Thyroid Disorders

Michael P. Kane and Gary Bakst

KEY CONCEPTS
1 Thyrotoxicosis is most commonly caused by Graves’
disease, which is an autoimmune disorder in which
5
Chapter 96
Adjunctive therapy with !-blockers controls the
adrenergic symptoms of thyrotoxicosis but does not
thyroid-stimulating antibody (TSAb) directed against the correct the underlying disorder; iodine may also be used
thyrotropin receptor elicits the same biologic response as adjunctively in preparation for surgery and acutely for
thyroid-stimulating hormone (TSH). thyroid storm.
2 Hyperthyroidism may be treated with antithyroid drugs such 6 Many patients choose to have ablative therapy with
as methimazole (MMI) or propylthiouracil (PTU), radioactive 131
I rather than undergo repeated courses of MMI or
iodine (RAI: sodium iodide-131 [131I]), or surgical removal of PTU treatment; most patients receiving RAI eventually
the thyroid gland; selection of the initial treatment approach become hypothyroid and require thyroid hormone
is based on patient characteristics such as age, concurrent supplementation.
physiology (eg, pregnancy), comorbidities (eg, chronic 7 Hypothyroidism is most often due to an autoimmune
obstructive lung disease), and convenience. disorder known as Hashimoto’s thyroiditis.
3 MMI and PTU reduce the synthesis of thyroid hormones 8 The drug of choice for replacement therapy in
and are similar in e!cacy, although their dosing ranges hypothyroidism is levothyroxine.
di"er by 20-fold. Overall, PTU has a greater incidence of side
9 Studies of combination therapy with levothyroxine and
e"ects. Agranulocytosis is a rare but severe adverse e"ect
liothyronine have not shown reproducible bene#ts. This
associated with both medications.
approach to the treatment of hypothyroidism requires
4 Response to MMI and PTU is seen in 4 to 6 weeks and further study.
therefore !-blocker therapy may be concurrently initiated
Monitoring of levothyroxine replacement therapy is
to reduce adrenergic symptoms. Maximal response is
achieved by observing clinical signs and symptoms and
typically seen in 4 to 6 months; treatment usually continues
by measuring the serum TSH level. An elevated TSH
for 1 to 2 years, and therapy is monitored by clinical signs
indicates under-replacement; a suppressed TSH indicates
and symptoms and by measuring the serum concentrations
over-replacement.
of TSH and free thyroxine (FT4).

secretion maintain peripheral free thyroid hormone levels within

BEYOND THE BOOK a narrow range. Patients seek medical attention for evaluation of
To get a basic understanding of hyperthyroidism and hypo- symptoms due to abnormal thyroid hormone levels or because of
thyroidism, visit the Websites of National Institutes of Health di"use or nodular thyroid enlargement.
and National Institute of Diabetes and Digestive and Kidney
Diseases for a quick overview: Thyroid Hormone Synthesis
https://www.niddk.nih.gov/health-information/endocrine- !e thyroid hormones thyroxine (T4) and triiodothyronine (T3)
diseases/hyperthyroidism (Fig. 96-1) are formed within thyroglobulin (TG), a large glycopro-
https://www.niddk.nih.gov/health-information/endocrine- tein synthesized in the thyroid cell. Because of the unique tertiary
structure of this glycoprotein, iodinated tyrosine residues present in
diseases/hypothyroidism
TG are able to bind together to form active thyroid hormones.
Iodide is actively transported through the basolateral mem-
brane via a Na+/I" symporter from the extracellular space into the
thyroid follicular cell against an electrochemical gradient, driven by
INTRODUCTION the coupled transport of sodium.1 Structurally related anions such as
!yroid hormones a"ect the function of virtually every organ sys- thiocyanate (SCN"), perchlorate (ClO4"), and pertechnetate (TcO4")
tem. In a child, thyroid hormone is critical for normal growth and are competitive inhibitors of iodine transport.1 In addition, bromine,
development. In an adult, the major role of thyroid hormone is to fluorine, and, under certain circumstances, lithium block iodide
maintain metabolic stability. Substantial reservoirs of thyroid hor- transport into the thyroid (Table 96-1). Inorganic iodide that enters
mone in the thyroid gland and blood provide constant thyroid hor- the thyroid follicular cell is ushered through the cell to the apical
mone availability. In addition, the hypothalamic-pituitary-thyroid membrane, where it is transported into the follicular lumen by pen-
axis is exquisitely sensitive to small changes in circulating thy- drin, and possibly other transport proteins.1 Located on the luminal
roid hormone concentrations, and alterations in thyroid hormone side of the apical membrane, thyroid peroxidase oxidizes iodide and
1241

AL G r a w a n y
1242
I I NH2 NH2
3,5,3',5'-Thyroxine 3' 3
HO O CH2 CH COOH HO CH2 CH COOH
(T4) 5' 5
I I Tyrosine
I I NH2 NH2
I NH2 I
3,5,3'-Triiodothyronine HO O CH2 CH COOH HO CH2 CH COOH HO CH2 CH COOH
(T3)
I I
SECTION

I I NH2 Monoiodotyrosine Diiodotyrosine

(MIT) (DIT)
3,3',5'-Triiodothyronine HO O CH2 CH COOH
(reverse T3, rT3, T3')
I I I NH2

HO O CH2 CH COOH
FIGURE 96!1 Structure of thyroid hormones.
10 I

Triiodothyronine (T3)
I I NH2
Endocrinologic Disorders

HO O CH2 CH COOH
TABLE 96!1 Thyroid Hormone Synthesis and Secretion I I
Inhibitors Thyroxine (tetraiodothyronine, T4)
Mechanism of Action Substance
FIGURE 96!3 Scheme of coupling reactions. After tyrosine is
Blocks iodide transport into the Bromine
thyroid Fluorine iodinated to form monoiodotyrosine (MIT) or diiodotyrosine
Lithium (DIT) (organi#cation of the iodine), MIT and DIT combine to form
Impairs organi#cation and coupling Thionamides triiodothyronine (T3) or two molecules of DIT combine to form
of thyroid hormones Sulfonamide thyroxine T4 (coupling).
Salicylamide
Antipyrine
Inhibits thyroid hormone secretion Iodide (large doses) Lithium

DIT constitute T3. In addition to its role in iodine organification,

the hemoprotein thyroid peroxidase also catalyzes the formation of
T4 iodothyronines (coupling).
Plasma Iodide Secretion Iodine deficiency causes an increase in the MIT:DIT ratio
in TG and leads to a relative increase in the production of T3:T4.
Basement Transport Because T3 is more potent than T4, the increase in T3 production in
membrane iodine-deficient areas may be beneficial. !e thionamide drugs used
I-recycling to treat hyperthyroidism inhibit thyroid peroxidase and thus block
Phagosome
Nucleus thyroid hormone synthesis.
!yroglobulin is stored in the follicular lumen and must reenter
ER
Lysosome the cell, where the process of proteolysis liberates thyroid hormone
TG synthesis
into the bloodstream. !yroid follicles active in hormone synthe-
sis are identified histologically by columnar epithelial cells lining a
Colloid droplets
follicular lumen, which is depleted of colloid. Inactive follicles are
Endocytosis
Apical TG lined by cuboidal epithelial cells and are replete with colloid. Both
membrane iodide and lithium block the release of preformed thyroid hormone,
Pseudopod
Organification through poorly understood mechanisms.
Coupling T4 and T3 are transported in the bloodstream primarily by three
proteins: (1) thyroxine-binding globulin (TBG), (2) transthyretin
Storage
(TTR; also known as TBPA, thyroxine-binding prealbumin), and
Colloid
(3) albumin. It is estimated that 99.96% of circulating T4 and 99.5%
FIGURE 96!2 Thyroid hormone synthesis. Iodide is transported of T3 are bound to these proteins. However, only the unbound (free)
from the plasma, through the cell, to the apical membrane, thyroid hormone is able to di"use into the cell, elicit a biologic e"ect,
where it is organi#ed and coupled to the thyroglobulin (TG) and regulate thyroid-stimulating hormone (TSH; also known as thy-
synthesized within the thyroid cell. Hormone stored as colloid rotropin) secretion from the pituitary. Multiple functions have been
re-enters the cell through endocytosis and moves back toward ascribed to these transport proteins, including (a) assuring minimal
the basal membrane, where thyroxine (T4) is secreted. urinary loss of iodide, (b) providing a mechanism for uniform tissue
distribution of free hormone, and (c) transporting hormone into the
central nervous system (CNS).
Whereas T4 is secreted solely from the thyroid gland, less
than 20% of T3 is produced in the thyroid. !e majority of T3 is
covalently binds the organified iodide to tyrosine residues within TG formed from the breakdown of T4 catalyzed by the 5#-monodeio-
(Fig. 96-2). It is interesting that although salivary glands and the dinase enzymes found in extrathyroidal peripheral tissues. Because
gastric mucosa are able to actively transport iodide, they are unable the binding a#nity of nuclear thyroid hormone receptors (TRs) is
to e"ectively incorporate iodide into proteins, given the lack of simi- 10 to 15 times higher for T3 than for T4, the deiodinase enzymes
lar oxidizing machinery. play a pivotal role in determining overall metabolic activity. !ree
!e iodinated tyrosine residues monoiodotyrosine (MIT) and di"erent monodeiodinase enzymes are present in the body. Of the
diiodotyrosine (DIT) combine to form iodothyronines (Fig. 96-3). enzymes that catalyze 5#-monodeiodination, type I enzymes are
!us, two molecules of DIT combine to form T4, whereas MIT and present in peripheral tissues such as the liver and kidney, whereas
 1243
TABLE 96!2 Properties of Iodothyronine 5#-Deiodinase Isoforms
Property Type I Type II Type III
Susceptibility to High Low Low
propylthiouracil
Tissue localization Thyroid, liver, kidney Pituitary, thyroid, CNS, brown adipose tissue Placenta, developing brain, skin
Preferred substrate rT3 and T3 T4 and rT3 T3 and T4

CHAPTER
Physiologic or Clearance of rT3 and T3, the Intracellular T3 production, especially for Clearance of T3 and T4
pathophysiologic role predominant extrathyroidal source the brain in hypothyroidism or iodine
of T3 in hyperthyroidism de#ciency, and maintenance of plasma T3
Developmental expression Expressed latest in development; Expressed second; especially high in brain Expressed #rst; high in developing
predominant deiodinase in adult and brown adipose tissue brain; may be important for fetal
thyroid hormone metabolism
96
rT3, reverse T3; T3, triiodothyronine; T4, thyroxine.

Thyroid Disorders
type II enzymes are found in the CNS, pituitary, and thyroid. Type required for basal and T3-dependent gene transcription. TRs exist in
III enzymes, found in the placenta, skin, and developing brain, inac- several isoforms, including TR!1, TR!2, and TR$1.3 !yroid hor-
tivate T4 and T3 by deiodinating the inner ring at the 5 position. !e mone has di"erent actions in di"erent tissues based on the tissue-
principal characteristics of these enzymes are listed in Table 96-2. specific expression of the di"erent TR isoforms. !ere is interest in
T4 may also be acted on by the enzyme 5#- monodeiodinase to form developing thyroid hormone analogs that selectively activate specific
reverse T3, but this accounts for a small component of hormone TR isoforms. Such agents could theoretically have targeted desir-
metabolism. Polymorphisms in the deiodinase genes may prove to able e"ects such as stimulating energy expenditure without having
be of clinical significance. For example, a polymorphism in the type adverse e"ects on other tissues.5
I deiodinase leading to increased activity seems to be associated with !e production of thyroid hormone is regulated in two main
an increased circulating ratio of free T3 to free T4.2 Reverse T3 has no ways. First, thyroid hormone is regulated by TSH secreted by the
known biological activity. T3 is removed from the body by deiodinat- anterior pituitary. !e secretion of TSH is itself under negative feed-
ing degradation and through the action of sulfotransferase enzyme back control by the circulating level of free thyroid hormone and the
systems converting to T3 sulfate and 3,3-diiodothyronine sulfates, positive influence of hypothalamic thyrotropin-releasing hormone
thus facilitating enterohepatic clearance. !yronamines are deriva- (TRH). Second, extrathyroidal deiodination of T4 to T3 is regulated
tives of thyroid hormones that are present in low concentrations in by a variety of factors including nutrition, nonthyroidal hormones,
human serum. !e most studied thyronamine, 3-iodothyronamine, ambient temperatures, drugs, and illness.
can theoretically be made from T4 by decarboxylation and deiodin-
ation. Administration of pharmacologic amounts of 3-iodothyron-
amine to animals has profound e"ects on temperature regulation
HYPERTHYROIDISM
and cardiac function and shi$s fuel metabolism from carbohydrates AND THYROTOXICOSIS
to lipids. However, a possible physiologic role for thyronamines has
yet to be determined, although altered levels may be associated with !yrotoxicosis results when tissues are exposed to excessive levels of
some disease states. T4, T3, or both.6 Hyperthyroidism, which is one cause of thyrotoxi-
cosis, refers specifically to overproduction of thyroid hormone by
Thyroid Hormone Regulation and Action the thyroid gland.

!e growth and function of the thyroid are stimulated by activa-

tion of the thyrotropin receptor by TSH.3 !e receptor belongs to EPIDEMIOLOGY!THYROTOXICOSIS
the family of G-protein–coupled receptors. !e thyrotropin receptor In the National Health and Nutrition Examination Survey
is coupled to the $ subunit of the stimulatory guanine-nucleotide– (NHANES) III, 0.7% of those surveyed who were not taking thyroid
binding protein (Gs$), activating adenylate cyclase and increasing medications and had no history of thyroid disease had subclinical
the accumulation of cyclic adenosine monophosphate. !rough this hyperthyroidism (TSH less than 0.1 mIU/L, and T4 normal), and
mechanism, TSH stimulates the expression of Na+/I" symporter, 0.5% had “clinically significant” hyperthyroidism (TSH less than
TG, and thyroid peroxidase genes as well as increases apical iodide 0.1 mIU/L, and T4 more than 13.2 mcg/dL [170 nmol/L]).7 !e
e%ux. Somatic activating mutations in the receptor are commonly prevalence of suppressed TSH values peaks in people aged 20 to 39,
seen in autonomously functioning thyroid nodules.4 Rarely, germ- declines in those 40 to 79, and increases again in those 80 or older.
line-activating mutations of the TSH receptor have been reported in Abnormal TSH levels were more common among women than
kindreds with Leclere syndrome, and thyrotoxicosis can result from among men.
germline-activating mutations in G-protein signaling in McCune–
Albright syndrome. Conversely, thyrotropin resistance results from
point mutations that prevent TSH binding, leading to abnormalities ETIOLOGY AND
in the thyrotropin receptor–adenylate cyclase system and congenital
hypothyroidism.3 Individuals with this abnormality have high levels
PATHOPHYSIOLOGY!THYROTOXICOSIS
of TSH but decreased TG levels and a normal or small thyroid gland. If the clinical history and examination do not provide pathogno-
!yroid hormone nuclear receptors regulate the transcrip- monic clues to the etiology of the patient’s thyrotoxicosis, mea-
tion of target genes in the presence of physiologic concentrations of surement of the radioactive iodine uptake (RAIU) is critical in the
T3.3 Unlike most other nuclear receptors, TRs also actively regulate evaluation (Table 96-3). !e normal 24-hour RAIU ranges from
gene expression in the absence of hormone, typically resulting in an 10% to 30% with some regional variation that is due to di"erences
opposite e"ect. TRs translocate from the cytoplasm to the nucleus, in iodine intake. An elevated RAIU indicates endogenous hyperthy-
interact in the nucleus with T3, and target genes and other proteins roidism; that is, the patient’s thyroid gland is actively overproducing

AL G r a w a n y
1244
TABLE 96!3 Di"erential Diagnosis of Thyrotoxicosis (30-40 mg daily) must be used to suppress the inflammatory process.
Based on Radioactive Iodine Uptake (RAIU) Antithyroid drugs (ATD) are not indicated because they will not be
e"ective as they do not decrease the release of preformed thyroid
Increased RAIUa Decreased RAIU
hormone.
TSAb (Graves’ disease) Exogenous sources of thyroid
hormone
Painless Thyroiditis
Multinodular goiter Medications containing thyroid
Painless (silent and lymphocytic) thyroiditis is a common cause of
SECTION

hormone or iodine
thyrotoxicosis and may represent up to 15% of cases of thyrotoxicosis
Toxic adenoma Painless thyroiditis
in North America. When lymphocytic thyroiditis develops during
hCG (trophoblastic diseases) Subacute thyroiditis the first 12 months a$er the end of pregnancy, the condition is also
TSH-induced hyperthyroidism In$ammatory thyroid disease called postpartum thyroiditis. !e etiology is not fully understood
TSH-secreting tumors Food sources containing thyroid and may be heterogeneous, but evidence indicates that autoimmunity
10 gland underlies most cases. !ere is an increased frequency of HLA-DR3
Selective pituitary resistance to T4 Ectopic thyroid tissue and DR5 in patients with painless thyroiditis; non-endocrine auto-
Thyroid stimulators other than TSH Struma ovarii immune diseases are also more common. Histologically, di"use lym-
Endocrinologic Disorders

