of patients during the 4 to 12 months postpartum.289 This
123I.282 Iodide itself should also not be used as therapy for more can be double in those with other autoimmune diseases. How-
than 2 to 3 weeks in the pregnant woman because it readily crosses ever, the rapid return of true Graves hyperthyroidism is less com-
the placenta and can induce a large goiter that may cause airway mon but is similarly dependent on the subsequent changes in the
obstruction in the newborn. Large amounts of iodide are contra- immune response.
indicated in the last month of pregnancy but can be used at earlier
times in emergent situations. Whether propranolol or other beta Presentation of Postpartum Graves Disease
blockers should be used in the pregnant woman with hyperthy- A high percentage of women with Graves disease age 20 to 35
roidism has been a matter of debate. In the experience of some, it years give a history of pregnancy in the 12 months before the
can cause intrauterine growth retardation, delayed lung develop- onset of Graves disease.290,291 Pregnancy and the postpartum
ment, and neonatal hypoglycemia or depression,283 but large stud- state also apparently influence the course of preexisting Graves
ies have suggested that it can be used with safety for short periods disease. Patients in clinical remission during pregnancy are prone
or at very low doses.284,285 to postpartum relapse. In 41 pregnancies in 35 patients in remis-
sion, 78% were followed by development of thyrotoxicosis dur-
Surgery ing the postpartum period. The patients with Graves disease and
Surgery during the first and third trimesters is not desirable postpartum thyrotoxicosis were classified into three categories: (1)
because of the possible induction of early pregnancy loss and later Some had persistent recurrent hyperthyroidism with an elevated
premature labor, respectively. Surgery may be successful during RAIU (classic Graves disease). (2) Some had a transient disorder
the second trimester, but it is best to avoid major surgery during associated with a normal or an elevated RAIU (transient Graves
disease). (3) Some patients, especially those with the highest titers the result of one of several pathogenetic factors.303 Its incidence is
of TPOAb, experienced transient thyrotoxicosis with a decreased highly dependent on the iodine intake of the population.
RAIU (the thyrotoxic phase of postpartum thyroiditis referred
to earlier). This phase in turn may be followed by a hypothyroid Pathogenesis
phase.292
The pathogenesis of toxic multinodular goiter cannot be con-
Preconception Counseling sidered apart from that of its invariable forerunner, nontoxic
A special problem related to hyperthyroidism and pregnancy is multinodular goiter, from which it may slowly emerge. Two
presented by the patient who wishes to conceive in the near future hallmarks of the disorder, structural and functional heterogene-
and is either in early remission after a course of antithyroid drug ity and functional autonomy, evolve over time; the increase in
treatment or is being treated with antithyroid agents for active the extent of autonomous function causes the disease to move
Graves disease.293 For the first scenario, antithyroid drugs can be from the nontoxic to the toxic phase. Somatic mutations in the
reluctantly reintroduced if required during pregnancy if symp- TSHR gene, first demonstrated in toxic adenomas,298 have been
tomatic thyrotoxicosis recurs. In the second situation, definitive demonstrated in toxic multinodular goiter, and the individual
therapy (radioiodine therapy or surgery) should be considered to mutations appear to differ from nodule to nodule. However,
forestall the complexities of managing hyperthyroidism during only about 60% of toxic nodules have reported TSHR muta-
pregnancy. As with the therapy of Graves disease in general, such tions, and only a very few have G protein mutations. Hence
decisions must involve education of the patient so that the risks there are many nodules with autonomy of undetermined
and benefits of the various alternatives are clearly appreciated. cause304 and that presumably involve mutations in additional
Fertile women who receive antithyroid drugs should be educated parts of the signaling pathways.
to perform pregnancy testing already within the first days after a Radioiodine scans show localization of isotope in one or more
missed menstrual period if pregnancy is possible, and if the test is discrete nodules, whereas iodine accumulation in the remainder
positive they should immediately contact the physician for further of the gland is usually suppressed because TSH is suppressed by
planning of therapy. The 1-year surge in TSHRAb after radioio- the hyperthyroidism. However, the degree of hyperthyroidism
dine therapy80,294 may increase the risk of fetal exposure to high can be variable and TSH may not be totally inhibited, so the
TSHRAb levels if the woman is treated with radioiodine shortly background uptake of radioisotope may also be variable. His-
before she becomes pregnant. In all cases where radioiodine ther- topathologically the functioning areas may resemble adenomas
apy is used, pregnancy should be delayed for at least 6 months in being reasonably well demarcated from surrounding tissue.
and until normal thyroid function has returned on replacement They generally consist of large follicles, sometimes with hyper-
therapy. plastic epithelium, but here, too, architecture correlates poorly
with functional state. The remaining tissue appears inactive,
Nursing and Antithyroid Drugs and zones of degeneration are present in both functioning and
Older studies suggested that relatively more methimazole than nonfunctioning areas. Hence, from the pathophysiologic stand-
PTU appeared in breast milk of women receiving these drugs point, these thyroids harbor multiple solitary hyperfunction-
during lactation, but more recent evidence shows little differing and hypofunctioning adenomas interspersed by suppressed
ence between them.265,295,296 It is occasionally recommended that normal thyroid tissue.
women who take high doses of antithyroid drugs not nurse their
infants because of the difficulty in monitoring thyroid function in Clinical Presentation
infants. The drug doses transferred via breast milk are very small,
and no drug side effects have been reported in neonates whose The overproduction of thyroid hormone in toxic multinodular
mothers were taking antithyroid drugs, including neurologic goiter is usually less than that in Graves disease, and the disease
function.297 presentation is milder (Fig. 12.18); in addition, toxic multinodu-
lar goiter usually occurs after the age of 50 in patients who have
Inherited Nonimmune Hyperthyroidism had nontoxic multinodular goiter for many years (Fig. 12.19).
Like its forerunner, toxic multinodular goiter is more common
Toxic diffuse thyroid hyperplasia without the pathologic char- in women than in men (6:1).305 Sometimes hyperthyroidism
acteristics of autoimmune disease has been reported in families develops abruptly, often after exposure to increased quantities of
and appears to be inherited as an autosomal dominant condi- iodine such as the contrast media for CT scanning, which permits
tion.298–300 Polymorphic genomic mutations in the TSHR gene autonomous foci to increase hormone secretion to excessive levels
have been reported to cause constitutively activated TSHRs and which may simply exacerbate already established mild hyper-
differing from family to family.301 Recessive mutations on thyroidism (see “Iodide-Induced Hyperthyroidism”). The serum
both chromosomes have also been described as causing hyper- T4 and T3 concentrations may be only marginally increased, and a
thyroidism while the parents remained euthyroid. These gain suppressed TSH may be the major abnormality. The total RAIU is
of function mutations, mostly in the transmembrane regions only slightly increased or within the normal range unless follow-
of the TSHR, are similar to those somatic mutations seen in ing iodine exposure.
toxic adenomas but are in the germline.302 Treatment is by A toxic multinodular goiter may also be found as part of
radioiodine ablation or thyroidectomy, depending on the age Graves disease as confirmed by the presence of TSHRAb of the
of the patient. stimulating variety.306 Presumably this represents two separate
diseases, although TSHRAbs have growth-stimulating activity
Toxic Multinodular Goiter but this should apply to all cells. Toxic multinodular goiter
alone is not accompanied by infiltrative ophthalmopathy, and
Toxic multinodular goiter is a disorder in which hyperthyroidism when the two coexist it represents the emergence of Graves
arises in a multinodular goiter, usually of long standing, and is disease.
Serum T3 (mmol/L) 5.5 250

5.0 Multinodular toxic goiter
4.5 Graves disease
4.0 200 Solitary toxic adenoma
3.5
IR, per 100,000 py

3.0
2.5 150
um
ne
se
n
TD
T
TG
ss
100
n
io
SA
ST
le
a
di
ro
at
PP
i
th
se
in
io
da
M
ul
Li
Pa
io
di
ip
io
ad
s
an
Am
ve
R
M
ra
G
50
A
275
0
Serum T4 (mmol/L)
250
10 9
20 9
30 9
40 9
50 9
60 9
70 9
9
+
225
–1
–2
–3
–4
–5
–6
–7
0–
80
200
Age (years)
175
• Fig. 12.19 An
example of age-specific incidence rates (IR) of the three
150 most common types of hyperthyroidism. py, person-years. (From Carlé
A, Pedersen IB, Knudsen N, et al. Epidemiology of subtypes of hyper-
thyroidism in Denmark: a population-based study. Eur J Endocrinol.
ss
ne
m
ne
TG
A
TD
2011;164:801–809.)
as
io
SA
ST
iu
le
di
ro
at
PP
th
se
in
io
da
M
ul
Li
Pa
io
di
ip
io
ad
s
an
Am
ve
R
M
ra
On palpation, the characteristics of the goiter are the same as

G
B those of the more common nontoxic multinodular goiter. In as

many as 20% of elderly patients with thyrotoxicosis, the thyroid
gland is firm and irregular but not distinctly enlarged. A thyroid
Total T3 : T4 ratio (1000)
24 scan and ultrasound examination will confirm the diagnosis as

22 toxic multinodular goiter rather than a single toxic adenoma or
20 Graves disease.
18
16 Laboratory Tests and Differential Diagnosis
14 All patients with a multinodular goiter should be screened annu-
ally with a serum TSH. If suppressed, the free T4 should be deter-
mined. Serum TSH levels intermediate between 0.1 and 0.4
m
ss
e
TG
TD
Pa e
mU/L are not usually associated with significant clinical symp-

in
as
io
n
Am SA
ST
iu
le
ro
od
PP
at
N
th
se
in
da
M
ul
toms. Such patients have thyroid autonomy but are not thyrotoxic
Li
oi
di
ip
io
i
ad
s
an
(see “Subclinical Hyperthyroidism”). For patients with established

ve
M
ra
thyrotoxicosis, an RAIU with scan will help in gauging the dose of

G
C 131I to be administered as well as identify the autonomously func-
• Fig. 12.18 Serum T3 (A), T4 (B), and T3:T4 ratio (C) in 10 types of hyper- tioning nodules. The latter can then be followed by 131I therapy.
thyroidism. Means (±SEM) are shown. MNTG, multinodular toxic goiter;
PPTD, postpartum thyroid disease; SAT, subacute thyroiditis; SEM, stan-
dard error of the mean; STA, solitary toxic adenoma; T3, triiodothyronine; Treatment
T4, thyroxine. (From Carlé A, Knudsen N, Pedersen IB, et al. Determinants The treatment of toxic multinodular goiter with overt hyperthy-
of serum T4 and T3 at the time of diagnosis in nosological types of thyro-
roidism can be approached with surgery, radioactive iodine ther-
toxicosis: a population-based study. Eur J Endocrinol. 2013;169:537–545.)
apy, or in some cases antithyroid drug therapy. The correct choice
depends upon a combination of patient preference with associated
Cardiovascular manifestations often predominate, possibly risk factors. For example, a gland with significantly high radioac-
because of patient age, and include atrial fibrillation or tachycardia tive iodine uptake in select nodules would be ideal for radioiodine
with or without heart failure. Weakness and wasting of muscles are therapy. In contrast, a large gland with compressive symptoms
common, the so-called apathetic or masked thyrotoxicosis. The ner- could be better addressed with surgery.134
vous manifestations are less prominent than in younger patients
with thyrotoxicosis, but emotional lability may be pronounced, Radioiodine Therapy
and even osteoporosis may be the factor leading to thyroid func- Radioiodine may be the treatment of choice for patients with
tion testing and diagnosis. Because of the physical characteris- toxic multinodular goiter despite disagreement about the size and
tics of the thyroid gland and its frequent retrosternal extension, number of doses required to achieve a therapeutic response.303,307
obstructive symptoms are more common than in Graves disease. In the United States, iodine intake is higher than in many regions
in Europe so that 24-hour RAIU values of 20% to 30% are not

unusual. Such patients will require significant doses of radioiodine
to restore a euthyroid state and may even require a second treatment.
Because a number of patients with this disorder have underly-
ing or the potential for heart disease, the administration of radio-
iodine should be preceded by a course of antithyroid therapy with
methimazole until a near eumetabolic state is achieved, but still with
a suppressed TSH to avoid iodine uptake in normal thyroid tissue.
Medication is then discontinued for at least 4 to 7 days before radio-
iodine is administered. A week later the antithyroid drug may be
reinstituted so that the thyrotoxicosis is controlled until radioiodine
takes effect, which typically requires 3 to 4 months. A decrease in
size of the hyperfunctioning nodules is a positive sign. At that time,
the antithyroid drug can be tapered, but if the TSH level remains
below 0.1 mU/L after 6 months, a second dose may be required.
Surgery
Surgical therapy is often recommended after adequate preopera-
tive preparation in patients with large goiters or obstructive mani-
festations. In these patients, a CT scan or MRI is recommended
to define the extent of the goiter and the adequacy of the tracheal
walls. Respiratory function studies may also be helpful in assess-
ing the need for surgery. Patients with fixed, especially partially • Fig. 12.20 Radioiodine (123I) thyroid scan shows a hyperfunctioning hot
retrosternal, goiter should be considered for surgery because of nodule corresponding to physical examination findings with a faint outline
the risk of more complete obstruction should hemorrhage into of the remaining suppressed gland. In this unusual case, Graves disease
a nodule occur. However, when surgery is contraindicated, even developed a few months later after an oral contrast agent load. (From
significant obstructive symptoms can be relieved by adequate Soule J, Mayfield R. Graves’ disease after 131I therapy for toxic nodule.
radioiodine therapy.308 In elderly patients who are not candidates Thyroid. 2001;11:91–92.)
for either radioiodine therapy or surgery, lifelong low-dose anti-
thyroid drug therapy remains an option.
occur in the TSHR gene and cause hypothyroidism (see later). A
Additional Treatment Options small number of autonomous adenomas have mutations in the G
Outside of the United States there is greater experience with newer stimulatory protein genes downstream of the TSH receptor that
treatment options, including ethanol ablation and radiofrequency lead to a similar state of constitutive activation.304 More recently,
ablation. Success with these techniques in context of diminished mutations have also been identified in the EZH1 genes in toxic
nodule size and function is reported. However, their utility has not adenomas from patients who possess a TSH receptor activating
been broadly studied and they should likely only be used when the mutation implying that a second hit may be necessary for full acti-
more standard modalities of radioactive iodine therapy, surgery, or vation of the toxic adenoma phenotype.313
antithyroid drugs are not possible or contraindicated.309,310
Clinical Presentation
Toxic Adenoma
The toxic adenoma often presents as a nodule in a patient with a
A third, less common form of hyperthyroidism (∼5% of cases)305 suppressed TSH; on ultrasound it appears as a single hypoecho-
is caused by one or more autonomous adenomas of the thyroid genic nodule. A radioiodine thyroid scan shows a localized area of
gland. As herein used, the term toxic adenoma refers to a tumor increased radioiodine accumulation (Fig. 12.20). This condition
in a thyroid that is otherwise intrinsically normal. The disorder is may occur at a younger age than toxic multinodular goiter and
usually caused by a single adenoma that is either palpable or seen may be seen in patients in their 30s and 40s.
on ultrasound as a solitary nodule and hence is sometimes referred Frequently there is a history of a long-standing, slowly grow-
to as a hyperfunctioning solitary nodule or toxic nodule. Occasion- ing lump in the neck. It is unusual for adenomas to produce thy-
ally two or three adenomas of similar character are present. rotoxicosis until they have achieved a diameter of greater than
3 cm303; up to that point, patients have subclinical hyperthyroid-
ism. The adenoma can undergo central necrosis and hemorrhage
Pathogenesis spontaneously, relieving the thyrotoxicosis, and the remainder of
Toxic adenomas are true follicular adenomas (for histopathologic the thyroid may then resume its function. Calcification in the
characteristics, see Chapter 14). The basic pathogenesis of many area of hemorrhage may take place and may be evident on sono-
toxic adenomas (up to 70%) is one of several somatic point muta- gram examination. Such calcification is usually macroscopic and
tions in the TSHR gene, commonly in the third transmembrane irregular and does not resemble the finely stippled calcification
loop.301,311 These single nucleotide substitutions cause amino suggestive of papillary cancers. The peripheral clinical manifesta-
acid changes that lead to constitutive activation of the TSHR tions of a toxic adenoma are generally milder than those of Graves
in the absence of TSH.312 It appears therefore that the TSHR is disease and are notable for the absence of infiltrative orbitopa-
allosterically switched from an off state to an on state. Similarly, thy and myopathy, although cardiovascular manifestations may
loss-of-function rather than gain-of-function mutations may also occur.
Laboratory Tests hypervascular, and consequently preoperative preparation with