Metastatic follicular carcinoma phocytic infiltration is generally identified. !e triphasic course of

this illness mimics that of subacute thyroiditis. Most patients present
a
The RAIU may be decreased if the patient has been recently exposed to excess
iodine.
with mild thyrotoxic symptoms. Lid retraction and lid lag are pres-
hCG, human chorionic gonadotropin; RAIU, radioactive iodine uptake; TSAb,
ent, but exophthalmos is absent. !e thyroid gland may be di"usely
thyroid-stimulating antibody. enlarged, but thyroid tenderness is absent.
!e 24-hour RAIU will typically be suppressed to less than 2%
during the thyrotoxic phase of painless thyroiditis. Anti-TG and
antithyroid peroxidase antibody (anti-TPOAb) levels are elevated
in more than 50% of patients. Patients with mild hyperthyroidism
T4, T3, or both. Conversely, a low RAIU in the absence of iodine
and painless thyroiditis should be reassured that they have a self-
excess indicates that high levels of thyroid hormone are not a con-
limited disease, although patients with postpartum thyroiditis may
sequence of thyroid gland hyperfunction but are likely due to thy-
experience a recurrence of the disease with subsequent pregnancies.
roiditis or hormone ingestion. !e importance of di"erentiating
As with other thyrotoxic syndromes, adrenergic symptoms may be
endogenous hyperthyroidism from other causes of thyrotoxicosis
ameliorated with propranolol or metoprolol. ATDs, which inhibit
lies in the widely di"erent prognosis and treatment of the diseases
new hormone synthesis, are not indicated because they do not
in these two categories. !erapy of thyrotoxicosis associated with
decrease the release of preformed thyroid hormone. A small propor-
thyroid hyperfunction is mainly directed at decreasing the rate of
tion of patients may have recurrent episodes of thyroiditis or may
thyroid hormone synthesis, secretion, or both. Such measures are
develop permanent hypothyroidism.17
ine"ective in treating thyrotoxicosis that is not the result of endog-
enous hyperthyroidism because hormone synthesis and regulated Exogenous Thyroid Hormone
hormone secretion are already at a minimum.
!yrotoxicosis factitia is hyperthyroidism due to ingestion of thyroid
Causes of Thyrotoxicosis Associated hormone. !is category includes hyperthyroidism produced by the
intentional ingestion of exogenous thyroid hormone. Obesity is the
with Suppressed RAIU most common non-thyroidal disorder for which thyroid hormone is
Subacute Thyroiditis inappropriately used, but thyroid hormone has been used for almost
Painful subacute (granulomatous or de Quervain) thyroiditis o$en every conceivable problem from menstrual irregularities and infer-
develops a$er a viral syndrome, but rarely has a specific virus been tility to hypercholesterolemia and baldness. !ere is little evidence
identified in thyroid parenchyma. A genetic predisposition exists, to suggest that treatment with thyroid hormone is bene&cial for
with a markedly higher risk for developing subacute thyroiditis for any of these conditions in euthyroid individuals.18 !yrotoxicosis
patients with HLA-Bw35. Systemic symptoms o$en accompany factitia can also occur when too large a dose of thyroid hormone
the syndrome, including fever, malaise, and myalgia, in addition to is used to treat conditions in which it is likely to be beneficial, such
those symptoms due to thyrotoxicosis. Typically, patients complain as di"erentiated thyroid carcinoma. In addition to this iatrogenic
of severe pain in the thyroid region, which o$en extends to the ear cause, thyrotoxicosis factitia may occur a$er accidental pediatric
on the a"ected side. With time, the pain may migrate from one side ingestion or pharmacy error. !yrotoxicosis factitia may also be
of the gland to the other. On physical examination, the thyroid gland caused by the purposeful and secretive ingestion of thyroid hor-
is &rm and exquisitely tender. Signs of thyrotoxicosis are present.17 mone by patients (usually with a healthcare background) who wish
!yroid function tests typically run a triphasic course. Initially, to obtain attention or lose weight.
serum T4 levels are elevated due to the release of preformed thyroid !yroid hormone may also be accidentally ingested in food
hormone from disrupted follicles. !e 24-hour RAIU during this sources. Reports of thyrotoxicosis in Minnesota and Nebraska in
time is less than 2% due to thyroid inflammation and TSH suppres- the 1980s were attributed to ingestion of ground beef contaminated
sion by the elevated T4 level. As the disease progresses, intrathyroidal by bovine thyroid glands. More recently thyrotoxicosis due to por-
hormone stores are depleted, and the patient may become mildly cine thyroid tissue in meat products has been reported in Spain and
hypothyroid with an appropriately elevated TSH level. During the Uruguay.
recovery phase, thyroid hormone stores are replenished, and serum !yrotoxicosis factitia should be suspected in a thyrotoxic
TSH concentration gradually returns to normal. Recovery is gen- patient without evidence of increased hormone production, thyroi-
erally complete within 2 to 6 months. Most patients remain euthy- dal inflammation, or ectopic thyroid tissue. !e RAIU is at low levels
roid, and recurrences of painful thyroiditis are extremely rare. !e because the patient’s thyroid gland function is suppressed by the exog-
patient with painful thyroiditis should be reassured that the disease enous thyroid hormone. Measurement of plasma TG is a valuable lab-
is self-limited and is unlikely to recur. !yrotoxic symptoms may oratory aid in the diagnosis of thyrotoxicosis factitia. TG is normally
be relieved with !-blockers. nonsteroidal anti-inflammatory drugs secreted in small amounts by the thyroid gland; however, when thyroid
(NSAIDs) will usually relieve the pain. Occasionally, prednisone hormone is taken orally, TG levels tend to be lower than the normal
 1245
range. In other entities characterized by a low RAIU, such as thyroiditis, !is extremely rare cause of thyrotoxicosis is suggested by the
leakage of preformed thyroid hormone results in elevated TG levels. If absence of thyroid enlargement in a thyrotoxic patient with a sup-
a history of thyroid hormone ingestion is elicited or deduced, exoge- pressed RAIU in the neck and no findings to suggest thyroiditis. !e
nous thyroid hormone should be withheld for 4 to 6 weeks, and thyroid diagnosis is established by localizing functioning thyroid tissue in
function tests should be repeated to ensure a euthyroid state has been the ovary with whole-body RAI (sodium iodide-131 [131I]) scanning.
restored. Rarely, thyroid hormones may be the drug of abuse and detec- Interestingly, struma ovarii not associated with hyperthyroidism is

CHAPTER
tion is di#cult with standard thyroid hormone assays. For example, much more common than struma ovarii associated with hyperthy-
tiratricol (TRIAC), an endogenous metabolite of T3 that has been used roidism. Because the tissue is neoplastic and potentially malignant,
for weight loss and paradoxically by bodybuilders, will suppress TSH at combined surgical and radioiodine treatment of malignant struma
high doses and may cross-react in many T3 immunoassays; thus, thy- ovarii for both monitoring and therapy of relapse is the recom-
rotoxicosis factitia due to tiratricol abuse may be misinterpreted as T3 mended treatment.
toxicosis, and also lead to serious side e"ects.
Causes of Thyrotoxicosis Associated 96
Medications Containing Iodine
Amiodarone may induce thyrotoxicosis (2%–3% of patients), overt
with Elevated RAIU
Graves’ Disease

Thyroid Disorders
hypothyroidism (5% of patients), subclinical hypothyroidism (25%
of patients), or euthyroid hyperthyroxinemia, depending on the 1 Graves’ disease is an autoimmune syndrome that usually includes
underlying thyroid function and pathology.19 Because amiodarone hyperthyroidism, di"use thyroid enlargement, exophthalmos, and, less
contains 37% iodine by weight, approximately 6 mg/day of iodine is commonly, pretibial myxedema and thyroid acropachy (Fig. 96-4).6,9
released for each 200 mg of amiodarone, 1,000 times greater than the Graves’ disease is the most common cause of hyperthyroidism,
recommended daily amount of iodine of 150 mcg/day. As a result of with a prevalence estimated to be 3 per 1,000 population in the
this iodine overload, iodine-exacerbated thyroid dysfunction com- United States. Hyperthyroidism results from the action of thyroid-
monly occurs among those patients with preexisting thyroid disease: stimulating antibodies (TSAbs), which are directed against the
thyrotoxicosis in patients with hyperthyroidism or euthyroid nodu- thyrotropin receptor on the surface of the thyroid cell. When these
lar autonomy and hypothyroidism in patients with autoimmune immunoglobulins bind to the receptor, they activate downstream
thyroid disease. In contrast to hyperthyroidism with increased syn- G-protein signaling and adenylate cyclase in the same manner as
thesis of thyroid hormone induced by amiodarone (type I), destruc- TSH. Autoantibodies that react with orbital muscle and fibroblast
tive thyroiditis with leakage of TG and thyroid hormones also tissue in the skin are responsible for the extrathyroidal manifesta-
occurs (type II), typically among individuals with otherwise normal tions of Graves’ disease, and these autoantibodies are encoded by
glands. !e two types of amiodarone-induced thyrotoxicosis may be the same germline genes that encode for other autoantibodies for
di"erentiated using color-flow Doppler ultrasonography. Such dis- striated muscle and thyroid peroxidase. Clinically, the extrathyroi-
tinction is critically important, given the therapeutic implications dal disorders may not appear at the same time that hyperthyroidism
of the two syndromes: type I amiodarone-induced hyperthyroidism develops.
responds somewhat to thionamides, whereas type II may respond !ere is now compelling evidence that heredity predisposes the
to glucocorticoids.19 Obviously, RAI therapy is inappropriate in susceptible individual to the development of clinically overt auto-
type I due to the drug-induced iodine excess, and in type II due to immune thyroid disease in the setting of appropriate environmental
lack of increased hormone synthesis. !e manifestations of amio- and hormonal triggers. A role for gender in the emergence of Graves’
darone-induced thyrotoxicosis may be atypical symptoms such as disease is suggested by the fact that hyperthyroidism is approxi-
ventricular tachycardia and exacerbation of the underlying chronic mately eight times more common in women than in men. Other
obstructive pulmonary disease, both of which are significant, given lines of evidence support a role for heredity. First, there is a well-
the severe underlying cardiac pathology that led to the use of amio- recognized clustering of Graves’ disease within some families. Twin
darone in the first place. Amiodarone also directly interferes with studies in Graves’ disease have revealed that a monozygotic twin has
type I 5#-deiodinase, leading to reduced conversion of T4 to T3 and a 35% likelihood of ultimately developing the disease compared with
hyperthyroxinemia without thyrotoxicosis.19 a 3% likelihood for a dizygotic twin, resulting in an estimation that
High intake of biotin can interfere with thyroid hormone assays, 79% of the predisposition to Graves’ disease is genetic. Second, the
leading to false results of thyroid function tests.20,21 Excess biotin leads occurrence of other autoimmune diseases, including Hashimoto’s
to falsely elevated results of TT4, FT4, and TT3 (competitive immu- thyroiditis, is also increased in families of patients with Graves’
noassays), and to falsely low TSH levels (immunometric or sandwich disease. !ird, several studies have demonstrated an increased fre-
immunoassays). !is is not an issue of endogenous interference but an quency of certain human leukocyte antigens (HLAs) in patients with
interference with the assay itself. Biotin doses of greater than 5,000 mcg/ Graves’ disease. Di"ering HLA associations have been identified in
day are associated with major interference on immunoassays; in such the various ethnic groups studied. In White patients, for example,
circumstances, it is recommended patients hold their biotin doses for the relative risk of Graves’ disease in carriers of the HLA-DR3 hap-
24 to 48 hours before laboratory testing. lotype is between 2.5 and 5, whereas lesser associations have been
reported for HLA-B8 and the HLA-DQA*0501allele. Several gene
Thyroid Cancer loci have been associated with autoimmune thyroid diseases such as
In widely metastatic di"erentiated papillary or follicular carcinomas Graves’ disease. It is thought that these susceptibility genes interact
with relatively well-preserved function, su#cient thyroid hormones with environmental triggers to induce thyroid disease through epi-
can be synthesized and secreted to produce thyrotoxicosis. In most genetic e"ects.
instances, a previous diagnosis of thyroid malignancy has been !e thyroid gland is di"usely enlarged in the majority of
made. !e diagnosis can be confirmed by whole-body 131I scanning. patients with Graves’ disease and is commonly 40 to 60 g (two
Treatment with 131I is generally e"ective at ablating functioning thy- to three times the normal size). !e surface of the gland is either
roid metastases. smooth or bosselated, and the consistency varies from so$ to firm.
For patients with severe disease, a thrill may be felt and a systolic
Struma Ovarii bruit may be heard over the gland, reflecting the increased intrag-
Struma ovarii is a teratoma of the ovary that contains di"erentiated landular vascularity typical of hyperplasia. Whereas the presence of
thyroid follicular cells and is capable of making thyroid hormones. any of the extrathyroidal manifestations of this syndrome, including

AL G r a w a n y
1246
SECTION

10
Endocrinologic Disorders

FIGURE 96!4 Features of Graves’ disease. (A) Facial appearance in Graves’ disease; lid retraction, periorbital edema, and proptosis are
marked. (B) Thyroid dermopathy over the lateral aspects of the shins. (C) Thyroid acropachy. (Reproduced with permission from Fauci AS,
Kasper DL, Longo DL, et al., eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw Hill; 2005:2114.)

exophthalmos, pretibial myxedema, or thyroid acropachy, in a thy- TABLE 96!4 Thyroid Function Tests in Di"erent Thyroid
rotoxic patient is pathognomonic of Graves’ disease, most patients Conditions
can be diagnosed on the basis of their history and examination of
Total T4 Free T4 Total T3 TSH
their di"use goiter (see Fig. 96-4). An important clinical feature of
Normal 4.5-10.9 mcg/ 0.8-2.7 ng/dL 60-181 ng/dL 0.5-4.7
Graves’ disease is the occurrence of spontaneous remissions, albeit
dL(58-140 (10.3-34.7 (0.92-2.79 mIU/L
uncommon. !e abnormalities in TSAb production may decrease or nmol/L) pmol/L) nmol/L)
disappear over time. Hyperthyroid %% %% %%% &&a
!e results of laboratory tests in thyrotoxic Graves’ disease
Hypothyroid && && & %%a
include an increase in the overall hormone production rate with a
disproportionate increase in T3 relative to T4 (Table 96-4). In an Increased % Normal % Normal
TBG
occasional patient, the disproportionate overproduction of T3 is
exaggerated, with the result that only the serum T3 concentration is Primary thyroid disease.
a

increased (T3 toxicosis). !e saturation of TBG is increased due to

the elevated levels of serum T4 and T3. As a result, the concentrations
of free T4 and free T3 are increased to an even greater extent than exercised before the attack. Cognition and sensory perception are
are the measured serum total T4 and T3 concentrations. !e TSH spared, whereas deep tendon reflexes are markedly diminished. !e
level will be suppressed or undetectable due to negative feedback by condition is characterized by hypokalemia and low urinary potas-
elevated levels of thyroid hormone at the pituitary. sium excretion. Hypokalemia results from a sudden shi$ of potas-
For the patient with symptomatic disease, measurement of the sium from extracellular to intracellular sites rather than reduced
serum-free T4 concentration, total T4, total T3, and the TSH value total body potassium. High-carbohydrate loads and exercise provoke
will confirm the diagnosis of thyrotoxicosis. For the patient who the attacks. Treatment includes correcting the hyperthyroid state,
is not pregnant or lactating, a 24-hour RAIU should be obtained potassium administration, spironolactone to conserve potassium,
if there is any diagnostic uncertainty, for example, recent onset of and propranolol to minimize intracellular shi$s. Some patients with
symptoms or other factors suggestive of thyroiditis. An increased this condition have a mutation in the inwardly rectifying potassium
RAIU indicates that the thyroid gland is inappropriately utilizing channel Kir2.6.11
the iodine to produce more thyroid hormone at a time when the
patient is thyrotoxic. Toxic Adenoma
!yrotoxic periodic paralysis is a rare complication of hyper- An autonomous thyroid nodule is a discrete thyroid mass whose
thyroidism most commonly observed in Asian and Hispanic popu- function is independent of pituitary and TSH control. !e preva-
lations.10 It presents as recurrent proximal muscle flaccidity ranging lence of toxic adenoma ranges from about 2% to 9% of thyrotoxic
from mild weakness to total paralysis. !e paralysis may be asym- patients and depends on iodine availability and geographic loca-
metric and usually involves muscle groups that are strenuously tion. Toxic adenomas are benign tumors that produce thyroid
 1247