iodine is not required. In the patient with overt thyrotoxicosis,
The results of laboratory tests depend on the stage and function however, a normal metabolic state should be restored with an anti-
of the adenoma. At first, serum thyroid hormone concentrations thyroid drug before surgery.
are normal except for borderline suppression of the serum TSH.
This, together with ultrasound examination to exclude multiple
nodules, confirms the diagnosis. Later a thyroid scan may show Subclinical Hyperthyroidism
localization of radioisotope in the palpated nodule, but this is
not obvious until TSH secretion is suppressed. If the nodule con-
Definition
tinues to grow, frank hyperthyroidism is accompanied by eleva- The availability of sensitive assays for TSH allowed the recog-
tion of serum thyroid hormone levels. Occasionally the serum nition of mild hyperthyroidism, in which there are no signs or
free T4 concentration is normal, and only the serum T3 level symptoms of thyrotoxicosis but the serum TSH is subnormal
is increased (T3 thyrotoxicosis). Incidental thyroid carcinoma despite normal serum free thyroid hormone concentrations. The
may rarely coexist within a gland exhibiting a hyperfunctioning term subclinical is somewhat of a misnomer because the condi-
adenoma. The incidence of carcinoma in these nodules is rare, tion is defined by biochemical characteristics, and it is preferable
but there are few clinical indicators of malignancy should it be to use the term mild thyroid dysfunction.317 Nonetheless, it is still
present. Thus if the nodule is not treated surgically it is reason- not clear whether a patient is classified as having mild hyperthy-
able to follow closely if any clinical or radiographic features of roidism simply because our ability to detect physiologic evidence
malignancy are seen.314 of excess thyroid hormone is less sensitive than our capacity to
measure changes in TSH. This is further complicated by the fact
Treatment that the hypothalamic-pituitary axis is sensitive to both serum
free T4 and T3, whereas the peripheral tissues such as the heart
Although hyperfunctioning adenomas may eventually cause clini- primarily sense the free T3 (see Chapter 11).318,319 It is easy to
cal hyperthyroidism, many do so slowly and others not at all.303 assume, given the wide normal range for free thyroid hormone
Therefore treatment of asymptomatic patients with functional concentrations, that an individual with a low-normal free T4 set-
adenomas is decided on an individual basis. Clinically euthyroid point for TSH secretion would have a reduced TSH if that con-
subjects who wish to avoid both surgery and radioiodine can in centration were increased by 50% but could still remain within
theory be followed with annual assessments. However, suppres- the normal range. In fact, in patients with primary hypothyroid-
sion of TSH below normal (particularly to <0.1 mU/L) indicates ism, small additional quantities of levothyroxine given to patients
hyperthyroidism, and therapy may be warranted. Two definitive with normal TSH will decrease TSH below normal without a
therapies are available: radioiodine and surgery. supranormal free T4.318 Thus the true lack of additional sensi-
tive biomarkers in the periphery makes it difficult to determine
Radioiodine Therapy whether all tissues are in fact hyperthyroid when the TSH is
In terms of the specificity of treatment, functioning thyroid nod- suppressed.
ules are candidates for radioiodine therapy. The radiation should On the other hand, in the now classic studies in the Framing-
in theory be directed almost exclusively to the diseased tissue. ham population over 60 years of age, the cumulative incidence of
This is because TSH is suppressed and the normal thyroid tis- atrial fibrillation over 10 years was 28% in patients with a serum
sue surrounding the nodule does not take up excess radioiodine. TSH concentration of 0.1 mU/L or less, whereas it was only 11%
However, this suppression may be incomplete, and a significant in those with serum TSH concentrations falling between 0.1 and
fraction of patients receiving radioiodine develop thyroid failure. 0.4 mU/L. The latter was only slightly higher than that in the
For the patient over age 18 with a nodule 5 cm in diameter or normal population.10,11 Similar results have been obtained in one
smaller, 131I is an appropriate treatment if the risk of eventual other prospective study.11 Furthermore, heart failure is the leading
hypothyroidism is acceptable to the patient. For such lesions, cause of increased cardiovascular mortality rate in both overt and
doses of radioiodine are given sufficient to result in the presence mild hyperthyroidism.320 Taken together these data support the
of 300 to 370 MBq (8–10 mCi) in the nodule at 24 hours based notion that a suppressed TSH is indicative of hyperthyroidism in
on the uptake.303 Clearly higher doses of RAI result in enhanced the heart.
success in treatment of the hyperthyroidism but also lead to an Bone density is another end point for such studies because it is
increased incidence of hypothyroidism.316 Recombinant TSH, well known that thyroid hormone causes a net resorption of corti-
used to enhance the RAIU to avoid a large treatment dose in cal bone321 and that lack of TSH may contribute to this phenom-
nontoxic multinodular goiters, is not appropriate here because it enon.34 Several studies demonstrate lower bone density in patients
will direct radioiodine into surrounding normal thyroid tissue. with mild thyrotoxicosis, although others do not.38,322 This is a
The potential for hypothyroidism also indicates the need for pro- subject of considerable interest because the condition is much
longed follow-up. more common than overt thyrotoxicosis (0.7% of the population
in NHANES III) and has broad implications with respect to the
Surgery cost of diagnosis, treatment, and follow-up.323 In general, nor-
Toxic nodules are readily treated by surgical excision. A hemithy- malization of thyroid function in postmenopausal women with
roidectomy may avoid the long-term development of hypothy- subclinical hyperthyroidism seems to improve bone density and
roidism and with modern surgical procedures can be performed certain aspects of cardiac function.324
on an outpatient basis or even under local anesthesia. Surgical Overall these data would generally favor treatment in the older
excision is always preferable in patients younger than 18 years of population, but unfortunately there are still no large, long-term
age to avoid the long-term consequences of irradiation, including randomized studies to allow evidence-based conclusions as to the
effects on perinodular tissue. The toxic adenoma is not diffusely risk-benefit ratio.325,326
Diagnosis population.99,333 Exposure to pharmacologic quantities of iodine