CHAPTER
96

Thyroid Disorders
FIGURE 96!5 Radioiodine thyroid scans. (A) Normal or increased thyroid uptake of iodine-125 (125I). (B) Thyroid with a marked decrease
in 125I uptake in a large palpable mass. (C) Increased 125I uptake isolated to a single nodule, the “hot nodule.” (D) Decreased thyroid 125I
uptake in an isolated region, the “cold nodule.” (Reproduced with permission from Molina PE. Endocrine Physiology. 2nd ed. New York:
McGraw Hill; 2006:90. Images courtesy of Dr. Luis Linares, Memorial Medical Center, New Orleans, LA.)

hormones. !ey arise from gain-of-function somatic mutations of Multinodular Goiters

the TSH receptor or, less commonly, the Gs$ protein; more than a In multinodular goiters (MNGs), follicles with autonomous function
dozen TSH receptor mutations have been described.6 !ese nodules coexist with normal or even nonfunctioning follicles. !e pathogen-
may be referred to as toxic adenomas, or “hot” nodules, because of esis of MNG is thought to be similar to that of toxic adenoma: di"use
their persistent uptake on a radioiodine thyroid scan, despite sup- hyperplasia caused by goitrogenic stimuli, leading to mutations and
pressed uptake in the surrounding non-nodular gland (Fig. 96-5). clonal expansion of benign neoplasms. !e functional status of
!e amount of thyroid hormone produced by an autonomous nod- the nodule(s) depends on the nature of the underlying mutations,
ule is mass related. !erefore, hyperthyroidism usually occurs with whether activating such as TSH receptor mutations or inhibitory
larger nodules (ie, those more than 3 cm in diameter). Older patients such as RAS mutations. !yrotoxicosis in an MNG occurs when a
(older than 60 years) are more likely (up to 60%) to be thyrotoxic su#cient mass of autonomous follicles generates enough thyroid
from autonomous nodules than are younger patients (12%). !ere hormone to exceed the needs of the patient. It is not surprising that
are many reports of isolated elevation of serum T3 in patients with this type of hyperthyroidism develops insidiously over a period of
autonomously functioning nodules. !erefore, if the T4 level is nor- several years and predominantly a"ects older individuals with long-
mal, a T3 level must be measured to rule out T3 toxicosis. If autono- standing goiters. !e patient’s complaints of weight loss, depression,
mous function is suspected but the TSH is normal, the diagnosis anxiety, and insomnia may be attributed to old age. Any unexplained
can be confirmed by a failure of the autonomous nodule to decrease chronic illness in an elderly patient presenting with an MNG calls for
its iodine uptake during exogenous T3 administration su#cient to the exclusion of hidden (silent) thyrotoxicosis.15 Current third-gen-
suppress TSH. Surgical resection, thionamides, percutaneous etha- eration TSH assays are able to detect subclinical hyperthyroidism.
nol injection, and radioactive iodine (RAI) ablation are treatment A thyroid scan will show patchy areas of autonomously func-
options, but since thionamides do not halt the proliferative process tioning thyroid tissue intermixed with hypofunctioning areas. When
in the nodule, definitive therapies are recommended. Ethanol abla- the patient is euthyroid, therapy is based on the need to reduce goi-
tion may be associated with pain and damage to surrounding extra- ter size due to mass-related symptoms such as dysphagia. Doses of
thyroidal tissues, limiting its acceptance in the United States. It has thyroid hormone su#cient to suppress TSH levels may slow goiter
been hypothesized that sublethal radiation doses received by the growth or cause some degree of shrinkage, but, in general, suppres-
surrounding non-nodular thyroid tissue during RAI therapy of toxic sion therapy for nodular disease is inadequate to address mass e"ect.
nodules may lead to induction of thyroid cancer. However, thyroid !e preferred treatment for toxic MNG is RAI or surgery. Surgery is
cancer has rarely been associated with RAI therapy, and newer stud- usually selected for younger patients and patients in whom large goi-
ies suggest hyperthyroidism itself, rather than RAI therapy, as being ters impinge on vital organs. Alternatively, percutaneous injection
associated with non-thyroid malignancies.12 !ere is a modest posi- of 95% ethanol has also been used to destroy single or multinodular
tive association between the dose of radioactive iodine absorbed into adenomas with a 5-year success rate approaching 80%.
the gland and risk of solid cancer death;13 however, the same authors
later indicated that a$er controlling for known confounding, there Trophoblastic Diseases Human chorionic gonadotropin (hCG) is
no longer appeared to be a signi&cant association in the risk of solid a stimulator of the TSH receptor and may cause hyperthyroidism. !e
cancer mortality by treatment group.14 An autonomously function- basis for the thyrotropic e"ect of hCG is the structural similarity of hCG
ing nodule, if not large enough to cause thyrotoxicosis, can o$en be to TSH (similar $ subunits and unique ! subunits). For patients with
managed conservatively without therapy. hyperthyroidism caused by trophoblastic tumors, serum hCG levels

AL G r a w a n y
1248
usually exceed 300 U/mL (kU/L) and always exceed 100 U/mL (kU/L). is around 40 years, with women being diagnosed more than men (8:7).
!e mean peak hCG level in normal pregnancy is 50 U/mL (kU/L). On !ese tumors may co-secrete prolactin or growth hormone; therefore,
a molar basis, hCG has only 1/10,000 the activity of pituitary TSH in the patients may present with amenorrhea/galactorrhea or signs of
mouse bioassays. Nevertheless, this thyrotropic activity may be very acromegaly. Most patients present with classic symptoms and signs of
substantial for patients with trophoblastic tumors, whose serum hCG thyrotoxicosis. Visual field defects may be present due to impingement
concentrations may reach 2,000 U/mL (kU/L). of the optic chiasm by the tumor. Tumor growth and worsening visual
field defects have been reported following antithyroid therapy because
SECTION

TSH-Induced Hyperthyroidism To better understand these syn- lowering of thyroid hormone levels is associated with loss of feedback
dromes, we must first review TSH biosynthesis and secretion. TSH inhibition from high thyroid hormone levels.
is synthesized in the anterior pituitary as separate $- and !-subunit Diagnosis of a TSH-secreting adenoma should be made by dem-
precursors. !e $ subunits from luteinizing hormone (LH), follicle- onstrating a lack of TSH response to TRH stimulation, inappropriate
stimulating hormone (FSH), hCG, and TSH are identical, whereas the TSH levels, elevated $-subunit levels, and radiologic imaging; given the
! subunits are unique and confer immunologic and biologic specificity.
10 Free ! subunits are devoid of receptor-binding and biologic activity and
lack of routine availability of TRH, the other three criteria are essential.
Note that some small tumors are not identified by MRI. Moreover, 10%
require combination with an $ subunit to express their activity. Criteria of “normal” individuals may have incidental pituitary tumors or other
Endocrinologic Disorders

for the diagnosis of TSH-induced hyperthyroidism include (a) evidence benign focal lesions noted on pituitary imaging.
of peripheral hypermetabolism, (b) di"use thyroid gland enlargement, Transsphenoidal pituitary surgery is the treatment of choice for
(c) elevated free thyroid hormone levels, and (d) elevated or inappro- TSH-secreting adenomas. Pituitary gland irradiation is o$en given
priately “normal” serum immunoreactive TSH concentrations. Because following surgery to prevent tumor recurrence. Dopamine agonists
the pituitary gland is extremely sensitive to even minimal elevations of and octreotide have been used to treat tumors, especially those that
free T4, a “normal” or elevated TSH level in any thyrotoxic patient indi- co-secrete prolactin.
cates the inappropriate production of TSH.
TSH-Secreting Pituitary Adenomas TSH-secreting pituitary Pituitary Resistance to Thyroid Hormone Resistance to
tumors occur sporadically and release a biologically active hormone that thyroid hormone is a rare condition that can be due to a num-
is unresponsive to normal feedback control.16 !e mean age at diagnosis ber of molecular defects, including mutations in the TR! gene.

CLINICAL PRESENTATION Thyrotoxicosis

General disease only), pretibial myxedema (in Graves’ disease
• Signs and symptoms of thyrotoxicosis a"ect multiple only), and unusually #ne hair. Separation of the end of
organ systems. Patients often have symptoms the #ngernails from the nail beds (onycholysis) may
for an extended period before the diagnosis of be noted. Ocular signs that result from thyrotoxicosis
hyperthyroidism is made. include retraction of the eyelids and lagging of the
upper lid behind the globe when the patient looks
Symptoms downward (lid lag). Physical signs of a hyperdynamic
circulatory state are common and include tachycardia
• The typical clinical manifestations of thyrotoxicosis at rest, a widened pulse pressure, and a systolic
include nervousness, anxiety, palpitations, emotional
ejection murmur. Gynecomastia is sometimes noted
lability, easy fatigability, menstrual disturbances, and
in men. Neuromuscular examination often reveals a
heat intolerance. A cardinal sign is weight loss despite
#ne tremor of the protruded tongue and outstretched
an increased appetite.
hands. Deep tendon re$exes are generally hyperactive.
• Elderly patients are more likely to develop atrial
Thyromegaly is usually present. Elderly patients may
#brillation with thyrotoxicosis than younger patients.
present with the absence of clinical evidence of excess
The frequency of bowel movements may increase,
thyroid hormones (palpitations, anxiety, tremor, heat
but frank diarrhea is unusual. For the elderly patient
intolerance, and diaphoresis), but instead present
and for the patient with severe disease, anorexia
with weight loss, apathy, and depression (apathetic
may be present as well. Palpitations are a prominent
hyperthyroidism).
and distressing symptom, particularly in the patient
with preexisting heart disease. Proximal muscle
weakness is common and is noted on climbing stairs
Diagnosis
or in getting up from a sitting position. Women may • Low TSH serum concentration. Elevated free and total
note their menses are becoming scanty and irregular. T4 and T3 serum concentrations, particularly in more
Extremely thyrotoxic patients may have tachycardia, severe disease.
heart failure, psychosis, hyperpyrexia, and coma, a • Elevated radioactive iodine uptake (RAIU) by
presentation described as thyroid storm.8 Long-term the thyroid gland when the hormone is being
hyperthyroidism may also be associated with a loss overproduced; suppressed RAIU in thyrotoxicosis due
of bone mineral density and an increased risk of to thyroid in$ammation (thyroiditis).
osteoporosis-related fracture.
Other Tests
Signs • Thyroid-stimulating antibodies (TSAbs)
• A variety of physical signs may be observed including • TG
warm, smooth, moist skin, exophthalmos (in Graves’ • Thyrotropin receptor antibodies
 1249

o Heart rate, blood pressure (BP), weight, and body mass

index (BMI)
o Labs (eg, FT4, TT3, TSH, thyroid-stimulating antibodies;

CHAPTER
serum electrolytes, Scr, ALT)
o Other diagnostic tests when indicated (eg, thyroid ultra-
sound, raidioactive iodine uptake [RAIU] scan)

Assess
• Cause of hyperthyroidism (see Table 96-3)
96
• Current medications that may contribute to or worsen
hyperthyroidism

Thyroid Disorders
• Current medications that may interact with antithyroid
therapy
• Appropriateness and e"ectiveness of current antithyroid
regimen

Plan*
• Drug therapy regimen including speci#c antithyroid
therapy, dose, and duration (see Table 96-5)
Patient Care Process for the Management • Monitoring parameters including e!cacy (eg, resolution
of Hyperthyroidism of signs and symptoms) and safety (symptomatic
hypothyroidism, adverse e"ects of medications), laboratory
The image shows the #ve fundamental steps included in The tests (TSH, FT4, TT3, LFTs, and CBC), and time frame
Pharmacist’s Care Process endorsed by the Joint Commission • Patient education (eg, purpose of treatment, dietary and
for Pharmacy Practitioners (2014). The tagline of this process lifestyle modi#cation, drug therapy)
reads collaborate, communicate, and document. The #ve
fundamental steps listed here are collect, assess, plan, Implement*
implement, and follow-up: monitor and evaluate. All these • Provide patient education regarding all elements of the
steps are listed in a circular block diagram. treatment plan
• Use motivational interviewing and coaching strategies to
Collect maximize adherence
• Patient characteristics (eg, age, race, sex, pregnancy status) • Schedule follow-up
• Patient history (past medical, family, social) including
patient signs and symptoms: warm, smooth, moist skin, Follow-up: Monitor and Evaluate
palpitations, exophthalmos, pretibial myxedema, and • Resolution of signs and symptoms
unusually #ne hair; anxiety, tremor, heat intolerance, • Presence of adverse e"ects
tachycardia, weight loss, and menstrual disturbances (see
• Patient adherence to treatment plan using multiple sources
Clinical Presentation Box)
of information
• Current medications (including over-the-counter [OTC] and
herbal medication use) *Collaborate with patient, caregivers, and other healthcare professionals.
• Objective data

Pituitary resistance to thyroid hormone (PRTH) refers to selec- Triiodothyroacetic acid (TRIAC), an agent that is devoid of thyro-
tive resistance of the pituitary thyrotrophs to thyroid hormone. mimetic properties on peripheral tissues, but blocks the secretion of
As nonpituitary tissues respond normally to thyroid hormone, TSH, has been used to treat this condition. However, it is not avail-
patients experience the toxic peripheral e"ects of thyroid hor- able in the United States. Given the ability of retinoid X receptor
mone excess. About 90% of patients studied have an appropriate ligands to inhibit TSH production, drugs such as bexarotene may
increase in TSH in response to TRH; conversely, the TSH will be have therapeutic benefit in PRTH.
suppressed by T3 administration.
Patients with PRTH require treatment to reduce their elevated
thyroid hormone levels. Determining the appropriate serum T4 level
is di#cult because TSH cannot be used to evaluate the adequacy
of therapy. Any reduction in thyroid hormone carries the risk of
TREATMENT
inducing thyrotroph hyperplasia. Ideally, agents that suppress TSH
secretion could be used to treat these individuals. Glucocorticoids, Thyrotoxicosis
dopaminergic drugs, somatostatin and its analogs, and thyroid hor- 2 !ree common treatment modalities are used in the manage-
mone analogs with reduced metabolic activity have all been tried, ment of hyperthyroidism: surgery, antithyroid medications, and RAI
but with relatively little benefit. !-Blocker therapy can also be used. (Table 96-5).

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1250

TABLE 96!5 Treatments for Hyperthyroidism Caused by Graves’ Disease

Treatment Advantages Disadvantages Comment
Methimazole (#rst-line Noninvasive Low cure rate (average 40%-50%) First-line treatment in children, adolescents,
pharmacotherapy) Low initial cost Adverse drug reactions and pregnancy
Propylthiouracil (second-line Low risk of permanent Drug compliance Initial treatment in severe cases or
pharmacotherapy) hypothyroidism preoperative preparation
Possible remissions due to
SECTION

immune e"ects
Radioactive iodine (131I) Cure of hyperthyroidism Permanent hypothyroidism almost Best treatment for toxic nodules and toxic
Lowest cost, before inevitable multinodular goiter
adjustment for quality Might worsen ophthalmopathy
of life Pregnancy must be deferred for 6-12
months; no breast-feeding
10 Small potential risk of exacerbation of
hyperthyroidism
Surgery Rapid, e"ective treatment, Most invasive Potential choice in pregnancy (2nd trimester) if
Endocrinologic Disorders

especially in patients with Least costly in long term after quality- major side e"ect from ATDs
large goiters of-life adjustment Potential complications (recurrent laryngeal
Permanent hypothyroidism nerve damage, hypoparathyroidism)
Pain, scar Useful when coexisting suspicious nodule
present
Option for patients who refuse radioiodine