may cause occasionally iodide-induced thyrotoxicosis (IIT), also
The diagnosis of subclinical hyperthyroidism requires tests reveal- called Jod-Basedow, more so in iodine-deficient areas than in
ing several subnormal TSH concentration results spaced months iodine-sufficient areas.336,337 Elderly subjects with nodular thyroid
apart in the presence of normal free T3 and T4 concentrations. disease or latent Graves disease (i.e., with autonomous thyroid
Several studies show that suppressed TSH can normalize sponta- function and low TSH) are at risk. Such patients with underlying
neously over several years, particularly in patients without nodular thyroid disease may have normal or even high thyroidal radioio-
goiter.327,328 As with overt thyrotoxicosis, there are two sources of dine uptake. In contrast, radioiodine uptake is low in IIT patients
excess thyroid hormones, endogenous and exogenous. In a study without preexistent thyroid disease, obviously caused by the cyto-
of over 25,000 individuals attending health fairs in Colorado, 58% toxic effect of iodine excess on thyrocytes resulting in destructive
of those with a TSH less than 0.3 mU/L were receiving thyroid thyroiditis. IIT usually resolves spontaneously in 6 months.
hormones.329 When this is not being done intentionally for the Many drugs contain huge quantities of iodine, such as expec-
treatment of persistent thyroid carcinoma, it is easily treated by torants, kelp tablets, and iodinated contrast agents. The risk for
more careful monitoring of the levothyroxine dosage using serum developing IIT is 0.3% in unselected people after coronary angi-
TSH concentrations. Endogenous subclinical thyrotoxicosis has ography in iodine-deficient areas.338 Treatment of patients who
the same causes as overt thyrotoxicosis. In the population over 60, had thyroid autonomy before coronary angiography (with 20 mg
multinodular goiter is a more likely cause of hyperthyroidism than thiamazole and/or 900 mg sodium perchlorate, starting the day
it is in younger individuals especially in the United States. before angiography and continued for 2 weeks) was not effective
in preventing IIT.339,340 Close monitoring of high-risk patients
Treatment rather than prophylaxis is thus recommended, with beta blockers
if thyrotoxicosis occurs.341
There are insufficient data to conclude that individuals with serum
TSH concentrations greater than 0.1 mU/L due to hyperthyroid- Amiodarone-Induced Thyrotoxicosis
ism will benefit from treatment.134,325 However, treatment should
be considered in those over age 65 with cardiac disease or osteopo- Amiodarone is a potent class III antiarrhythmic drug. It has hypo-
rosis. There is increasing support for treatment of individuals with thyroid-like effects such as bradycardia, reduction of myocardial
persistently subnormal TSH concentrations less than 0.1 mU/L oxygen consumption, lengthening of the cardiac action potential,
(with normal free thyroid hormones) who are over age 65 and for and hypercholesterolemia342; these effects can be reversed by thy-
those younger than age 65 with cardiac disease or risk factors for roid hormone. Its main metabolite desethylamiodarone acts as a
cardiac disease or significant risk for osteoporosis.134 competitive inhibitor of T3 binding to thyroid hormone recep-
Identifying the cause of the hyperthyroidism allows assessment tor α (TRα) and as a noncompetitive inhibitor of T3 binding to
of the potential risks of treatment. At one extreme, the treatment of TRβ.343 One of the mechanisms of action of amiodarone might
mild Graves disease with radioiodine usually causes hypothyroid- thus be induction of a hypothyroid-like condition in extrathyroi-
ism, whereas this typically does not occur in patients with multi- dal tissues. The drug contains 37% iodine by weight and generates
nodular toxic goiter. Thus, in an asymptomatic patient with mild iodine excess; one 200-mg tablet/day releases 6 mg of iodide daily.
Graves disease, watchful waiting for several years, awaiting a pos- Amiodarone has obligatory and facultative effects on the thyroid.
sible spontaneous remission, may be the best course of action330; Obligatory effects occur in everyone taking the drug. They consist
if therapy is considered necessary, the chance of prolonged remis- of a transient rise of serum TSH up to 5 to 10 mU/L, caused by
sion after a course of antithyroid drug therapy is good. On the the Wolff-Chaikoff effect induced by the iodine overload, usually
other hand, patients with subclinical hyperthyroidism due to toxic followed by an escape of the Wolff-Chaikoff effect and sponta-
nodular goiter or a solitary hyperfunctioning adenoma can often neous normalization of TSH in 3 months. Serum total and free
be treated with a single dose of radioactive iodine with a relatively T4 and reverse T3 increase, and total and free T3 decrease due to
low risk of subsequent hypothyroidism. Thus the threshold for decreased metabolic clearance rate of T4 and inhibition of liver
treatment of such patients is lower. As always, the rationale for deiodinase type 1. Facultative effects of amiodarone develop in a
treatment, its risks, and its benefits should be carefully discussed subset of patients. Amiodarone-induced hypothyroidisim (AIH)
with the patient, and one should be guided by common sense and is caused by a failure to escape from the Wolff-Chaikoff effect.
not by the principle of simply treating an abnormal test result.331 It occurs especially in women with TPO antibodies and is more
prevalent in iodine-sufficient regions. Amiodarone-induced thyro-
Induced Hyperthyroidism toxicosis (AIT), in contrast, is more prevalent in iodine-deficient
regions. AIT type 1 is caused by iodine excess superimposed on
The incidence of hyperthyroidism corresponds in general to popu- preexistent thyroid disease such as Graves disease or nontoxic goi-
lation iodine nutrition. Rates are lower in iodine-sufficient coun- ter. AIT type 2 is due to the cytotoxic effect of amiodarone on
tries and higher in iodine-deficient countries mostly due to an thyrocytes resulting in transient destructive thyroiditis.344
excess of nodular thyroid disease in the elderly.332–334 In China,
the prevalence of overt and subclinical hyperthyroidism was like-
wise higher in iodine-deficient areas compared with iodine-suffi-
Epidemiology and Screening
cient areas.335 Iodine fortification in previously iodine-deficient In a prospective study with a median follow-up of 3.3 years in
regions will result in an adequate iodine intake but is associated an area with an average daily iodine intake of 150 μg, 8% of
with a transient increase in the incidence of hyperthyroidism patients taking amiodarone developed AIT and 6% AIH.345 Inci-
(mainly due to toxic nodular goiter); in the long run, however, dence rates of AIT were 1.9 and of AIH 1.6 per 100 person-years
the incidence of hyperthyroidism may be lower than the initial (Fig. 12.21). It is striking that no new cases of AIH developed
rate due to a decrease in the prevalence of thyroid nodules in the after 2 years on amiodarone therapy, whereas new cases of AIT
TABLE 12.10 Differences Between Amiodarone-

Thyroid dysfunction-free survival 1.00
Induced Thyrotoxicosis Type 1 and Type 2
0.95 Amiodarone- AIT Type 1 AIT Type 2
associated
hypothyroidism Underlying thyroid Yes No
0.90 abnormality
Amiodarone-
Onset after start amio- Short (3 months) Long (30 months)
0.85 associated
thyrotoxicosis darone
Thyroid antibodies Present in Graves Usually absent
0.80
0 1 2 3 4 5 Color flow Doppler High vascularity Low/absent vascu-
Time (years) sonography larity
• Fig. 12.21 Kaplan-Meier curve depicting the incidence of amiodarone- Thyroid radioiodine Low, normal, high Suppressed
associated thyrotoxicosis and hypothyroidism. (Redrawn from Ahmed S, uptake
Van Gelder IC, Wiesfeld AC, et al. Determinants of outcome of amioda-
Preferred treatment Antithyroid drugs Oral prednisone
rone-associated dysfunction. Clin Endocrinol. 2011;75:388–394.)
Amiodarone continu- No Possible
ation
continued to occur with continuation of amiodarone.345,346 Thus
one of every five to six patients taking amiodarone will develop Spontaneous remission No Frequent
overt thyroid dysfunction. It provides the rationale for the rec- Subsequent hypothy- No Possible (17%)
ommendation to measure TSH before starting amiodarone and roidism
at regular intervals during amiodarone.347 Limitations of regular
tests are, however, twofold. First, AIT type 2 often has a sudden, Subsequent definitive Generally yes No
unpredictable onset. It may happen shortly after a previous blood treatment
test found a perfectly normal TSH, which may thus give rise to a AIT, Amiodarone-induced thyrotoxicosis.
false sense of security. Second, a suppressed TSH might just indi-
cate subclinical hyperthyroidism, which spontaneously reverts to
a normal TSH in 30% to 50% of cases despite continuation of
amiodarone.346,348 AIT occurs without preceding subclinical AIT coadminister sodium perchlorate (not available in the United
in 64% of patients, and only 25% of patients with subclinical AIT States), which acutely inhibits further thyroidal iodine uptake. To
progress to overt AIT.348 AIT type 1 develops rather shortly after restrict its toxic side effects, NaClO4 should be used no longer
the start of amiodarone (median onset time is 3.5 months with than 4 to 6 weeks in a daily dose not exceeding 1 g (e.g., 500
just a single case occurring after 2.5 years), whereas the median mg twice daily). Amiodarone itself should be stopped, if feasi-
onset time of AIT type 2 is 30 months.349 Nowadays most AIT ble. Management is completely different in AIT type 2. Here the
patients have AIT type 2. An iodine-free analog of amiodarone has preferred drug is oral prednisone, in a daily dose of 30 mg.344
been developed, called dronedarone, to get rid of the side effects Tapering down prednisone can be started when TSH has become
caused by iodine excess. The pharmacologic properties of drone- normal, which takes about 3 months. In view of the self-limiting
darone, however, do not match those of amiodarone, and drone- character of AIT type 2, it is possible to continue amiodarone
darone has not displaced amiodarone in clinical practice. in these patients.350 Time to restoration of euthyroidism is little
affected by continuation of amiodarone in type 2 patients.
Diagnosis Occasionally it is difficult to decide whether type 1 or type 2
AIT exists, and mixed forms do occur. One may opt for triple ther-
About half of AIT patients experience complaints, mainly palpita- apy (prednisone + methimazole + NaClO4) under such circum-
tions but also weight loss and agitation.345 Biochemical diagnosis stances, also when the response to instituted treatment is too slow.
of AIT is by suppressed TSH and elevated FT4. FT3 can be nor- Some patients do not fare well, and guidelines recommend total
mal, however, due to the drug’s inhibition of type I deiodinase, thyroidectomy to be performed without delay in AIT patients with
and cases of T4 toxicosis occur. Although AIT type 1 currently deterioration of cardiac function (reduced left ventricular ejection
appears to be much less common than type 2, identifying the type fraction) or severe underlying cardiac disease and in those patients
may still be of value because the treatments of types 1 and 2 differ. whose thyrotoxicosis is unresponsive to medical therapies.344
Diagnostic features are listed in Table 12.10. Type 2 patients usu-
ally have no goiter and no thyroid antibodies. Most useful is color
flow Doppler sonography that provides a noninvasive, real-time
Prognosis
assessment of thyroid vascularity. Patients with AIT have more major adverse cardiovascular
events than patients who remain euthyroid (31.6% vs. 10.7%, p
Management < 0.01).351 Mortality is also higher in AIT patients with severe left
ventricle dysfunction (31% at ejection fraction <50% vs 14% at
Specific ETA guidelines recommend treatment with antithyroid ejection fraction ≥50%).352 Total thyroidectomy improves cardiac
drugs in AIT type 1344 (Fig. 12.22). The iodine-replete thyroid function and mortality, especially in those with ejection fraction
gland of AIT patients is less sensitive to methimazole, requiring below 40% preoperatively.353
rather high daily doses of 40 to 60 mg for longer periods than Thyroid ablation is preferred before reintroduction of amioda-
usual. To increase the response to methimazole, one may opt to rone after successful treatment of AIT type 1.354 Continuation of
Amiodarone-induced thyrotoxicosis
(AIT)
AIT 1 Suspected mixed/indefinite AIT AIT 2
Stop amiodarone, if feasible Amiodarone can be continued
Emergency thyroidectomy in selected cases
Thionamides Thionamides Oral

± sodium perchlorate ± sodium perchlorate glucocorticoids
± oral glucocorticoids
Euthyroidism Poor response Remission
Definitive thyroid treatment Add oral glucocorticoids

with thyroidectomy or radioiodine (if not given initially) Follow-up
• Fig. 12.22 Algorithm for the management of amiodarone-induced thyrotoxicosis. (Redrawn from Bartalena
L, Bogazzi F, Chiovato L, et al. 2018 European Thyroid Association (ETA) guidelines for the management of
amiodarone-associated thyroid dysfunction. Eur Thyroid J. 2018;7:55–66.)
amiodarone after cure of AIT type 2 is feasible; some patients will of inappropriate TSH secretion in the presence of elevated cir-
experience recurrent AIT (6–18%), which apparently is less severe culating levels of thyroid hormones because the beta isoform is
and more easy to handle.354,355 Permanent hypothyroidism devel- responsible for the regulation of TSH. Similarly, TRβ is highly
ops in 17% of cured AIT type 2 patients, occurring at 10 months expressed in the liver, which is also functionally hypothyroid in
(range 6–24 months) after reaching euthyroidism.350,356 RTHβ patients. However, in tissues that express primarily the
TRα isoform, such as the heart and bone, tissue-specific hyper-
thyroidism may be present because these TRα expressing tissues
Hyperthyroidism Due to Thyrotropin sense the higher circulating thyroid hormone levels appropriately
as high.359–361 These patients may therefore present with a hyper-
Secretion thyroid appearance with tachycardia, nervousness, and goiter
associated with an elevated free T4 and may require tissue-specific
Pituitary Tumor treatment such as with β-adrenergic receptor blocking agents
Excess TSH is an exceedingly rare cause of hyperthyroidism. rather than antithyroid drugs (see Chapter 13 for a more extensive
However, pituitary thyrotroph tumors cause this condition and discussion of RTH). RTHβ should be suspected in patients who
may present as a Graves-like syndrome with diffuse goiter and present with hyperthyroidism and inappropriate TSH secretion
substantial thyrotoxicosis. Only 1% of pituitary adenomas are without an apparent pituitary adenoma. Furthermore, a careful
TSH producing and 25% may co-secrete growth hormone or pro- family history should be taken as the disorder is inherited in an
lactin.357 Guidelines for the management of such patients have autosomal dominant fashion. In contrast to RTHβ, RTHα due to
recently been released.358 Laboratory studies demonstrating an mutations in TRα isoform leads to a syndrome of tissue-specific
inappropriately detectable or somewhat elevated TSH in the pres- hypothyroidism because the TRα isoform is not involved in the
ence of elevated thyroid hormone levels must first be confirmed regulation of the HPT axis and thus thyroid hormone levels are
by eliminating assay artifacts. This condition is discussed in depth not elevated.362
in Chapter 9 and must be differentiated from the rare patient who
has resistance to thyroid hormone (RTH).359–361
Tumor Chorionic Gonadotropin-Induced
Thyroid Hormone Resistance Hyperthyroidism
The syndromes of RTH are now known to be caused by inher- hCG exhibits specificity crossover with the TSHR (see ear-
ited mutations in both of the thyroid hormone receptor isoforms. lier discussion under “Pregnancy and the Thyroid”). Thyroid
RTHβ (due to mutations in the beta isoform) leads to a syndrome hyperfunction may therefore accompany hydatidiform mole,
choriocarcinoma, or metastatic embryonal carcinoma of the tes-