Desired Outcomes include hypoparathyroidism (up to 2%) and laryngeal nerve injury
(up to 1%).
!e overall therapeutic objectives are to eliminate the excess thyroid
hormone and minimize the symptoms and long-term consequences
of hyperthyroidism. Pharmacologic Therapy
Antithyroid Medications
General Approach to Treatment 3 Thionamide Drugs Two drugs within this category, MMI
!erapy must be individualized based on the type and severity of and PTU, are approved for the treatment of hyperthyroidism in the
hyperthyroidism, patient age and gender, the existence of nonthy- United States.23 !ey are classified as thioureylenes (thionamides),
roidal conditions, and response to previous therapy.22,23 For example, which incorporate an N–C–S=N group into their ring structures.
patients with swallowing or breathing di#culties due to impinge-
Mechanism of Action MMI and PTU share several mechanisms
ment of the esophagus or trachea are generally taken for surgical
to inhibit the biosynthesis of thyroid hormone.24 !ese drugs serve
removal of the thyroid. Clinical guidelines for the treatment of
as preferential substrates for the iodinating intermediate of thyroid
hyperthyroidism have been published.6 Selected recommendations
peroxidase and divert iodine away from potential iodination sites in
from these guidelines are shown in Table 96-6.
TG. !is prevents subsequent incorporation of iodine into iodotyro-
Nonpharmacologic Therapy sines and ultimately iodothyronine (“organification”). Second, they
inhibit the coupling of MIT and DIT to form T4 and T3. !e coupling
Surgery should be considered for patients with a large thyroid gland
reaction may be more sensitive to these drugs than the iodination
(more than 80 g), severe ophthalmopathy, and a lack of remission
reaction. Experimentally, these drugs exhibit immunosuppressive
on antithyroid drug treatment. In case of cosmetic issues or pres-
e"ects, although the clinical relevance of this finding is unclear. For
sure symptoms, the choice in MNG stands between surgery, which
patients with Graves’ disease, antithyroid drug treatment has been
is still the first choice, and radioiodine therapy if uptake is adequate.
associated with lower TSAb titers and restoration of normal sup-
In addition to surgery, the solitary nodule, whether hot or cold, can
pressor T-cell function. However, perchlorate (ClO4"), which has a
be treated with percutaneous ethanol injection therapy. For hot nod-
di"erent mechanism of action, also decreases TSAbs, suggesting that
ules, radioiodine is the therapy of choice.6 Appropriate preparation
normalization of the thyroid hormone level may itself improve the
of the patient for thyroidectomy includes MMI until the patient is
abnormal immune function. PTU inhibits the peripheral conversion
biochemically euthyroid (usually 6-8 weeks), followed by the addi-
of T4 to T3. !is e"ect is dose-related and occurs within hours of
tion of iodides (500 mg/day) for 10 to 14 days before surgery to
PTU administration. MMI does not have this e"ect. A$er several
decrease the vascularity of the gland. Propranolol for several weeks
weeks of use, depletion of stored hormone and lack of continuing
preoperatively and 7 to 10 days a$er surgery has also been used to
synthesis of thyroid hormone results in the clinical e"ects of these
maintain a pulse rate of less than 90 beats/min. Combined pretreat-
drugs.
ment with propranolol and 10 to 14 days of potassium iodide has
also been advocated. Pharmacokinetics Both ATDs are well absorbed (80%-95%) from
!e overall complication rate when surgery is performed for the gastrointestinal tract, with peak serum concentrations about 1
MNG by an experienced endocrine surgeon is low. If subtotal thy- hour a$er ingestion. !e plasma half-life ranges of PTU and MMI
roidectomy, or an operation that attempts to maintain euthyroid- are 1 to 2.5 and 6 to 9 hours, respectively, and are not appreciably
ism, is performed for Graves’ disease, there is a risk of recurrence a"ected by thyroid status. Urinary excretion is about 35% for PTU
of hyperthyroidism that is directly related to remnant thyroid gland and less than 10% for MMI. !ese drugs are actively concentrated in
size. Near-total thyroidectomy is generally recognized as the proce- the thyroid gland, which may account for the disparity between their
dure of choice for patients with Graves’ disease.6 !e complication relatively short plasma half-lives and the e"ectiveness of once-daily
rates of surgery for Graves’ disease are low when surgery is per- dosing regimens even with PTU. Approximately 60% to 80% of PTU
formed by a high-volume thyroid surgeon. Surgical complications is bound to plasma albumin, whereas MMI is not protein-bound.
 1251
TABLE 96!6 Selected Recommendations from the American Thyroid Association Hyperthyroidism Guidelines
Question Recommendation Strength Quality of Evidence
How should thyrotoxicosis be evaluated and !-Adrenergic blockade is recommended in all patients with Strong recommendation,
initially managed? symptomatic thyrotoxicosis, especially elderly patients and moderate quality
thyrotoxic patients with resting heart rates in excess of 90 beats
per minute or coexistent cardiovascular disease.

CHAPTER
If 131I therapy is chosen (for GD), how should it be Su!cient radiation should be administered in a single dose Strong recommendation,
accomplished? (typically 10-15 mCi [370-555 MBq]) to render the patient with moderate quality
GD hypothyroid.
If ATDs are chosen as initial management of GD, Methimazole should be used in virtually every patient who chooses Strong recommendation,
how should the therapy be managed? antithyroid drug therapy for GD, except during the #rst trimester moderate quality
of pregnancy when propylthiouracil is preferred, in the treatment
of thyroid storm, and in patients with minor reactions to
methimazole who refuse radioactive iodine therapy or surgery. 96
If ATDs are chosen as initial management of GD, A di"erential WBC count should be obtained during febrile illness Strong recommendation,
how should patients be monitored? and at the onset of pharyngitis in all patients taking antithyroid low-quality

Thyroid Disorders
medication.
If thyroidectomy is chosen for treatment of GD, If surgery is chosen as the primary therapy for GD, near-total or total Strong recommendation, low
how should it be accomplished? thyroidectomy is the procedure of choice. quality
If thyroidectomy is chosen for treatment of GD, Patients should be rendered euthyroid prior to the procedure. Strong recommendation,
how should it be accomplished? moderate quality
How should overt hyperthyroidism due to TMNG or Patients should be treated with RAI therapy or thyroidectomy. Weak recommendation,
TA be managed? moderate quality
How should GD be managed in children and Children with GD should be treated with MMI, RAI therapy, or Strong recommendation,
adolescents? thyroidectomy. RAI therapy should be avoided in very young moderate quality
children (<5 years). Under age 5, thyroidectomy should be
performed.
How should hyperthyroidism in pregnancy be ATD therapy should be used for overt hyperthyroidism due to GD Strong recommendation, low
managed? during pregnancy. PTU should be used when ATD therapy is quality
given during the #rst trimester. MMI should be used when ATD
therapy is started after the #rst trimester.
How should antithyroid treatment be managed GD during pregnancy should be treated with the lowest possible Strong recommendation, low
during pregnancy? dose of ATDs needed to keep the mother’s thyroid hormone quality
levels at or slightly above the reference range for total T4 and T3
values in pregnancy (1.5 times above nonpregnant reference
ranges in the second and third trimesters), and the TSH below
the reference range for pregnancy. Similarly, free T4 levels should
be kept at or slightly above the upper limit of the pregnancy
trimester reference range for the assay. Thyroid function should
be assessed monthly, and the ATD dose adjusted as required.
How should other causes of thyrotoxicosis be Patients taking medications known to cause thyrotoxicosis, Strong recommendation, low
managed? including interferon (IFN)-$, interleukin-2, tyrosine kinase quality
inhibitors, and lithium, should be monitored clinically and
biochemically at 6-month intervals for the development of
thyroid dysfunction.

GD, Graves’ disease; 131I, radioactive I-131; TMNG, toxic multinodular goiter; TA, toxic adenoma; SH, subclinical hyperthyroidism.
Data from Reference 6.

MMI readily crosses the placenta and appears in breast milk. Older is su#ciently blocked, clinical improvement should ensue. Usually,
studies suggested that PTU crosses the placental membranes only within 4 to 8 weeks of initiating therapy, symptoms will diminish
one-tenth as well as MMI; however, these studies were done in the and circulating thyroid hormone levels will return to normal. Now,
course of therapeutic abortion early in pregnancy. Newer studies the tapering regimen can be started. Changes in dose for each drug
show little di"erence between fetal concentrations of PTU and MMI, should be made monthly because the endogenously produced T4
and both are associated with elevated TSH in about 20% and low T4 will reach a new steady-state concentration in this interval. Typical
in about 7% of fetuses. ranges of daily maintenance doses for MMI and PTU are 5 to 30 mg
and 50 to 300 mg, respectively.
4 Dosing and Administration MMI is available as 5 and 10 mg If the objective of therapy is to induce long-term remission in a
tablets and PTU as 50 mg tablets. MMI is approximately 10 to 20 patient with Graves’ Disease, the patient should remain on continu-
times more potent than PTU. Initial therapy with MMI is given in ous antithyroid drug therapy for a minimum of 12 to 24 months.
two or three divided doses totaling 30 to 60 mg/day. PTU is given Antithyroid drug therapy induces permanent remission rates of 10%
in dose ranges from 300 to 600 mg daily, usually in three or four to 98%, with an overall average of about 40% to 50%. !is is much
divided doses. Although the traditional recommendation is for higher than the remission rate seen with propranolol alone (22%–
divided doses, evidence exists that both drugs can be given as single 36%). Patient characteristics for a favorable outcome include older
daily doses. Patients with severe hyperthyroidism may require larger patients (older than 40 years), low T4:T3 ratio (less than 20), a small
initial doses, and some may respond better at these larger doses if goiter (less than 50 g), short duration of disease (less than 6 months),
the dose is divided. !e maximal blocking doses of MMI and PTU no previous history of relapse with ATDs, duration of therapy 1 to
are 120 and 1,200 mg daily, respectively. Once the intrathyroidal 2 years or longer, and low TSAb titers at baseline or a reduction with
pool of thyroid hormone is reduced and new hormone synthesis treatment.24 A 2012 study provides preliminary evidence that a new

AL G r a w a n y
1252
assay that has better specificity for detection of antibodies that stim- more serious adverse e"ect of agranulocytosis, so therapy can usu-
ulate the TSH receptors, without detecting coexistent blocking anti- ally be continued. If a minor adverse reaction occurs with one ATD,
bodies, may be a useful predictor of remission of Graves’ disease.25 the alternate thiourea may be tried, but cross-sensitivity occurs for
A remission of Graves’ hyperthyroidism most o$en occurs about 50% of patients.23
a$er 4 to 11 years of treatment, with a better prognosis if TSH bind- Agranulocytosis is one of the serious adverse e"ects of thiourea
ing inhibitor immunoglobulin (TBII) activity disappeared within drug therapy and is characterized by fever, malaise, gingivitis, oro-
5 years without TBII 'uctuation or enlargement of the goiter. A lon- pharyngeal infection, and a granulocyte count less than 250/mm3
SECTION

ger duration until normalization of TBII and higher &nal thyroid (0.250 ' 109/L).23 !ese drugs are concentrated in granulocytes, and
weight were associated with a poor prognosis.26 this reaction may represent a direct toxic e"ect rather than hyper-
In another study in which patients were treated for their &rst sensitivity. !is toxic reaction has occurred with both thioureas, and
episodes of Graves’ hyperthyroidism, patients were treated for a the incidence varies from 0.5% to 6%. It is higher for patients over
minimum of 18 to 24 months of methimazole and then randomized age 40 receiving an MMI dose greater than 40 mg/day or the equiva-
10 to receive an additional 36 to 102 months of treatment or discontin- lent dose of PTU, and is more frequent with initial MMI doses of 30
ued methimazole. Patients in both treatment groups were followed mg compared with 15 mg. A systematic review and meta(analysis
48 months a$er discontinuing methimazole. Patients who received found strong associations of ATD(induced agranulocytosis with
Endocrinologic Disorders

60 to 120 months of methimazole were signi&cantly more likely to HLAB* 27:05, HLA(B*38:02, and HLA(DRB1*08:03 alleles, espe-
achieve remission compared to patients who received only an 18- to cially in carbimazole/methimazole-induced agranulocytosis.32
24-month course of treatment (85% vs 47%).27 Agranulocytosis usually develops in the first 3 months of ther-
A systematic review on remission rates in children with Graves’ apy. Because the onset is sudden, routine WBC count monitoring
disease found that 23.7% of the participants achieved remission has not been recommended. Colony-stimulating factors have been
a$er 1.5 to 2.5 years of treatment and 75% achieved remission a$er used with some success to restore cell counts to normal, but it is
9 years of treatment. Adverse events occurred in 17.6% of patients unclear how e"ective this form of therapy is compared with rou-
but major side e"ects occurred in only 1.1%. In summary, longer tine supportive care. Peripheral lymphocytes obtained from patients
treatment was associated with greater e#cacy and is generally well with PTU-induced agranulocytosis undergo a transformation in the
tolerated.28 presence of other thionamides, suggesting that these severe reactions
It is important that patients be followed every 6 to 12 months are immunologically mediated and patients should not receive other
a$er remission occurs. If a relapse occurs, alternate therapy with RAI thionamides. Aplastic anemia has been reported with MMI and may
is preferred over a second course of ATDs, however, continued long- be associated with an inhibitor to colony-forming units. Once ATDs
term low-dose MMI can be considered.29 Relapses seem to plateau are discontinued, clinical improvement is seen over several days
a$er about 5 years and eventually, 5% to 20% of patients will develop to weeks. Patients should be counseled to discontinue therapy and
spontaneous hypothyroidism. Some researchers have speculated contact their physician when flu-like symptoms such as fever, mal-
whether concurrent administration of T4 with thionamide therapy aise, or a sore throat develops. Treatment of agranulocytosis requires
for thyrotoxicosis and subclinical hyperthyroidism can reduce auto- immediate suspension of the ATD and initiation of broad-spectrum
antibodies directed toward the thyroid gland and improve the remis- antibiotics. De&nitive treatment of hyperthyroidism is subsequently
sion rate. In general, this approach is not recommended because of required.33 Clinicians will o$en concomitantly provide an order for
the higher rates of side e"ects seen with the larger doses of ATDs a complete blood cell count (with WBC count di"erential) when
needed for this regimen.6 prescribing MMI or PTU therapy. If the patient becomes ill and is
Subclinical hyperthyroidism is defined as a serum TSH below unable to reach the provider, the patient can still visit the nearest
the lower limit of the reference range combined with free T4 and laboratory to have potential agranulocytosis diagnosed.
T3 concentrations that are normal. Subclinical hyperthyroidism is Arthralgias and a lupus-like syndrome (sometimes in the
associated with an increased risk of atrial fibrillation and may be absence of antinuclear antibodies) have been reported in 4% to
associated with increased all-cause mortality. Some studies show 5% of patients. !is generally occurs a$er 6 months of therapy.
an increased risk of hip fractures in postmenopausal women with Uncommonly, polymyositis, presenting as proximal muscle weak-
subclinical hyperthyroidism. Most practitioners agree that the treat- ness and elevated creatine phosphokinase, has been reported with
ment of older patients (greater than 65 years) with TSH values below PTU administration. Gastrointestinal intolerance is also reported to
0.1 mIU/L is reasonable. In patients who are younger or have TSH occur in 4% to 5% of patients. Hypoprothrombinemia is a rare com-
values of 0.1 to 0.4 mIU/L a decision whether to treat the patient for plication of thionamide therapy. Patients who have experienced a
mild hyperthyroidism or to monitor thyroid function depends on major adverse reaction to one thiourea drug should not be converted
the patient’s cardiovascular risk factors and bone health.6,30 to the alternate drug because of cross-sensitivity.6
In 2019 the European Medicines Agency (EMA) issued a
Adverse E!ects Minor adverse reactions to MMI and PTU have warning and the product labeling for methimazole was changed to
an overall incidence of 5% to 25% depending on the dose and the include acute pancreatitis as a serious side e"ect. !is decision was
drug, whereas major adverse e"ects occur in 1.5% to 4.6% of patients based on six case reports of acute pancreatitis in patients treated
receiving these drugs.23 Pruritic maculopapular rashes (sometimes with methimazole, developing within 90 days of starting the drug.
associated with vasculitis based on skin biopsy), arthralgias, and In one study, ongoing use of methimazole was associated with a
fevers occur in up to 5% of patients and may occur at a greater fre- 56% increase in the risk of being admitted to the hospital for acute
quency with higher doses and in children. Rashes o$en disappear pancreatitis, whereas propylthiouracil was not associated with an
spontaneously but, if persistent, may be managed with antihis- increased risk.34
tamines. Under the supervision of an allergist, desensitization to Hepatotoxicity can be seen with both MMI and PTU, with a
methimazole is an option for treating patients who experience rash prevalence of approximately 1.3%. At moderate doses, some authors
or itching from the drug.31 have found that initial hepatic enzyme elevations eventually nor-
One of the most common side e"ects is a benign transient malize in most patients with continued therapy. PTU-induced
leukopenia characterized by a WBC count of less than 4,000/mm3 subclinical liver injury is common and is usually transient and
(4 ' 109/L) !is condition occurs in up to 12% of adults and 25% of asymptomatic. !us, it has generally been thought that therapy with
children and sometimes can be confused with mild leukopenia seen PTU may be continued with caution in the absence of symptoms and
in Graves’ disease. !is mild leukopenia is not a harbinger of the hyperbilirubinemia. However, a 1997 literature review documented
 1253
49 cases of hepatotoxicity. Twenty-eight cases were associated with o$en used as adjunctive therapy to prepare a patient with Graves’
PTU use, and 21 cases were associated with MMI use. !e hepa- disease for surgery, to acutely inhibit thyroid hormone release and
totoxicity was associated with seven deaths and three deaths in the quickly attain the euthyroid state in severely thyrotoxic patients with
PTU and MMI groups, respectively. !ere did not appear to be a cardiac decompensation, or to inhibit thyroid hormone release fol-
relationship between the dose or duration of thionamide treatment lowing RAI therapy. However, large doses of iodine may exacerbate
and outcome. During the past 20 years of PTU use in the United hyperthyroidism or indeed precipitate hyperthyroidism in some