tis.258 Such neoplasms, particularly hydatidiform mole, elaborate
differentially glycosylated hCG molecules that exhibit crossover
specificity for binding to the TSHR and can induce variable
degrees of thyroid overactivity.232,363 Some patients have clinically
overt thyrotoxicosis; however, clinical manifestations are usually
not prominent, and goiter is absent or minimal. The free T4 and
free T3 levels are increased, and TSH values are suppressed. The
possibility of a molar pregnancy should be considered in a young
woman with hyperthyroidism and amenorrhea because the appro-
priate therapy is evacuation of the uterus.
Transient Thyrotoxicosis
Overview
As mentioned at the outset of this chapter, transient thyrotoxi-
cosis must be differentiated from the sustained hyperthyroidism • Fig. 12.23 Lymphocytic thyroiditis in a patient with transient thyrotoxico-
of Graves disease and other causes of hyperthyroidism. Transient sis (painless thyroiditis) secondary to autoimmune (Hashimoto) thyroiditis.
thyrotoxicosis is caused by thyroid cell breakdown, and the hyper- Notice the diffuse lymphocytic invasion of the tissue, including the follicular
thyroid symptoms are of abrupt onset and shorter duration. This epithelium, and the loss of follicles. Multinucleated giant cells may also
process may be followed by recovery of thyroid function or the be seen in the follicular lumen. (Courtesy Dr. Vania Nosé, Brigham and
development of transient or permanent thyroid failure. The discus- Women’s Hospital, Boston, MA.)
sion in this chapter focuses on thyroiditis as the most common
cause of transient thyrotoxicosis, and this disorder is covered more shows diffuse or local lymphocytic infiltration, varying degrees of
completely in Chapter 13 because Hashimoto disease most com- fibrosis, and disruption of the follicular architecture (Fig. 12.23).
monly causes hypothyroidism after the initial phase of transient
hyperthyroidism. Unfortunately transient thyrotoxicosis continues Transient Thyrotoxicosis From Painless Autoimmune
to have a confusing nomenclature, which can be clarified as follows: Thyroiditis
Painless autoimmune thyroiditis may occur postpartum or spon-
Autoimmune thyroiditis: In the autoimmune forms (Hashimoto taneously. Postpartum thyroiditis is the most common example;
thyroiditis) there are typically no local symptoms of thyroid its pathophysiology, postpartum enhancement of thyroid-directed
inflammation, leading to the terms silent or painless thyroiditis, autoimmunity (Hashimoto disease), is analogous to the postpar-
also referred to as lymphocytic thyroiditis or hashitoxicosis. This tum exacerbation of Graves disease (see “Graves Disease in the
condition may uncommonly present with thyroid tenderness if Postpartum Period”). The incidence of postpartum thyroiditis var-
the thyroid has expanded rapidly, stretching the capsule. ies but may occur in as many as 10% of women and in more than
Viral thyroiditis: In what is thought to be postviral thyroiditis 30% of those with positive TPOAb and even a larger fraction in
(also termed subacute, de Quervain, or granulomatous thyroid- patients with type 1 diabetes mellitus.245,289 In women found to
itis), thyroid tenderness may be the most prominent symptom, be TPOAb positive prenatally, postpartum assessment of thyroid
and thyrotoxicosis is rare and typically self-limited, although function is recommended at 3, 6, and 12 months. Thyrotoxicosis
this form may rarely also be painless. from spontaneous autoimmune thyroiditis has all the same char-
Acute thyroiditis: Acute thyroiditis due to bacterial or fungal in- acteristics as postpartum thyroiditis and is seen in patients early
fections is only rarely accompanied by thyrotoxicosis, and the in their development of classic Hashimoto disease and before the
local symptoms predominate (see Chapter 13). onset of hypothyroidism.
Drug-induced thyroiditis: Thyroiditis may also be drug induced,
the principal offenders being amiodarone and lithium. Some of Transient Thyrotoxicosis from Painful Autoimmune
the new small molecule kinase inhibitors (such as sunitinib) may Thyroiditis
also cause this form of thyroiditis, resulting eventually in hypo- Although some patients may present with local thyroid tender-
thyroidism.364,365 In addition, the introduction of immunother- ness, this occurrence is uncommon. Such tender episodes, which
apy for cancer treatment, including CTLA4 inhibitors and PD1 may be unilateral, may recur until the thyroid gland is completely
inhibitors, has dramatically increased the incidence of several destroyed by the disease process. Only rarely does the pain persist,
endocrine toxicities, including transient hyperthyroidism.366 sometimes requiring surgical intervention.
Transient Thyrotoxicosis Due to Autoimmune Clinical Presentation of Transient Autoimmune

(Hashimoto) Thyroiditis Thyrotoxicosis
As described earlier, Hashimoto disease causes two different thyro- More than 75% of patients are women who present with the
toxicosis-associated transient syndromes. The most common is the acute onset of symptoms of thyrotoxicosis, usually nervousness,
painless form in which the symptoms of thyrotoxicosis are usually palpitations, and irritability; they can often pinpoint the time of
mild and predominate; the much more uncommon form has a recent onset. In the postpartum syndrome, symptoms present 4 to
painful presentation probably secondary to a more acute onset. 12 months after delivery but may be mild and overlooked in the
Histopathologic examination in such patients with thyroiditis myriad of events involved in the care of the newborn.288 After 1 to
Graves disease
Thyroid function
Transient
thyrotoxicosis
Delivery
Transient
Hashimoto thyroiditis
0 2 4 6 8
Time after delivery (months)
• Fig. 12.24 The postpartum thyroid syndromes. These potential patterns
of thyroid dysfunction may be seen in the postpartum period.
2 months the thyrotoxic symptoms fade but are often replaced by • Fig. 12.25 Subacute (viral or postviral) thyroiditis. Diffuse neutrophilic
those suggesting hypothyroidism (Fig. 12.24). invasion with active destruction of follicles and a multinucleated giant cell.
In a significant number of postpartum patients the thyrotoxic Fibrosis and near-complete loss of follicles have occurred. (Courtesy Dr.
phase is too mild to be noticed, and the patient presents somewhat Vania Nose, Brigham and Women’s Hospital, Boston, MA.)
later after delivery with hypothyroid symptoms. The physical
examination shows mild signs of thyrotoxicosis, tachycardia being
the most prominent, without the specific eye signs or dermopathy (20–40 mg/day) may decrease the duration of the thyrotoxic
associated with Graves disease. The thyroid gland is normal in size phase but is typically not needed except when the painful form
but may be firm if the Hashimoto disease is chronic. of the disease is present. If mild and brief, the hypothyroid phase
may also not require treatment. When treatment with levothyrox-
Diagnosis ine is required, it should be withdrawn slowly approximately 6
months later because the hypothyroidism is often not permanent.
Thyrotoxicosis is usually mild and is reflected in the degree of
suppression of the serum TSH level and elevation of the serum
free T4. Significant elevation of the TPOAb is typical. Systemic
Subacute Thyroiditis
manifestations of inflammation are lacking, and the erythrocyte Subacute thyroiditis (also termed granulomatous, giant cell, or de
sedimentation rate is normal or nearly normal, but the ultra- Quervain thyroiditis) is thought to be caused directly or indirectly
sound may indicate the heterogeneity of an inflamed gland. If by a viral infection of the thyroid gland and often follows an upper
true hyperthyroidism cannot be eliminated as a diagnosis on clini- respiratory illness. A tendency to appear in the spring in the northern
cal grounds, TRAb should be measured or an RAIU test should latitudes has been noted, and again it predominates in the female.
be performed unless the patient is nursing. The classic decreased The mumps virus has been implicated in some cases; coxsackievirus,
RAIU is due partly to feedback suppression of TSH secretion but influenza virus, echovirus, and adenoviruses may also be etiologic
also to thyroid follicular cell destruction. The tendency of the dis- agents. Positive TPOAb are present transiently during the active
order to pass through a hypothyroid phase is not surprising in phase of the disease, although some patients may retain evidence of
view of the extensive depletion of Tg, which is processed to T4 and thyroid autoimmunity for many years. A small number of patients
not replaced by the dysfunctional cells. eventually develop AITD.369 Subacute thyroiditis is uncommon,
but mild cases may be mistakenly diagnosed as pharyngitis.
Natural History Pathology
The duration of the thyrotoxic phase, typically not severe enough The histopathologic changes are different from those in Hashi-
to require treatment, averages about 1 to 2 months. About one- moto disease. The lesions are patchy in distribution and vary in
half of the patients return to a euthyroid phase and remain well in their stage of development from area to area. Affected follicles
the short term. In the remaining half, a hypothyroid phase may are infiltrated predominantly with mononuclear cells and show
follow and may last from 2 to 9 months. In most, there is even- disruption of epithelium, partial or complete loss of colloid, and
tual restoration of euthyroidism, but some develop permanent fragmentation and duplication of the basement membrane (Fig.
hypothyroidism years later.367,368 About one-third retain a goiter, 12.25). To this extent, the histopathologic appearance may resem-
usually with persistence of thyroid autoantibodies in the serum. ble that in Hashimoto disease. A characteristic feature is the well-
The opposite sequela, recurrence of thyrotoxicosis, may also occur developed follicular lesion that consists of a central core of colloid
months or years after restoration of a euthyroid state or particu- surrounded by the multinucleated giant cells (MNGCs), from
larly after pregnancy. which stems the designation giant cell thyroiditis. Colloid may be
found in the interstitium or within the giant cells. The follicu-
Treatment lar changes progress to form granulomas. Interfollicular fibrosis
and an interstitial inflammatory reaction are present to varying
The thyrotoxic phase may require alleviation of the peripheral degrees. When the disease subsides, an essentially normal histo-
manifestations through the use of beta blockers. Prednisone logic appearance is restored.
600
500
400
300 40
200
100 20
Tg (ng/mL)
16 50 10
TSH (µU/mL)
14 40 8
12 30 6
10 20 4
Normal
range
8 10 2
FTI
6 0 0
4
2
10 20 30 40 50 60 70 150
Days from the onset of symptoms
• Fig. 12.26 Thyroid function in a patient during the course of subacute (viral or postviral) thyroiditis. Dur-
ing the thyrotoxic phase (days 10–20), the serum thyroglobulin (Tg) concentration was greatly elevated,
the free thyroxine index (FTI) was high, and the thyroid-stimulating hormone (TSH) was suppressed; the
erythrocyte sedimentation rate was 86 mm/hour, and the thyroidal radioactive iodine uptake (RAIU) was
2%. The Tg level and the FTI declined in parallel. During the phase of hypothyroidism (days 30–63), when
the FTI was below normal, a modest transient increase in serum Tg occurred in parallel with the increase
in serum TSH. All parameters of thyroid function were normal by day 150, 5 months after the onset of
symptoms. (From DeGroot LJ, Larsen PR, Hennemann G. Acute and subacute thyroiditis. In: DeGroot LJ,
Larsen PR, Hennemann G, eds. The Thyroid and Its Diseases. 6th ed. New York: Churchill Livingstone;
1996:705.)
Pathophysiology On palpation at least part of the thyroid is slightly to moder-

Apoptosis of follicular epithelium and loss of follicular integ- ately enlarged, firm, often nodular, and usually exquisitely tender,
rity are the primary events in the pathophysiology. Tg, T4, and one lobe frequently being more severely affected than the other.
iodinated Tg fragments are released into the circulation, often in Indeed the symptoms may be truly unilateral. The overlying
quantities sufficient to elevate not just the serum Tg level but also skin may be warm and erythematous. Occasionally the locus of
the serum free T4 level, producing clinical thyrotoxicosis and sup- maximal involvement migrates over the course of a few weeks to
pressing TSH secretion. As a result, the RAIU decreases to low lev- other parts of the gland. The disease usually subsides within a few
els, and hormone synthesis ceases. Later in the disease, when stores months, leaving no residual deficiency of thyroid function in 90%
of preformed hormone are depleted, serum T4 and T3 concen- of patients. In rare patients the disease smolders, with repeated
trations decline, sometimes into the hypothyroid range, and the exacerbations over many months, hypothyroidism sometimes
serum TSH level rises, often to elevated values exactly as occurs in being the final result.
silent thyroiditis (Fig. 12.26). As the disease becomes inactive, the
RAIU may be greater than normal for a time as hormone stores Diagnosis
are repleted. Ultimately, when hormone secretion resumes, serum The laboratory findings vary with the phase of the disease. During
T4 and T3 concentrations rise, and serum TSH concentration the active phase, the erythrocyte sedimentation rate is increased,
decreases to normal values. often to a remarkable extent (>100 mm/hour). Indeed a diagnosis
of active subacute thyroiditis is hardly tenable when the sedimen-
Clinical Picture tation rate is normal. The white blood cell count is normal or, at
The characteristic feature is the gradual or sudden appearance of most, moderately increased. The serum Tg level is characteristi-
pain in the region of the thyroid gland with or without fever. cally high, in keeping with the degree of thyroid destruction.
The pain, which is aggravated by turning the head or swallow- Subacute thyroiditis must be differentiated from acute hemor-
ing, characteristically radiates to the ear, jaw, or occiput and rhagic degeneration in a preexisting thyroid nodule, Hashimoto
may mimic disorders arising in these areas. The absence of pain disease with painful recurrence (see earlier), acute pyogenic thy-
does not exclude the diagnosis, because biopsy-proven painless roiditis or fungal infection, and rarely thyroid malignancy with
subacute thyroiditis occurs, but it must be distinguished from painful nodules. Acute painful exacerbations of Hashimoto thy-
acute autoimmune thyroiditis. Hoarseness and dysphagia may roiditis may be difficult to distinguish from subacute thyroiditis.
be present; patients may complain of palpitation, nervousness, Lack of elevation of the erythrocyte sedimentation rate and high
and lassitude. The latter symptoms can be extreme, considering titers of thyroid autoantibodies strongly suggest the former. Acute
the local nature of the disease, and suggest a systemic compo- pyogenic thyroiditis is distinguished by the presence of a septic
nent. Although acute manifestations are present in severe cases, focus elsewhere, by a greater inflammatory reaction in the tissues
in milder disease symptoms may be present for months yet are adjacent to the thyroid, and by much greater leukocytic and febrile
often overlooked. responses (see Chapter 13). The RAIU and thyroid function are
usually preserved in acute pyogenic thyroiditis. Rarely, widespread thyroid hormone but may adamantly deny it. In other instances,
infiltrating cancer of the thyroid can present with a clinical and large doses of thyroid hormone or other thyroactive material may
laboratory picture almost indistinguishable from that of subacute be given without the knowledge of the patient, usually as part of a
thyroiditis. Ultrasound and fine-needle aspiration should be per- regimen for weight reduction. Some “natural” products for weight
formed if this is a consideration. reduction stated not to contain thyroid hormone nonetheless do.
Symptoms are typical of thyrotoxicosis and may be severe.
Treatment In the absence of preexisting disease of the thyroid, the diagno-
In mild cases, aspirin or nonsteroidal antiinflammatory drugs or sis is made from the combination of typical thyrotoxic manifesta-
cyclooxygenase 2 (COX2) inhibitors may control the symptoms. tions, together with thyroid atrophy and hypofunction. Infiltrative
With more severe pain, glucocorticoids (e.g., prednisone up to 40 ophthalmopathy never occurs, but lid lag, stare, and other thyro-
mg/day) are the only solution for the extreme discomfort. This toxic eye signs may be present; TSH levels are suppressed. Serum
drug may be required for several months and should then be with- T4 concentrations are increased unless the patient is taking T3,
drawn gradually. If the TSH is not suppressed, TSH-suppressive in which case they will be subnormal. Serum T3 concentrations
therapy with levothyroxine may decrease the size of the gland, are increased in either case. Hypofunction of the thyroid gland is
relieving the pressure on the thyroid capsule. TSH is needed for evidenced by the subnormal values of RAIU. The presence of low,
thyroid cell regeneration, so such therapy should be decreased as rather than elevated, values of serum Tg is a clear indication that
the symptoms subside. the thyrotoxicosis results from exogenous hormone rather than
thyroid hyperfunction.
This disorder may be confused with other varieties of thyro-
Drug-Associated Thyroiditis toxicosis associated with a subnormal RAIU and absence of goiter,
Thyroiditis is an uncommon complication of pharmacotherapy. including silent thyroiditis, ectopic thyroid tissue, and hyperfunc-
Amiodarone is an important exception and was discussed earlier. tioning metastatic follicular carcinoma. Evidence for the two lat-
Most of the thyroiditis associated with various therapeutic agents ter disorders can be obtained by demonstration of the ectopic
appears to be due to drug-induced exacerbation of underlying focus or foci by external radioiodine scanning or the presence
autoimmune disease. This effect is understandable with agents of normal to elevated serum Tg concentrations. Differentiation
that are specifically administered to modify the immune system. from silent thyroiditis may be difficult. The presence of TPOAb
They include IL2, interferon alpha, granulocyte/macrophage points to painless chronic autoimmune thyroiditis, whereas a firm
colony-stimulating factor (GM-CSF), and the newer immune thyroid and brief history suggest the painless variant of subacute
therapy modulators, all of which can precipitate silent thyroid- thyroiditis. Treatment of thyrotoxicosis factitia consists of with-
itis.108,366,370,371 This has also been described with lithium and the drawing the offending medication. Psychiatric consultation is
GnRH agonist leuprolide, but the pathophysiologic mechanism often required.
is obscure.372–374
Thyroiditis has been found in association with multitargeting Hamburger Thyrotoxicosis
kinase inhibitors such as sunitinib and sorafenib given for a variety
of tumors, including gastrointestinal stromal tumors, hepatocel- An unusual form of exogenous thyrotoxicosis occurred in the
lular carcinoma, and renal cell carcinoma.365,375 This may present midwestern portion of the United States in 1984 and 1985. The
as subacute thyroiditis with a suppressed TSH as the major mani- source was the inclusion of large quantities of bovine thyroid in
festation of the early phase but then progress to destruction of ground beef preparations.377 When the slaughtering practices were
the gland through an unclear mechanism. Although imatinib has changed, this condition disappeared. Such a possibility, although
been associated with an increase in levothyroxine requirements remote, should be considered, especially if one is confronted with
in hypothyroid patients (analogous to the effects of phenytoin, epidemic exogenous thyrotoxicosis.
carbamazepine, and rifampin), those changes are independent of
thyroid function.376 Thyrotoxicosis Due to Extrathyroidal Tissue
Struma Ovarii
Other Causes of Thyrotoxicosis With a Low Thyroid tissue may be present in 5% to 10% of ovarian terato-
Radioiodine Uptake mas, and occasionally such foci are hyperfunctional.378,379 About
5% to 10% of these tumors are bilateral. Although thyrotoxicosis
In addition to silent and subacute thyroiditis, several other entities is unusual, it may occur in as many as 8% to 10% of patients.
should be considered in the patient with thyrotoxicosis in whom Rarely, males with germ cell tumors may also develop hCG-
the thyroid gland is either not palpable or not enlarged and who induced hyperthyroidism.380
has biochemical findings of thyrotoxicosis accompanied by a low
RAIU. Clinical Presentation
Patients present with variable degrees of thyrotoxicosis but with-
out goiter and generally have lower abdominal symptoms such
Thyrotoxicosis Factitia as pain or a mass. Rarely ascites is present. Laboratory studies
Thyrotoxicosis that arises from the ingestion, usually chronic, of show reduced TSH and increased free T4 of a variable degree,
excessive quantities of thyroid hormone usually occurs in individu- but the RAIU is low. The Tg may be elevated, particularly if the
als with a background of underlying psychiatric disease, especially teratoma is malignant and has metastasized to the peritoneum.
in paramedical personnel who have access to thyroid hormone Abdominal CT scan or MRI shows a multilocular ovarian mass
or in patients for whom thyroid hormone medication has been or masses.381 Rarely a struma ovarii is accompanied by Graves
prescribed in the past. Generally the patient is aware of taking disease.382
Treatment vary and the metastatic disease is usually obvious from radio-
The patient should be rendered euthyroid if thyrotoxicosis is sig- logic studies. On occasion, the presentation may be confusing
nificant, followed by removal of the involved ovary or ovaries. if the patient is receiving TSH-suppressive therapy, and diag-
Therapeutic radioiodine will be required for metastatic disease nosis will require its discontinuation. In spite of that, TSH will
after ablation of the normal thyroid gland. remain suppressed and the serum free T4 is elevated. Treatment
of this condition is typical for that of thyroid carcinoma and
Thyrotoxicosis Due to Metastatic Thyroid is described in Chapter 14. In patients with thyrotoxicosis due
to metastatic tumor, serum Tg is quite elevated, indicating
Carcinoma that the thyrotoxicosis is caused by thyroidal tissue that is not
In general, thyroid carcinomas are made up of poorly function- located in the neck. An RAIU during the thyrotoxic phase will
ing tissue. On occasion, follicular thyroid carcinomas will have show no neck uptake due to TSH suppression even if the thy-
sufficient function when combined with the total mass of the roid is still present.
metastases to result in an elevation in serum free T4 or T3 and
may even be seen in Graves disease with TRAbs activating the References
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Hyperthyroid Disorders