CHAPTER
States, 22 adults developed severe hepatotoxicity leading to nine previously euthyroid individuals (Jod–Basedow disease). !is Jod–
deaths and five liver transplants. !e risk of this complication was Basedow phenomenon is most common in iodine-deficient areas,
greater in children (1:2,000) than in adults (1:10,000). A recent particularly for patients with pre-existing nontoxic goiter. Iodide
reanalysis of data reported to the Food and Drug Administration is contraindicated in toxic MNG as the autonomous tissue utilizes
(FDA) from 1982 to 2008 found that toxicity in children was gener- the iodine for subsequent thyroid hormone synthesis. Although it
ally related to higher doses of PTU and that toxicity in both children is not the standard of care in the United States, potassium iodide
and adults was associated with therapy lasting more than 4 months therapy was e"ective in two-thirds of cases, and induced remission 96
in duration.35 !us, the American !yroid Association (ATA) and in approximately 40% of the patients in a Japanese study of hyper-
the FDA recommend against the use of PTU as first-line therapy in thyroid patients with thionamide-associated side e"ects.40 Because

Thyroid Disorders
either adults or children.6 One of three exceptions includes the first iodide crosses the placenta and may cause hypothyroidism and goi-
trimester of pregnancy, when the risk of MMI-induced embryopa- ter in the newborn, its use is generally avoided in pregnant women.
thy may exceed that of PTU-induced hepatotoxicity. Other excep- Potassium iodide is available either as a saturated solution
tions include intolerance to MMI and thyroid storm. (SSKI), which contains 38 mg of iodide per drop or as Lugol’s solu-
Older reports suggested that congenital skin defects (ie, aplasia tion, which contains 6.3 mg of iodide per drop. !e typical starting
cutis) may be caused by MMI and carbimazole, although a registry dose of SSKI is 3 to 10 drops daily (120-400 mg) in water or juice.
review from the Netherlands could not find an association between !ere is no documented advantage to using doses in excess of 6 to
maternal use of these drugs and skin defects. Several serious con- 8 mg/day. When used to prepare a patient for surgery, it should be
genital malformations including tracheoesophageal fistulas and cho- administered 7 to 14 days preoperatively. As an adjunct to RAI, SSKI
anal atresia have been observed with MMI and carbimazole but not should not be used before, but rather 3 to 7 days a$er RAI treatment,
PTU use during pregnancy. PTU has traditionally been considered so that the radioactive iodide can concentrate in the thyroid. !e
the drug of choice throughout pregnancy for women with hyperthy- most frequent toxic e"ects with iodide therapy are hypersensitiv-
roidism, because of concerns about the possible teratogenic e"ects ity reactions (skin rashes, drug fever, rhinitis, and conjunctivitis),
of MMI. However, currently heightened concerns about the greater salivary gland swelling, “iodism” (metallic taste, burning mouth and
risk of hepatotoxicity with PTU when compared to MMI have led to throat, sore teeth and gums, symptoms of a head cold, and some-
the recommendation that PTU no longer be considered a first-line times stomach upset and diarrhea), and gynecomastia.
drug, except during the first trimester of pregnancy. !e choice of Other compounds containing organic iodide have also been
antithyroid agent during pregnancy has been further complicated by used therapeutically for hyperthyroidism. !ese include various
two studies that suggest that fetuses exposed to either MMI or PTU radiologic contrast media that share a triiodoaminobenzene and
during gestation may increase the risk of drug-induced fetal malfor- monoaminobenzene ring with a propionic acid chain (eg, iopanoic
mations. A Danish study revealed that 2% to 3% of children exposed acid and sodium ipodate). !e e"ect of these compounds is a result
to PTU developed birth defects associated with this therapy.36 In of the iodine content inhibiting thyroid hormone release as well as
another study, PTU associated birth defects, though less severe than competitive inhibition of 5#- monodeiodinase conversion related
MMI-associated birth defects, occurred with similar incidence in a to their structures, which resemble thyroid analogs. Unfortunately,
Korean population.37 Recommendations regarding the management these extremely useful agents are no longer available in the United
of thyroid disease during pregnancy recommends using the lowest States.
e"ective dose of the ATD as possible, targeting maternal serum FT4/
TT4 at the upper limit or moderately above the reference range and 5 Adrenergic Blockers Because many of the manifestations of
utilizing a team approach with close collaboration among endocri- hyperthyroidism are mediated by !-adrenergic receptors, !-blockers
nologists, maternal-fetal medicine specialists, and neonatologists.38 (especially propranolol) have been used widely to ameliorate symp-
While there is debate regarding optimal therapy of Graves’ dis- toms such as palpitations, anxiety, tremor, and heat intolerance.
ease, a study assessing the quality of life (QoL) in patients 6 to 10 Although !-blockers are quite e"ective for symptom control, they
years a$er treatment for Graves’ disease with RAI, thyroidectomy, or have no e"ect on the urinary excretion of calcium, phosphorus,
ATDs. Patients treated with RAI had worse thyroid-related and gen- hydroxyproline, creatinine, or various amino acids, suggesting a
eral QoL than patients treated with ATD or thyroidectomy on the lack of e"ect on peripheral thyrotoxicosis and protein metabolism.
majority of QoL scales. However, regardless of treatment modality, Furthermore, !-blockers neither reduce TSAb nor prevent thyroid
patients with GD had worse thyroid-related QoL 6 to 10 years a$er storm. Propranolol and nadolol partially block the conversion of T4
diagnosis compared to the general population.39 to T3, but this contribution to the overall therapeutic e"ect is small
in magnitude. Inhibition of conversion of T4 to T3 is mediated by
Iodides Iodide was the first form of drug therapy for Graves’ dis- D-propranolol, which is devoid of !-blocking activity, and L-pro-
ease. Its mechanism of action is to acutely block thyroid hormone pranolol, which is responsible for the antiadrenergic e"ects, has little
release, inhibit thyroid hormone biosynthesis by interfering with e"ect on the conversion.
intrathyroidal iodide utilization (the Wol"–Chaiko" e"ect), and !-Blockers are usually used as adjunctive therapy with ATDs,
decrease the size and vascularity of the gland. !is early inhibitory RAI, or iodides when treating Graves’ disease or toxic nodules; in
e"ect provides symptom improvement within 2 to 7 days of initiat- preparation for surgery; or in thyroid storm. !e only conditions for
ing therapy, and serum T4 and T3 concentrations may be reduced which !-blockers are primary therapy for thyrotoxicosis are those
for a few weeks. Despite the reduced release of T4 and T3, thyroid associated with thyroiditis. !e dose of propranolol required to
hormone synthesis continues at an accelerated rate, resulting in a relieve adrenergic symptoms is variable, but an initial dose of 20 to
gland rich in stored hormones. !e normal and hyperfunctioning 40 mg four times daily is e"ective (goal heart rate less than 90 beats/
thyroid soon escapes from this inhibitory e"ect within 1 to 2 weeks min) for most patients. Younger or more severely toxic patients may
by decreasing the active transfer of iodide into the gland. Iodides are require as much as 240 to 480 mg/day because there seems to be

AL G r a w a n y
1254
an increased clearance rate for these patients. !-Blockers are con- or persistent hyperthyroidism. Pretreatment with PTU may lead to
traindicated for patients with decompensated heart failure unless it higher rates of treatment failure, but this does not appear to be the
is caused solely by tachycardia (high output failure). Nonselective case with MMI pretreatment. !e use of lithium, as adjunctive ther-
agents and those lacking intrinsic sympathomimetic activity should apy to RAI therapy, has multiple benefits of increasing the cure rate,
be used with caution for patients with asthma and bronchospastic shortening the time to cure, and preventing a post-therapy increase
chronic obstructive lung disease. !-Blockers that are cardioselec- in thyroid hormone levels.42 Lithium is likely to achieve these e"ects
tive and have intrinsic sympathomimetic activity may have a slight by increasing RAI retention in the thyroid and inhibiting thyroid
SECTION

margin of safety in these situations. Other patients in whom con- hormone release from the gland, although it is not commonly used
traindications exist are those with sinus bradycardia, those receiv- due to its narrow therapeutic index.
ing monoamine oxidase inhibitors or tricyclic antidepressants, and Corticosteroid administration will blunt and delay the rise in
those with spontaneous hypoglycemia. !-Blockers may also prolong antibodies to the TSH receptor, TG, and thyroid peroxidase while
gestation and labor during pregnancy. Other side e"ects include reducing T3 and T4 concentrations following RAI. !eoretically, if
10 nausea, vomiting, anxiety, insomnia, light-headedness, bradycardia, a shared thyroidal and orbital antigen is involved in the pathogen-
and hematologic disturbances. esis of Graves’ ophthalmopathy, antigen released with RAI treatment
Antiadrenergic agents such as centrally acting sympatholytics could aggravate pre-existing eye disease. !ere is some disagreement
Endocrinologic Disorders

and calcium channel antagonists may have some role in the symp- as to what degree of ophthalmopathy should be considered a con-
tomatic treatment of hyperthyroidism. !ese drugs might be useful traindication to RAI. However, in those with moderate or severe
when contraindications to !-blockade exist. When compared with orbitopathy, it seems reasonable to delay RAI until the patient’s eye
nadolol 40 mg twice daily, clonidine 150 mcg twice daily reduced disease has been stable. Traditionally, corticosteroids, radiation ther-
plasma catecholamines, whereas nadolol increased both epineph- apy, and surgical correction have been the mainstays of therapy for
rine and norepinephrine a$er 1 week of treatment. Diltiazem Graves’ ophthalmopathy. Rituximab, tocilizumab, and teprotumum-
120 mg given every 8 hours reduced heart rate by 17%; fewer ven- abIn have been assessed in RCTs.43 In 2020, the FDA approved tepro-
tricular extrasystoles were noted a$er 10 days of therapy, and diltia- tumumab, a monoclonal anti-insulin-like growth factor I receptor
zem has been shown to be comparable to propranolol in lowering antibody for the treatment of thyroid eye disease. Patients com-
heart rate and BP. pleting the eight-infusion treatment course of teprotumumab over
!erapeutic plasmapheresis is an e"ective alternative treatment 24 weeks demonstrated signi&cant improvement in proptosis, diplo-
option to prepare for ablative treatment in patients that have side pia, quality of life, and Clinical Activity Score.44 !e most commonly
e"ects or who do not respond adequately to anti-thyroid drugs.41 In reported adverse events with teprotumumab were muscle spasm
a retrospective study in patients with Graves’ disease, amiodarone- (18%), hearing loss (10%), and hyperglycemia (8%).
induced thyrotoxicosis, or toxic nodular goiter, the median free tri- Destruction of the gland attenuates the hyperthyroid state,
iodothyronine (FT3) fell from 9.9 pg/mL to 4.0 pg/mL (0.15 pmol/L and hypothyroidism commonly occurs months to years following
to 0.06 pmol/L) and FT4 levels fell from 2.9 ng/dL to 1.6 ng/dL (37.3 RAI.6,24 !e goal of therapy is to destroy overactive thyroid cells, and
pmol/L to 20.6 pmol/L). Each apheresis session lasted for 2.5 to a single dose of 4,000 to 8,000 rad (40 to 80 Gy) results in a euthy-
3 hours and was performed daily until normal thyroid function was roid state in 60% of patients at 6 months or less. !e remaining 40%
achieved (median 4, range 1-7 days). become euthyroid within 1 year, requiring two or more doses. It is
advisable that a second dose of RAI be given 6 months a$er the first
6 Radioactive Iodine Although other radioisotopes have been RAI treatment if the patient remains hyperthyroid.6 Variables that
used to ablate thyroid tissue, 131I is considered to be the agent of predict an unsuccessful outcome of RAI include gender (men are
choice for Graves’ disease, toxic autonomous nodules, and toxic less likely to develop hypothyroidism), race, the size of the thyroid
MNGs.6 RAI is administered as a colorless and tasteless liquid that (euthyroidism is less likely in large glands), the severity of disease,
is well absorbed and concentrates in the thyroid. 131I is a !- and and perhaps a higher level of TSAb. Predictors of successful treat-
(-emitter with a tissue penetration of 2 mm and a half-life of 8 days. ment with RAI included higher ablative dose, female gender, lower
Other organs take up 131I, but the thyroid gland is the only organ free T4 levels at diagnosis, and absence of a palpable goiter.24 !e
in which organification of the absorbed iodine takes place. Initially, acute, short-term side e"ects of 131I therapy are minimal and include
RAI disrupts hormone synthesis by incorporating into thyroid hor- mild thyroidal tenderness and dysphagia. Concern about mutations
mones and TG. Over a period of weeks, follicles that have taken up and congenital defects now appears to be unfounded because long-
RAI and surrounding follicles develop evidence of cellular necrosis, term follow-up studies have not revealed an increased risk for these
breakdown of follicles, development of bizarre cell forms, nuclear complications.45 Although RAI is very e"ective in the treatment of
pyknosis, and destruction of small vessels within the gland, lead- hyperthyroidism, long-term follow-up from Great Britain suggests
ing to edema and fibrosis of the interstitial tissue. Pregnancy is an that among patients with hyperthyroidism treated with RAI, mortal-
absolute contraindication to the use of RAI since radiation will be ity from all causes and mortality resulting from cardiovascular and
delivered to the fetal tissue, including the fetal thyroid. cerebrovascular disease and fracture are increased.
!-Blockers may be given any time without compromising RAI A common approach to Graves’ hyperthyroidism is to admin-
therapy, accounting for their role as a mainstay of adjunctive ther- ister a single dose of 5 to 15 mCi (185 to 555 mBq; 80-200 µCi/g
apy to RAI treatment. If iodides are administered, they should be of tissue [3.0 to 7.4 mBq/g]). !e optimal method for determining
given 3 to 7 days a$er RAI to prevent interference with the uptake of 131
I treatment doses for Graves’ hyperthyroidism is unknown, and
RAI in the thyroid gland. Because thyroid hormone levels will tran- techniques have varied from a fixed dose to more elaborate calcula-
siently increase following RAI treatment due to the release of pre- tions based on gland size, iodine uptake, and iodine turnover.6 In a
formed thyroid hormone, patients with cardiac disease and elderly trial of 88 patients with Graves’ disease, no di"erence in outcome
patients are o$en treated with thionamides prior to RAI ablation. was seen among high or low, &xed or adjusted doses. !yroid glands
For patients with underlying cardiac disease, it may be necessary estimated to weigh more than 80 g may require larger doses of RAI.
to reinstitute antithyroid drug therapy following RAI ablation. !e Larger doses are likely to induce hypothyroidism and are seldom
standard practice is to withdraw the thionamide 4 to 6 days prior to given outside the United States due to the imposition of stringent
RAI treatment and to reinstitute it 4 days a$er therapy is concluded. safety restrictions. For example, in the United Kingdom, a nursery
Administering antithyroid drug therapy immediately following RAI school teacher is advised to stay out of school for 3 weeks following
treatment may result in a higher rate of posttreatment recurrence a 15 mCi (555 mBq) dose of 131I.
 1255
Special Populations long as 8 to 12 weeks until the antibody is cleared (immunoglobu-
lin G half-life is about 2 weeks). Iodide (potassium iodide one drop
Graves’ Disease and Pregnancy per day or Lugol’s solution one to three drops per day) and sodium
Inappropriate increase in the production of hCG is a cause of abnor- ipodate may be used for the &rst few days to acutely inhibit hormone
mal thyroid function tests during the first half of pregnancy, and release.
hCG can cause either subclinical (normal T4 and suppressed TSH) Childhood hyperthyroidism has classically been managed with
or overt hyperthyroidism. !is is because the homology of hCG and

CHAPTER
either MMI or PTU. Long-term follow-up studies suggest that this
TSH leads to hCG-mediated stimulation through the TSH receptor. form of therapy is quite acceptable, with 25% of a cohort experienc-
At hCG concentrations greater than 400 IU/mL (kIU/L), TSH levels ing remission every 2 years. Again, current recommendations sug-
were invariably suppressed and free T4 levels were generally above gest using MMI as a first-line agent in both adults and children.6
the normal range. Most patients with hCG greater than 200 IU/mL
(kIU/L) did not have symptoms of hyperthyroidism. !e variability Thyroid Storm
of the thyrotropic potency of hCG is believed to depend on its car- !yroid storm is a life-threatening medical emergency character- 96
bohydrate composition. ized by decompensated thyrotoxicosis, high fever (o$en more than
A very comprehensive guideline has been published by the 39.4°C [103°F]), tachycardia, tachypnea, dehydration, delirium,

Thyroid Disorders
ATA regarding the management of thyroid disease during preg- coma, nausea, vomiting, and diarrhea.8 Graves’ disease and less
nancy.38 Hyperthyroidism during pregnancy is almost solely caused commonly toxic nodular goiter are usually the underlying thyrotoxic
by Graves’ disease, with approximately 0.1% to 0.4% of pregnancies pathology.
a"ected. Although the increased metabolic rate is usually well tol- Precipitating factors for thyroid storm include infection,
erated in pregnant women, two symptoms suggestive of hyperthy- trauma, surgery, RAI treatment, and withdrawal from ATDs.
roidism during pregnancy are failure to gain weight despite a good Although the duration of clinical decompensation lasts for an aver-
appetite and persistent tachycardia. !ere is no increase in maternal age duration of 72 hours, symptoms may persist up to 8 days. With
mortality or morbidity in well-controlled patients. However, post- aggressive treatment, the mortality rate has been lowered to 20%.
partum thyroid storm has been reported in about 20% of untreated !e following therapeutic measures should be instituted promptly:
individuals. Fetal loss is also more common, due to the fact that (a) suppression of thyroid hormone formation and secretion,
spontaneous abortion and premature delivery are more common (b) antiadrenergic therapy, (c) administration of corticosteroids,
in untreated pregnant women, as are low-birth-weight infants and and (d) treatment of associated complications or coexisting factors
eclampsia. Transplacental passage of TSAb may occur, causing that may have precipitated the storm. Specific agents used in thy-
fetal as well as neonatal hyperthyroidism. An uncommon cause of roid storm are outlined in Table 96-7. PTU in large doses may be
hyperthyroidism is molar pregnancy; women present with a large- the preferred thionamide because, in addition to interfering with
for-dates uterus and evacuation of the uterus is the preferred man- the production of thyroid hormones, it also blocks the peripheral
agement approach. conversion of T4 to T3. However, !-blockers and corticosteroids will
Because RAI is contraindicated in pregnancy and surgery is serve the same purpose. A theoretical advantage of MMI is that it
usually not recommended (especially during the first trimester), has a longer duration of action. If patients are unable to take medica-
antithyroid drug therapy is usually the treatment of choice for tions orally, the tablets can be crushed into suspension and instilled
hyperthyroidism. MMI readily crosses the placenta and appears in by a gastric or rectal tube. Iodides, which rapidly block the release
breast milk. of preformed thyroid hormone, should be administered a$er thi-
As previously mentioned, propylthiouracil has been considered onamide is initiated to inhibit iodide utilization by the overactive
the drug of choice during the first trimester of pregnancy, with the gland. If iodide is administered first, it could theoretically provide a
lowest possible doses used to maintain the maternal T4 level in the substrate to produce even higher levels of thyroid hormone.
high-normal range.38 During this period the risk of MMI-associated Antiadrenergic therapy with the short-acting agent esmolol is
embryopathy is believed to outweigh that of PTU-associated hepa- preferred, both because it may be used in the patient with pulmo-
totoxicity. To prevent fetal goiter and suppression of fetal thyroid nary disease or at risk for cardiac failure and because its e"ects may
function, PTU is usually prescribed in daily doses of 300 mg or less be rapidly reversed. Corticosteroids are generally recommended,
and tapered to 50 to 150 mg daily a$er 4 to 6 weeks. PTU doses of
less than 200 mg daily are unlikely to produce fetal goiter. During
the second and third trimesters, when the critical period of organo-
genesis is complete, MMI has been thought to be the drug of choice
because of the greater risk of hepatotoxicity with PTU.38 However, TABLE 96!7 Drug Dosages Used in the Management of
it is unclear whether this strategy of switching thionamides, and Thyroid Storm
thus exposing the fetus to both drugs, is the optimum approach.36 Drug Regimen
!ionamide doses should be adjusted to maintain free T4 within Propylthiouracil 900-1,200 mg/day orally in four or six
10% of the upper normal limit of the nonpregnant reference range. divided doses
During the last trimester, TSAbs fall spontaneously, and some Methimazole 90-120 mg/day orally in four or six divided
patients will go into remission so that ATD doses may be reduced. doses
A rebound in maternal hyperthyroidism occurs in about 10% of Sodium iodide Up to 2 g/day IV in single or divided doses
women postpartum and may require more intensive treatment than Lugol’s solution 5-10 drops three times a day in water or
in the last trimester of pregnancy. juice
Saturated solution of 1-2 drops three times a day in water or juice
Neonatal and Pediatric Hyperthyroidism potassium iodide (SSKI)
Following delivery, some babies of hyperthyroid mothers will be Propranolol 40-80 mg every 6 hours
hyperthyroid due to placental transfer of TSAbs, which stimulates Dexamethasone 5-20 mg/day orally or IV in divided doses
thyroid hormone production in utero and postpartum. !is is likely Prednisone 25-100 mg/day orally in divided doses
if the maternal TSAb titers were quite high. !e disease is usually Methylprednisolone 20-80 mg/day IV in divided doses
expressed 7 to 10 days postpartum and treatment with ATDs (PTU Hydrocortisone 100-400 mg/day IV in divided doses
5-10 mg/kg/day or MMI 0.5-1 mg/kg/day) may be needed for as

AL G r a w a n y
1256
although there is no convincing evidence of adrenocortical of thyroid disease, 3.9% had subclinical hypothyroidism (serum
insu#ciency in thyroid storm, and the benefits derived from steroids TSH more than 4.5 mIU/L, and T4 normal), and 0.2% had “clinically
may be caused by their antipyretic action and their e"ect of stabi- significant” hypothyroidism (TSH more than 4.5 mIU/L, and T4 less
lizing BP.8 General supportive measures, including acetaminophen than 4.5 mcg/dL [58 nmol/L]).7 Subclinical hypothyroidism is com-
as an antipyretic (do not use aspirin or other NSAIDs because they monly regarded as a sign of impending thyroid failure.
may displace bound thyroid hormone), fluid and electrolyte replace-
ment, sedatives, digitalis, antiarrhythmics, insulin, and antibiotics,
ETIOLOGY AND PATHOPHYSIOLOGY !
SECTION

should be given as indicated. Plasmapheresis and peritoneal dialysis

have been used to remove excess hormone (and to remove thyroid- HYPOTHYROIDISM
stimulating immunoglobulins in Graves’ disease) when the patient
has not responded to more conservative measures, although these !e vast majority of patients have primary hypothyroidism due to
measures do not always work. thyroid gland failure caused by chronic autoimmune thyroiditis.
Special populations with higher risk of developing hypothyroidism
10 include postpartum women, individuals with a family history of
EVALUATION OF THERAPEUTIC autoimmune thyroid disorders and patients with previous head and
neck or thyroid irradiation or surgery, other autoimmune endocrine
Endocrinologic Disorders

OUTCOMES!THYROTOXICOSIS conditions (eg, type 1 diabetes mellitus, adrenal insu#ciency, and

A$er therapy (surgery, thionamides, or RAI) for hyperthyroidism ovarian failure), some other nonendocrine autoimmune disorders
has been initiated, patients should be evaluated on a monthly basis (eg, celiac disease, vitiligo, pernicious anemia, Sjögren’s syndrome,
until they reach a euthyroid condition. Clinical signs of continuing and multiple sclerosis), primary pulmonary hypertension, and
thyrotoxicosis (tachycardia, weight loss, and heat intolerance, among Down’s and Turner’s syndromes.
others) or the development of hypothyroidism (bradycardia, weight Central hypothyroidism is rare and a"ects both sexes equally. It
gain, and lethargy, among others) should be noted. !-Blockers may is more o$en associated with pituitary than hypothalamic disorders
be used to control symptoms of thyrotoxicosis until the definitive but frequently involves both.47 Biochemically, central hypothyroid-
treatment has returned the patient to a euthyroid state. If T4 replace- ism is defined by low or low-to-normal TSH concentrations and a
ment is initiated, the goal is to maintain both the free T4 level and disproportionately low concentration of FT4. Secondary hypothy-
the TSH concentration in the normal range. Once a stable dose of T4 roidism due to pituitary failure is uncommon but should be sus-
is identified, the patient may be followed up every 6 to 12 months. pected in a patient with decreased levels of T4 and inappropriately
A common, potentially confusing clinical situation should be normal or low TSH levels. Most patients with secondary hypothy-
mentioned. Some patients may have TSH concentrations that con- roidism due to inadequate TSH production will have clinical signs
tinue to be suppressed despite having free T4 concentrations that of more generalized pituitary insu#ciency, such as abnormal men-
become normal or low. For patients with long-standing hyperthy- ses and decreased libido, or evidence of a pituitary adenoma, such
roidism, the pituitary thyrotrophs are responsible for making TSH as visual field defects, galactorrhea, or acromegaloid features, but
become atrophic. !e average amount of time required for these isolated TSH deficiency can be congenital or acquired as a result of
cells to resume normal functioning is 6 to 8 weeks. !erefore, if a autoimmune hypophysitis.48 Generalized (peripheral and central)
thyrotoxic patient has his or her free T4 concentration lowered rap- resistance to thyroid hormone is extremely rare.
idly before the thyrotrophs resume normal function, a period of Table 96-8 outlines the causes of hypothyroidism. !ese causes
“transient central hypothyroidism” will be observed. In addition, fall into two broad categories involving dysfunction of the thyroid
autoimmune mechanisms may also play a role, with a slower TSH gland (primary hypothyroidism) or dysfunction of the pituitary or
recovery in patients with higher titers of thyroid-binding inhibitory hypothalamus (secondary hypothyroidism).
immunoglobulins.
Chronic Autoimmune Thyroiditis
7 Autoimmune thyroiditis (Hashimoto’s disease) is the most com-
CONCLUSION!HYPERTHYROIDISM mon cause of spontaneous hypothyroidism in the adult.46 Patients
Management of hyperthyroidism includes treatment with ATDs, may present either with goitrous thyroid gland enlargement and
RAI, or thyroidectomy. Optimal treatment is patient-speci&c, mild hypothyroidism or with thyroid gland atrophy and more severe
depending on patient clinical presentation, including age, history thyroid hormone de&ciency. Both forms of autoimmune thyroiditis
of arrhythmias or atherosclerotic disease, goiter size, and severity probably result from cell- and antibody-mediated thyroid injury.
of thyrotoxicosis. ATDs are the primary therapy during pregnancy. !e presence of specific defects in suppressor T-lymphocyte func-
tion leads to the survival of a randomly mutating clone of helper
T lymphocytes, which are directed against normally occurring
HYPOTHYROIDISM antigens on the thyroid membrane. Once these T lymphocytes
Hypothyroidism is defined as the clinical and biochemical syn-
drome resulting from decreased thyroid hormone production.46
Biochemically, primary hypothyroidism is defined as TSH concen-
trations above the reference range and FT4 and/or triiodothyronine TABLE 96!8 Causes of Hypothyroidism
levels below the reference range. Primary hypothyroidism
Hashimoto’s disease
Iatrogenic hypothyroidism
EPIDEMIOLOGY!HYPOTHYROIDISM Less common:
• Iodine de#ciency
Overt hypothyroidism occurs in 1.5% to 2% of women and 0.2% • Enzyme defects
of men, and its incidence increases with age. In the !ird National • Thyroid hypoplasia
• Goitrogens
Health and Nutrition Examination Survey (NHANES III), levels of
serum TSH and total T4 were measured in a representative sample Secondary hypothyroidism
Pituitary disease
of adolescents and adults (age 12 or older). Among 16,533 people Hypothalamic disease
who neither were taking thyroid medication nor reported histories
 1257

CLINICAL PRESENTATION Hypothyroidism

General • The most common signs of decreased levels of
• Hypothyroidism can lead to a variety of end-organ thyroid hormone include coarse skin and hair, cold or
e"ects with a wide range of disease severity, from dry skin, periorbital pu!ness, and bradycardia.
•

CHAPTER
entirely asymptomatic to coma with multisystem Speech is often slow, and the voice may be hoarse.
failure. In the adult, manifestations of hypothyroidism • Reversible neurologic syndromes such as carpal
are nonspeci#c. In the child, thyroid hormone tunnel syndrome, polyneuropathy, and cerebellar
de#ciency may manifest as delays in growth or dysfunction may also occur.
intellectual development. • Galactorrhea may be found in women.
• Thyroid hormone is essential for normal growth and
development during embryonic life. Uncorrected Diagnosis 96
thyroid hormone de#ciency during fetal and neonatal • A rise in the TSH is the #rst evidence of
development results in mental retardation and/ hypothyroidism in primary hypothyroidism.

Thyroid Disorders
or cretinism. Both in children and adults, there is a • In secondary hypothyroidism in patients with
slowing of physical and mental activity, as well as of pituitary disease, serum TSH concentrations are
cardiovascular, gastrointestinal, and neuromuscular generally low or normal. A serum TSH concentration
function. in the normal range is clearly inappropriate if the
patient’s T4 is low.
Symptoms • Many patients will have a free T4 level within
• Common symptoms of hypothyroidism include dry the normal range (compensated or subclinical
skin, cold intolerance, weight gain, constipation, and hypothyroidism), with few, if any, symptoms of
weakness. hypothyroidism. As the disease progresses, the free
• Complaints of lethargy, depression, fatigue, exercise T4 concentration will drop below the normal level.
intolerance, or loss of ambition and energy are also With increased TSH stimulation, thyroidal production
common but are less speci#c. will shift toward greater amounts of T3, and thus T3
• Muscle cramps, myalgia, and sti"ness are frequent concentrations will often be maintained in the normal
complaints of hypothyroid patients. range in spite of a low T4. Eventually, free and/or total
• Menorrhagia and infertility may present commonly in T4 and T3 serum concentrations should be low.
women.
Other Tests
Signs • TPOAbs and anti-TG antibodies are likely to be
• Objective weakness is common, with proximal elevated in autoimmune thyroiditis.
muscles being a"ected more than distal muscles.
Slow relaxation of deep tendon re$exes is common.

interact with thyroid membrane antigen, B lymphocytes are stimu- 1 month. Excessive doses of thionamides used to treat hyperthyroid-
lated to produce thyroid antibodies. Readers are referred to an excel- ism can also cause iatrogenic hypothyroidism.
lent review regarding biochemical testing in thyroid disorders.49
Antithyroid peroxidase (antimicrosomal) antibodies are present in Other Causes of Primary Hypothyroidism
virtually all patients with Hashimoto’s thyroiditis and appear to be Iodine deficiency, enzymatic defects within the thyroid gland, thy-
directed against the enzyme thyroid peroxidase. !ese antibodies roid hypoplasia, and maternal ingestion of goitrogens during fetal
are capable of fixing complement and inducing cytotoxic changes development may cause cretinism. Early recognition and treatment
in thyroid cells. Antibodies that are capable of stimulating thyroid of the resultant thyroid hormone deficiency is essential for opti-
growth through interaction with the TSH receptor may occasionally mal mental development. Large-scale neonatal screening programs
be found particularly in goitrous hypothyroidism; conversely, anti- in North America, Europe, Japan, and Australia are now in place.
bodies that inhibit the trophic e"ects of TSH may be present in the !e frequency of congenital hypothyroidism in North America and
atrophic type. Europe is 1 per 3,500 to 4,000 live births. In the United States, there
are racial di"erences in the incidence of congenital hypothyroidism,
Iatrogenic Hypothyroidism with White patients being a"ected seven times as frequently as Black
Iatrogenic hypothyroidism follows exposure to destructive patients.
amounts of radiation (radioiodine or external radiation) or surgery. In the adult, hypothyroidism is rarely caused by iodine
Hypothyroidism occurs within 3 months to a year a$er 131I therapy deficiency and goitrogens. Iodine ingestion in the form of expecto-
in most patients treated for Graves’ disease. !erea$er, it occurs at rants can lead to hypothyroidism. In sensitive persons (particularly
a rate of approximately 2.5% each year. External radiation therapy those with autoimmune thyroiditis), the iodide blocks the synthe-
to the region of the thyroid using doses of greater than 2,500 centi- sis of thyroid hormone, leading to increased secretion of TSH and
gray (cGy) for therapy of neck carcinoma also causes hypothyroid- thyroid enlargement. !us, both iodine excess and iodine deficiency
ism. !is e"ect is dose-dependent and more than 50% of patients can cause decreased secretion of thyroid hormone. An example
who receive more than 4,000 cGy to the thyroid bed develop hypo- of a goitrogen that can induce hypothyroidism is raw bok choy.
thyroidism. Total thyroidectomy causes hypothyroidism within Several medications can cause hypothyroidism, including lithium,

AL G r a w a n y
1258

• Objective data
o Heart rate, BP, weight, and BMI
o Labs (eg, TSH, FT4, TT3, anti-TG antibodies, TPO antibod-
SECTION

ies; serum electrolytes, Scr, ALT)

o Other diagnostic tests when indicated (eg, thyroid ultra-
sound, RAIU scan)

Assess
10 • Cause of hypothyroidism (see Table 96-8)
• Current medications that may contribute to or worsen
hypothyroidism
Endocrinologic Disorders

• Current medications that may interact with thyroid

hormone replacement therapy
• Appropriateness and e"ectiveness of current thyroid
hormone replacement regimen