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12

GRAVES DISEASE Graves dermopathy 0.5 4

ICLs β EXISTENTIAL FACTORS

21% Class II+

70 TABLE 12.6 Advantages and Disadvantages

TABLE 12.7 Clinical Conditions That Favor a Graves’ disease:

Percentage of patients treated (%)

ATD, Antithyroid drug; RAI, radioactive iodine

100 No GO at baseline (n = 194)

74% 20% 5.8% 0.3%

Orbital fibroblast PLC

Hyaluronic acid (HA)

Expanded orbital muscles

that GO immunoglobulins exert their action via TSHR/IGF1R 100

No differences are found in the frequency of known susceptibil- 100

TABLE 12.8 Clinical Assessment of the Patient With

All patients with GO

Mild Moderate to severe Sight threatening (DON)

Stable and Progression i.v. GCs Inactive Prompt

Rehabilitative surgery i.v. GCs

of fetal thyrotoxicosis. Fortunately fetal and neonatal thyrotoxi- 6

Diagnosis TABLE 12.9 Complications of Hyperthyroidism in

population risk of giving birth to a child who has a birth defect

pregnancy if possible. Nevertheless, if antithyroid drug require-

Serum T3 (mmol/L) 5.5 250

IR, per 100,000 py

On palpation, the characteristics of the goiter are the same as

B those of the more common nontoxic multinodular goiter. In as

24 scan and ultrasound examination will confirm the diagnosis as

mU/L are not usually associated with significant clinical symp-

(see “Subclinical Hyperthyroidism”). For patients with established

thyrotoxicosis, an RAIU with scan will help in gauging the dose of

C 131I to be administered as well as identify the autonomously func-

in Europe so that 24-hour RAIU values of 20% to 30% are not

Laboratory Tests hypervascular, and consequently preoperative preparation with

Diagnosis population.99,333 Exposure to pharmacologic quantities of iodine

TABLE 12.10 Differences Between Amiodarone-

AIT 1 Suspected mixed/indefinite AIT AIT 2

Stop amiodarone, if feasible Amiodarone can be continued

Emergency thyroidectomy in selected cases

Thionamides Thionamides Oral

Euthyroidism Poor response Remission

Definitive thyroid treatment Add oral glucocorticoids

choriocarcinoma, or metastatic embryonal carcinoma of the tes-

Transient Thyrotoxicosis Due to Autoimmune Clinical Presentation of Transient Autoimmune

Pathophysiology On palpation at least part of the thyroid is slightly to moder-

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70 TABLE 12.6 Advantages and Disadvantages

TABLE 12.7 Clinical Conditions That Favor a Graves’ disease:

TABLE 12.8 Clinical Assessment of the Patient With

Diagnosis TABLE 12.9 Complications of Hyperthyroidism in

TABLE 12.10 Differences Between Amiodarone-