Plan*
• Drug therapy regimen including speci#c thyroid hormone
Patient Care Process for the Management replacement therapy and dose (see Table 96-9)
• Monitoring parameters including e!cacy (eg, resolution
of Hypothyroidism of signs and symptoms) and safety (arrhythmias, angina,
osteoporosis, or symptomatic hyperthyroidism), laboratory
The image shows the five fundamental steps included in The data (TSH, FT4, TT3), and follow-up monitoring time frame
Pharmacist’s Care Process endorsed by the Joint Commission • Patient education (eg, purpose of treatment, dietary and
for Pharmacy Practitioners (2014). The tagline of this process lifestyle modi#cation, drug therapy)
reads collaborate, communicate, and document. The five
fundamental steps listed here are collect, assess, plan, Implement*
implement, and follow-up: monitor and evaluate. All these • Provide patient education regarding all elements of the
steps are listed in a circular block diagram. treatment plan
• Use motivational interviewing and coaching strategies to
Collect maximize adherence
• Patient characteristics (eg, age, race, sex, pregnancy status) • Schedule follow-up visits and laboratory tests
• Patient history (past medical, family, social) including
signs and symptoms: coarse skin and hair, cold or Follow-up: Monitor and Evaluate
dry skin, periorbital puffiness, and bradycardia; cold • Resolution of signs and symptoms
intolerance, weight gain, constipation, weakness, • Presence of adverse e"ects
muscle cramps, myalgia, and galactorrhea (see Clinical • Patient adherence to treatment plan using multiple sources
Presentation Box) of information
• Current medications (including OTC and herbal medication
use) *Collaborate with patient, caregivers, and other healthcare professionals.

amiodarone, interferon-$, interleukin-2, tyrosine kinase inhibitors, Note that pituitary enlargement in hypothyroidism does
perchlorate, and checkpoint inhibitors.50 not invariably indicate the presence of a primary pituitary tumor.
Pituitary enlargement is seen in patients with severe primary hypo-
Pituitary Disease thyroidism due to compensatory hyperplasia and hypertrophy
TSH is required for normal thyroid secretion. !yroid atrophy of the thyrotrophs. With thyroid hormone replacement therapy,
and decreased thyroid secretion follow pituitary failure. Pituitary serum TSH concentrations decline, indicating that the TSH secre-
insu#ciency may be caused by the destruction of thyrotrophs by tion is not autonomous, and the pituitary resumes a more normal
either functioning or nonfunctioning pituitary tumors, surgical configuration. !ese patients are easily separated from patients with
therapy, external pituitary radiation, postpartum pituitary necro- primary pituitary failure by measuring a TSH level.
sis (Sheehan’s syndrome), trauma, and infiltrative processes of the
pituitary such as metastatic tumors, tuberculosis, histiocytosis, and
autoimmune mechanisms.51 In all these situations, TSH deficiency Hypothalamic Disease
most o$en occurs in association with other pituitary hormone TRH deficiency also causes a rare form of secondary hypothyroid-
deficiencies. !e identification of secondary hypothyroidism due to ism (also referred to as tertiary hypothyroidism). In both adults and
bexarotene use has led to a recognition of the role of rexinoids and children, it may occur from cranial irradiation, trauma, infiltrative
retinoids to cause dysregulation of TSH production.52 diseases, or neoplastic diseases.
 1259
uniform potency. Levothyroxine (T4) administration results in a pool
TREATMENT of thyroid hormones that is readily converted to T3 when needed; in
this regard, levothyroxine may be thought of as a prohormone.
Liothyronine (T3) is chemically pure with a known potency and
Hypothyroidism has a shorter half-life of 1.5 days. Although it can be used diagnosti-
Most cases of hypothyroidism result from progressive and perma- cally in the T3 suppression test, T3 has some clinical disadvantages,
nent damage to the thyroid gland. Replacement of thyroid hormone

CHAPTER
including a higher incidence of cardiac adverse e"ects, higher cost,
is the cornerstone of treatment. and di#culty in monitoring with conventional laboratory tests.
If used, T3 needs to be administered three times a day and it may
Desired Outcomes take a prolonged period of adjustment to achieve stable euthyroid-
!e goals of therapy are to restore normal thyroid hormone con- ism. Liotrix is a combination of synthetic T4 and T3 in a 4:1 ratio.
centrations in tissue, provide symptomatic relief, prevent neuro- It is chemically stable and pure and has a predictable potency. !e
logic deficits in newborns and children, and reverse the biochemical major limitations to this product are high cost and lack of therapeu- 96
abnormalities of hypothyroidism. tic rationale because most T3 is peripherally converted from T4. In
addition, the T4:T3 ratio is much higher than the 14:1 molar ratio
General Approach to Treatment

Thyroid Disorders
produced by the thyroid gland in humans.
8 Levothyroxine (L-thyroxine, T4) is considered to be the drug of 9 !e use of combination therapy of levothyroxine and lio-
choice for treatment of hypothyroidism (Table 96-9).18 Other com- thyronine remains highly controversial with con'icting results from
mercially available thyroid preparations can be obtained but are not clinical trials.53 !e American !yroid Association, British !yroid
considered preferred therapy. Available thyroid preparations are Association, and European !yroid Association reviewed the lat-
synthetic (L-thyroxine, liothyronine, and liotrix) or natural in origin est basic science and clinical evidence regarding thyroid hormone
(ie, desiccated thyroid). !e preparations containing both T4 and T3 combination therapy and published a position statement to guide
(liotrix, desiccated thyroid) have relatively high proportions of T3 the design of future clinical trials of T4/T3 therapy.54 A well-designed,
and may cause thyrotoxicosis.18 Liothyronine is a short-acting prep- adequately powered clinical trial of combination therapy in patients
aration that requires dosing multiple times a day in order to achieve dissatis&ed with levothyroxine replacement therapy is anticipated.
stable hormone concentrations. !e availability of sensitive and A study conducted in rats suggested impairment of type 2 deio-
specific assays for total and free hormone levels as well as TSH now dinase activity in the whole body during levothyroxine monotherapy
allows precise dose titration to make adequate replacement without due to deiodinase inactivation, compared with maintenance of deio-
inadvertent overdose. !e response of TSH to TRH had been advo- dinase activity in the hypothalamus.55 !e lesser activation in the
cated for use by some in order to “fine tune” thyroid replacement, hypothalamus leads to e#cient T3 production in the hypothalamus
but this is not necessary if the third-generation chemiluminometric and normalization of TSH before T3 is normalized in the rest of the
assays for TSH, which have detection limits of about 0.01 mIU/L, body. Accompanying the inactivation of type 2 deiodinase in other
are used. Clinical guidelines for the management of hypothyroid- tissues, lower serum T3 and higher T4/T3 ratios were seen in rats
ism have been published by the ATA and provide specific treatment during monotherapy with L-thyroxine, compared with combination
recommendations and critically examine the use of combination therapy employing a subcutaneous slow-release T3 pellet. Clinical
therapy with T4 and T318 (Table 96-10). trials of a slow-release T3 preparation, other than a pharmacokinetic
study of T3 sulfate in profoundly hypothyroid individuals,56 has yet
Pharmacologic Therapy to be conducted.
Levothyroxine is the drug of choice for thyroid replacement and sup- Desiccated thyroid has historically been derived from pig, beef,
pressive therapy because it is chemically stable, relatively inexpen- or sheep thyroid glands, although pigs are currently the usual source.
sive, active when orally administered, free of antigenicity, and has !e United States Pharmacopeia requires thyroid USP to contain

TABLE 96!9 Thyroid Preparations Used in the Treatment of Hypothyroidism

Drug (Brand Name) Dosage Form Content Relative Dose Comments/Equivalency
Thyroid USP Doses include 1/4, 1/2, 1, 2, 3, 4, and 5 Desiccated 1 grain (equivalent High T3:T4 ratio; inexpensive
(Armour Thyroid, Nature-Throid, grain tabletsArmour 1 grain = pork to 74 mcg of T4)
Westhroid, WP Thyroid) 60 mg; Nature-Throid and thyroid
T4:T3 ratio approximately 4.2:1 Westhroid, 1 grain = 65 mg. gland
Levothyroxine 25, 50, 75, 88, 100, 112, 125, 137, 150, Synthetic T4 100 mcg Stable; predictable potency;
(Euthyrox, Levoxyl, 175, 200, 300 mcg tablets Tirosint generics may be bioequivalent;
Synthroid,Unithroid,Tirosint, 13-150 mcg liquid in gelatin capsule when switching from natural
and Tirosint-SOL) Liquid solution: 13, 25, 50, 75, 88, 100, thyroid to L-thyroxine, lower
112, 125, 137, 150, 175, and 200 mcg dose by one-half grain;
in unit-dose ampules injection: 200 variable absorption between
and 500 mcg per vial products; half-life = 7 days, so
daily dosing; considered to be
drug of choice
Liothyronine 5, 25, and 50 mcg tablets Synthetic T3 33 mcg Uniform absorption, rapid onset;
(Cytomel) (~equivalent to half-life = 1.5 days, rapid peak
100 mcg T4) and troughs
Liotrix 1/4-, 1/2-, 1-, 2-, and 3-grain tablets Synthetic T4:T3 Thyrolar 1 = 50 mcg Stable; predictable; expensive;
(Thyrolar) in 4:1 ratio T4 and 12.5 mcg risk of T3 thyrotoxicosis
T3 (~equivalent to because of high ratio of T3
100 mcg T4) relative to T4

AL G r a w a n y
1260
TABLE 96!10 Selected Recommendations from the American Thyroid Association Hypothyroidism Guidelines
Question Synopsis or Paraphrase of Recommendation Grading
Is levothyroxine monotherapy considered to be the standard of Levothyroxine is recommended as the preparation of choice Strong
care for hypothyroidism? for the treatment of hypothyroidism due to its e!cacy in recommendation,
resolving the symptoms of hypothyroidism. moderate quality
What are the clinical and biochemical goals for levothyroxine Levothyroxine replacement therapy has three main goals. Strong
SECTION

replacement in primary hypothyroidism? These are (i) to provide resolution of the patients’ symptoms recommendation,
and hypothyroid signs, (ii) to achieve normalization of serum moderate quality
thyrotropin, and (iii) to avoid overtreatment.
Are there situations in which therapy with levothyroxine Although there are preliminary small studies suggesting Weak
dissolved in glycerin and supplied in gelatin capsules may that levothyroxine dissolved in glycerin and supplied in recommendation,
have advantages over standard levothyroxine? gelatin capsules may be better absorbed than standard low quality
levothyroxine, the present lack of controlled long-term
10 outcome studies does not support a recommendation for
the use of such preparations in these circumstances.
What factors determine the levothyroxine dose required by When deciding on a starting dose of levothyroxine, the Strong
Endocrinologic Disorders

a hypothyroid patient for reaching the appropriate serum patient’s weight, lean body mass, pregnancy status, etiology recommendation,
thyrotropin goal? of hypothyroidism, degree of thyrotropin elevation, age, and moderate quality
general clinical context should all be considered.
What is the best approach to initiating and adjusting Thyroid hormone therapy should be initiated as an initial Strong
levothyroxine therapy? full replacement or as a partial replacement with gradual recommendation,
increments in the dose titrated upward using serum moderate quality
thyrotropin as the goal. Dose adjustments should be made,
with thyrotropin assessment 4-6 weeks after any dosage
change.
What approach should be taken in patients treated for A minority of patients with hypothyroidism, but normal Weak
hypothyroidism who have normal serum thyrotropin values serum thyrotropin values, may perceive a suboptimal recommendation,
but still have unresolved symptoms? health status of unclear etiology. Acknowledgment of the low quality
patients’ symptoms and evaluation for alternative causes is
recommended in such cases.
In adults requiring thyroid hormone replacement treatment for We recommend that levothyroxine be considered as routine Strong
primary hypothyroidism, is treatment with thyroid extracts care for patients with primary hypothyroidism, in preference recommendation,
superior to treatment with levothyroxine alone? to use of thyroid extracts. High-quality controlled long-term moderate quality
outcome data are lacking to document the superiority of this
treatment compared to levothyroxine therapy.
In adults requiring thyroid hormone replacement treatment There is no consistently strong evidence of superiority of Weak
for primary hypothyroidism, is combination treatment combination therapy over monotherapy with levothyroxine. recommendation,
including levothyroxine and liothyronine superior to the use Therefore, we recommend against the routine use of moderate quality
of levothyroxine alone? combination treatment with levothyroxine and liothyronine
as a form of thyroid replacement therapy in patients with
primary hypothyroidism.
In adults requiring thyroid hormone replacement treatment For patients with primary hypothyroidism who feel unwell Insu!cient evidence
for primary hypothyroidism who feel unwell while taking on levothyroxine therapy alone, there is currently
levothyroxine, is combination treatment including insu!cient evidence to support the routine use of a
levothyroxine and liothyronine superior to the use of trial of a combination of levothyroxine and liothyronine
levothyroxine alone? therapy outside a formal clinical trial or N-of-1 trial, due
to uncertainty in the long-term risk-bene#t ratio of the
treatment.
Are there data regarding therapy with triiodothyronine alone, Although short-term outcome data in hypothyroid patients Strong
either as standard liothyronine or as sustained release suggest that thrice-daily synthetic liothyronine may be recommendation,
triiodothyronine, that support the use of triiodothyronine associated with bene#cial e"ects on parameters such as moderate quality
therapy alone for the treatment of hypothyroidism? weight and lipids, longer-term controlled clinical trials are
needed before considering synthetic liothyronine therapy
for routine clinical use.

Data from Reference 10.

Strong recommendation: Bene#ts clearly outweigh risks and burden, or risks and burden clearly outweigh bene#ts. Weak recommendation: Bene#ts #nely balanced with risks
and burden. Quality of evidence: High, moderate, or low.

38 mcg (±15%) of L-thyroxine and 9 mcg (±10%) of liothyronine however, this product has been reformulated, and the average bio-
for each 60 to 65 mg (one grain). !yroid USP, as an animal protein- availability improved to approximately 80%. Di"erent levothyroxine
derived product, may be antigenic in allergic or sensitive patients. preparations contain di"erent excipients such as dyes and fillers.
Even though desiccated thyroid is inexpensive, its limitations pre- However, because the relationship between T4 concentration and
clude it from being considered as a drug of choice for hypothyroid TSH is not linear, very small changes in T4 concentration can lead
patients. to substantial changes in TSH, which is a more accurate reflection
of hormone replacement status. !e FDA mandates that L-thyroxine
Pharmacokinetics bioequivalency testing be done using normal volunteers (600 mcg in
!e half-life of levothyroxine is approximately 7 days. !is long the fasted state) and three baseline free T4 concentrations be used to
half-life is responsible for a stable pool of prohormone and the need correct for endogenous T4 production. Bioequivalency is based on
for only once-daily dosing with levothyroxine. Older studies with the area under the curve (AUC) and maximum concentration (Cmax)
levothyroxine suggested that bioavailability was low and erratic; of T4 out to 48 hours. Approximately 70% of the AUC is derived from
 1261
endogenous production. TSH is not considered, and it is now very Several non-randomized studies have suggested that liquid for-
clear that T4 is too insensitive as a measure of bioequivalency.57 To mulations of levothyroxine or formulations in which the levothy-
avoid overtreatment and undertreatment, once a product is selected, roxine is dissolved in glycerin and encased in a gelatin capsule may
switches between levothyroxine products in patients who are stable circumvent the impaired absorption of levothyroxine that may occur
are not recommended. Several levothyroxine products are available, with tablet preparations.61 For patients receiving enteral feeding, liq-
including AB1, AB2, AB3, and AB4 rated products. !is has created uid levothyroxine added directly to the feeding tube was associated

CHAPTER
several permutations for product interchangeability since no refer- with a similar serum TSH to that seen in another group of patients
ence drug is mandated in bioequivalency testing. in whom the feeding was interrupted in order to administer crushed
tablets.62 !e former procedure was found to be more convenient
Adverse E"ects by providers. In a study of patients taking proton pump inhibitors,
Serious untoward e"ects are unusual if dosing is appropriate and switching to an oral solution was associated with a decrease in serum
the patient is carefully monitored during the initial treatment. TSH from a mean of 5.4 to 1.7 mIU/L, suggesting better absorption
Suboptimal thyroid hormone therapy including under-replacement of the liquid preparation in these patients.63 A study of patients with 96
and over-replacement is common among patients with hypothyroid- gastritis who had a stable serum TSH while taking levothyroxine
ism.58 Levothyroxine replacement in athyreotic hypothyroid patients tablets and were then switched to a lower dose of levothyroxine gel

Thyroid Disorders
restores systolic and diastolic le$ ventricular performance within capsules showed that two-thirds of patients had a similar TSH on
2 weeks, and the use of levothyroxine may increase the frequency the lower dose, again suggesting better absorption of the gel cap-
of atrial premature beats but not necessarily ventricular premature sule formulation.64 In a double-blind, randomized, crossover trial of
beats. Excessive doses of thyroid hormone may lead to heart failure, liquid thyroxine in 77 treatment-naive patients with hypothyroid-
atrial &brillation, angina pectoris, and myocardial infarction; rarely, ism, no significant di"erences in thyroid function tests were seen
the latter may be caused by coronary artery spasm. Allergic or idio- when the liquid preparation was ingested at breakfast or 30 minutes
syncratic reactions can occur with natural animal-derived products before breakfast.65 !is could provide a solution for patients with
such as desiccated thyroid, but these are extremely rare with the syn- di#culties ingesting levothyroxine before breakfast. If the findings
thetic products used today. !e 0.05 mg (50 mcg) Synthroid tablet of these studies are bolstered by randomized controlled studies in
is the least allergenic (due to a lack of dye and few excipients) and the future, these levothyroxine formulations may prove very conve-
should be tried for the patient suspected to be allergic to thyroid nient for hypothyroid patients. Alternatively, studies in adults with
hormone tablets. hypothyroidism suggest an equal e#cacy of bedtime versus early
Hyper-remodeling of cortical and trabecular bone due to morning intake of levothyroxine.66
hyperthyroidism leads to reduced bone density and may increase
the risk of fracture. Compared with normal controls, excess exog- Dosing and Administration
enous thyroid hormone results in histomorphometric and bio- !e average maintenance dose of levothyroxine for most adults
chemical changes similar to those observed in osteoporosis and is about 125 mcg/day.53 !e replacement dose of levothyroxine
untreated hyperthyroidism.59 !e risk for this complication seems is a"ected by body weight. Estimates of weight-based doses for
to be related to the dose of levothyroxine, patient age, and gen- replacement in hypothyroid patients without any autonomous thy-
der. Markers for bone turnover include urinary N-telopeptides, roid function include 1.6 and 1.7 mcg/kg/day, though hypothyroid
pyridinoline crosslinks of type I collagen, osteocalcin, procollagen patients still producing some thyroid hormone will require lower
type 1 N-terminal propeptide, and bone-specific alkaline phos- doses.18 !ere is, however, a wide range of replacement doses, neces-
phatase. When doses of levothyroxine are used to suppress TSH sitating individualized therapy and appropriate TSH monitoring to
concentrations to below-normal values (eg, less than 0.3 mIU/L) determine an adequate but not excessive dose.
in postmenopausal women, this adverse e"ect is more likely to be In addition to alleviation of symptoms, the goal of treatment for
seen. Cortical bone is a"ected to a greater degree than trabecular patients with hypothyroidism is to maintain the patient’s TSH within
bone at suppressive doses of L-thyroxine. In contrast, it appears the normal range. Some clinicians are of the opinion that the tradi-
to be much less likely in men and in premenopausal women. tional reference range of approximately 0.5 to 4.5 mIU/L includes at
Maintaining the TSH between 0.7 and 1.5 mIU/L does not alter its upper end some individuals who have unrecognized thyroid dis-
bone mineral density in premenopausal women. Although not ease. !us, some believe that the reference range should be modified
all studies have shown consistent results, a cohort study suggests downward to 0.5 to 3.5 mIU/L or even 0.5 to 2.5 mIU/L.67 If this
that treatment with L-thyroxine to achieve a normal TSH has no premise is accepted, both the TSH values that trigger L-thyroxine
adverse e"ect on bone density.60 treatment and the TSH treatment goal could potentially be altered.
!ere are cogent arguments on both sides of the issue. !ose who
Drug-Drug and Drug-Food Interactions suggest maintaining current reference ranges believe that lowering
!e time to maximal absorption of levothyroxine is about 2 hours the upper limit of the reference range could result in treating many
and this should be considered when T4 concentrations are deter- individuals with thyroid hormone who would not necessarily benefit
mined. Ingestion of L-thyroxine with food can impair its absorp- from such treatment.68 !ose who favor narrowing the reference
tion.18 !is can potentially a"ect the TSH concentration achieved range suggest that additional patients would, in fact, derive benefit
if levothyroxine timing with respect to food is varied. Mucosal from thyroid hormone treatment.67 !ere are calls by some for
diseases, such as celiac sprue, diabetic diarrhea, and ileal bypass increasing the thyrotropin reference range speci&cally among indi-
surgery, can also reduce absorption. Cholestyramine, calcium car- viduals aged 80 years and older.69 TSH reference ranges also di"er
bonate, sucralfate, aluminum hydroxide, ferrous sulfate, soybean for di"erent populations, such as those who are pregnant, specific
formula, dietary fiber supplements, and espresso co"ee may also ethnic groups, and older individuals.18
impair the absorption of levothyroxine from the gastrointestinal !e required dose of levothyroxine is dependent on the patient’s
tract (reviewed extensively in recent hypothyroidism guidelines18). age and the presence of associated disorders, as well as the severity
Acid suppression with histamine blockers and proton pump inhibi- and duration of hypothyroidism.18 Most patients devoid of any thy-
tors may also reduce levothyroxine absorption. Drugs that increase roid function will require approximately 1.7 mcg/kg/day once they
nondeiodinative T4 clearance include rifampin, carbamazepine, and reach steady-state for full replacement. Dose requirement may be
possibly phenytoin. Selenium de&ciency and amiodarone may block better estimated based on ideal body weight, rather than actual body
the conversion of T4 to T3. weight. In patients with long-standing disease and older individuals

AL G r a w a n y
1262
without known cardiac disease, therapy should be initiated with be suspected for patients with a dose that is higher than expected,
50 mcg daily of levothyroxine and increased a$er 1 month. !e rec- variable thyroid function test results that do not correlate well with
ommended initial daily dose for older patients with known cardiac prescribed doses, and an elevated serum TSH concentration with
disease is 25 mcg daily titrated upward in increments of 25 mcg at serum-free T4 at the upper end of the normal range, which can sug-
monthly intervals to prevent stress on the cardiovascular system. gest improved compliance immediately before testing, with a lag in
Some patients may experience an exacerbation of angina with higher the thyrotropin response.
doses of thyroid hormone. Although TSH is an indicator of under- For patients with central hypothyroidism caused by hypotha-
SECTION

replacement or over-replacement, clinicians o$en fail to alter the lamic or pituitary failure, the serum TSH cannot be used to assess
dose based on TSH values clearly outside of the normal range. the adequacy of replacement. Alleviation of the clinical syndrome
Subclinical hypothyroidism is a laboratory-de&ned phenom- and restoration of serum T4 to the normal range are the only cri-
enon in which a patient has an elevated TSH level in the presence of teria available for estimating the appropriate replacement dose of
a normal FT4 level. Patients with subclinical hypothyroidism o$en L-thyroxine. Keeping free T4 values in the upper part of the nor-
10 complain of symptoms commonly seen in patients with overt hypo- mal laboratory reference range is a reasonable approach, with
thyroidism such as cold insensitivity, dry skin, fatigue, constipation, modification of this goal to the middle of the normal range in older
muscle cramps, poor memory, slowed thinking, and depression. patients or patients with comorbidities. Concurrent use of dopa-
Endocrinologic Disorders

However, up to a quarter of people with normal TSH levels report up mine, dopaminergic agents (bromocriptine), somatostatin or soma-
to two of these symptoms, pointing to the nonspeci&c nature of these tostatin analogs (octreotide), and corticosteroids suppresses TSH
symptoms. An estimated 13 million people in the United States have concentrations in individuals with primary hypothyroidism and
subclinical hypothyroidism. Subclinical hypothyroidism progresses may confound the interpretation of this monitoring parameter.18
to overt hypothyroidism in 2% to 5% of patients per year.70 !e risk TSH-suppressive levothyroxine therapy can be given to patients
of progression is signi&cantly greater in individuals with antibodies with nodular thyroid disease and di"use goiter, and to patients with
to thyroid peroxidase (TPO) and in those with higher baseline TSH a history of thyroid irradiation. It is also usually given to patients
levels. Levothyroxine therapy was not associated with a signi&cant with papillary or follicular thyroid cancer. !e rationale for suppres-
improvement in hypothyroid symptoms, fatigue, or quality-of-life sion therapy is to reduce TSH secretion, which promotes the growth
in patients age 80 years or older with subclinical hypothyroidism.71 and function of abnormal thyroid tissue. However, such manage-
!ese results argue against the routine use of levothyroxine for the ment, other than for patients with thyroid cancer or with elevated
treatment of subclinical hypothyroidism, particularly in the elderly. TSH levels, is quite controversial. Some clinicians rarely recommend
!yroid hormone therapy was associated with lowering the mean or use such therapy; others will recommend a trial of levothyrox-
thyrotropin value into the normal reference range compared with ine as suppressive therapy in some patients. !ree meta-analyses
placebo but was not associated with improvements in general quality concluded that suppressive therapy for nodules was associated with
of life or thyroid-related symptoms.72 While most patients with sub- a small decrease in nodule growth, a nonsigni&cant reduction in
clinical hypothyroidism can be observed without treatment, treat- nodule growth, and a signi&cant reduction in nodule growth with
ment may be indicated for patients with subclinical hypothyroidism longer-term treatment. L-Tyroxine may be given in nontoxic MNG
and serum thyrotropin levels of 10 mU/L or higher, or for young to suppress the TSH to low- normal levels of 0.5 to 1 mIU/L if the
and middle-aged individuals with subclinical hypothyroidism and baseline TSH is more than 1 mIU/L. Goiter size and thyroid volume
symptoms consistent with mild hypothyroidism.70 may be reduced with suppression therapy. Di"use goiter associated
Once euthyroidism is attained, the daily maintenance dose of with autoimmune thyroiditis may also be treated with levothyroxine
levothyroxine does not fluctuate greatly. As patients age, the dos- to reduce goiter size and thyroid volume. If suppressive therapy with
ing requirement may be reduced.18 !ird-generation TSH assays levothyroxine is pursued, the age, gender, and menopausal status
improved the accuracy with which thyroid hormone replacement of the patient need to be considered, along with the risk of cardiac
can be monitored. !e TSH concentration is the most sensitive arrhythmias and reduced bone mineral density. Levothyroxine sup-
and specific monitoring parameter for adjustment of levothyrox- pression therapy is of benefit to all but the lowest-risk thyroid cancer
ine dose. Plasma TSH concentrations begin to fall within hours patients and is generally used in the management of patients with
and are usually normalized within 2 weeks, but they may take up di"erentiated thyroid cancer, with the TSH goal being influenced
to 6 weeks for some patients, depending on the baseline value. Both by the patient’s thyroid cancer stage and other risk factors. Current
TSH and T4 concentrations are used to monitor therapy, and they guidelines from the ATA suggest suppressing the TSH to below
should be checked every 6 weeks until a euthyroid state is achieved.18 0.1 mIU/L in higher-risk patients but keeping TSH around the lower
Laboratory assessment of thyroid function should be performed limit of normal (0.1-0.5 mIU/L) in low-risk patients.74
approximately 6 weeks a$er levothyroxine dose initiation or change.
!is time frame allows achievement of steady-state, as the half-life of
levothyroxine is approximately 1 week. Serum T4 concentrations can
Special Populations
be useful in detecting noncompliance, malabsorption, or changes Myxedema Coma
in levothyroxine product bioequivalence, among other things.73 An Myxedema coma is a rare consequence of decompensated hypothy-
elevated TSH concentration indicates insu#cient replacement. !e roidism.8 Clinical features include hypothermia, advanced stages of
appropriate dose maintains the TSH concentration in the normal hypothyroid symptoms, and altered sensorium ranging from delir-
range. T4 disposal is accelerated by nephrotic syndrome, other severe ium to coma. Mortality rates of 60% to 70% necessitate immediate
systemic illnesses, and several antiseizure medications (phenobar- and aggressive therapy. Traditionally, the initial treatment has been
bital, phenytoin, and carbamazepine) and rifampin. Pregnancy IV bolus levothyroxine 300 to 500 mcg.18 However, as deiodinase
increases the T4 dose requirement for 75% of women, probably activity is markedly reduced, impairing T4 to T3 conversion, initial
because of factors such as increased degradation by the placental treatment with IV T3, or a combination of both hormones, has also
deiodinase, increased T4 pool size, and transfer of T4 to the fetus. been advocated.8 Glucocorticoid therapy with IV hydrocortisone
!e etiology of hypothyroidism also a"ects the magnitude of the 100 mg every 8 hours should be given until coexisting adrenal sup-
dosage increase. Initiating postmenopausal hormone replacement pression is ruled out.18 All therapies must be administered paren-
therapy increases the dose needed in 35% of women, perhaps due to terally as cessation of gastrointestinal peristalsis occurs, preventing
an increased circulating TBG level. Patient noncompliance with pre- the absorption of orally administered medications. Consciousness,
scribed T4, the most common cause of inadequate treatment, might lowered TSH concentrations, and improvement in vital signs are
 1263
expected within 24 hours. Maintenance doses of levothyroxine are appropriate monitoring interval for follow-up thyroid function test-
typically 75 to 100 mcg given IV until the patient stabilizes and oral ing is no more frequent than every 4 to 6 weeks. !e signs and symp-
therapy is begun. Supportive therapy must be instituted to maintain toms of hypothyroidism should be improved or absent (see Clinical
adequate ventilation, BP, and body temperature, and ensure eugly- Presentation of Hypothyroidism discussed earlier), although it may
cemia. Any underlying disorder which may have precipitated the take several months for the full benefit of therapy to manifest.
event, such as sepsis or myocardial infarction, obviously must be

CHAPTER
diagnosed and treated.
CONCLUSION
Congenital Hypothyroidism Hypothyroidism is a common disorder but if le$ untreated it can
In congenital hypothyroidism, full maintenance therapy should be progress into myxedema coma in the absence of an adequate endog-
instituted early to improve the prognosis for mental and physical enous thyroid reserve. Levothyroxine is a readily available and
development. !e average maintenance dose in infants and children highly e"ective treatment that rapidly reverses the biochemical and
depends on the age and weight of the child. Several studies dem- clinical abnormalities that characterize hypothyroidism. Serum TSH 96
onstrate that aggressive therapy with levothyroxine is important for and thyroid hormone levels are useful measures for adjusting the
normal development, and current recommendations are for ini- levothyroxine dose.

Thyroid Disorders
tiation of therapy as soon as possible a$er birth at a dose of 10 to
15 mcg/kg/day. !is dose is used to keep T4 concentrations at about
10 mcg/dL (130 nmol/L) within 30 days of starting therapy and is
ABBREVIATIONS
associated with improved IQs. !e dose is progressively decreased
to a typical adult dose as the child ages, with the adult dose given anti-TPO Ab anti-thyroid peroxidase antibody
starting in puberty. ATD antithyroid drug
AUC area under the curve
Hypothyroidism During Pregnancy
BMI body mass index
Hypothyroidism during pregnancy leads to an increased rate of
BP blood pressure
stillbirths and possibly lower neuropsychological scores in infants
born of women who received inadequate replacement during preg- cGy centigray
nancy.38 !yroid hormone is necessary for fetal growth and must C
max maximum concentration
come from the maternal side during the first 2 months of gestation. ClO4 "
perchlorate
Although liothyronine may cross the placental membrane slightly
CNS central nervous system
better than levothyroxine, the latter is considered the drug of choice.
!e objective of treatment is to decrease TSH to normal, based on DIT diiodotyrosine
the normal reference range for pregnancy. Current guidelines sug- FSH follicle-stimulating hormone
gest a TSH below 2.5 mIU/L during the first trimester and a TSH FT3 free triiodothyronine
below 3 mIU/L during the remainder of the pregnancy.38 Based on
FT4 free thyroxine
elevated TSH levels during pregnancy, the mean dose of levothyrox-
ine had to be increased by 48% to decrease TSH into the normal Gs$ the $ subunit of the stimulatory guanine-
range. However, in individual women, the dosage increase needed nucleotide–binding protein
may vary from approximately 10% to 80%. Increased production of hCG human chorionic gonadotropin
binding proteins, a marginal decrease in free hormone concentra- HLA human leukocyte antigen
tion, modification of peripheral thyroid hormone metabolism, and 131
I sodium iodide-131
increased T4 metabolism by the fetal-placental unit all may contrib-
L-thyroxine levothyroxine
ute to increased thyroid hormone demand. As these changes regress
a$er delivery, the need for increased levothyroxine will decline.38 LH luteinizing hormone
Up to 60% of women need to have levothyroxine dose adjustment MIT monoiodotyrosine
during pregnancy. An upward adjustment in the dose will usually MMI methimazole
be needed by the eighth week of pregnancy. Current guidelines rec-
MNG multinodular goiter
ommend that hypothyroid patients receiving levothyroxine who
become pregnant should increase their levothyroxine dose by 20% NHANES III !ird National Health and Nutrition
to 30% (two additional tablets weekly) as soon as they know they Examination Survey
are pregnant.38 A$er delivery the levothyroxine dose can be reduced OTC over the counter
based on T4 concentrations and measurement of TSH, typically PRTH pituitary resistance to thyroid hormone
about 6 to 8 weeks a$er delivery. Many patients can return to their
PTU propylthiouracil
pre-pregnancy dose requirement.
RAI radioactive iodine
RAIU radioactive iodine uptake
EVALUATION OF THERAPEUTIC rT3 reverse triiodothyronine
OUTCOMES!HYPOTHYROIDISM SCN" thiocyanate

Patients with idiopathic hypothyroidism and Hashimoto’s thyroid- SSKI saturated solution of potassium iodide
itis on optimal thyroid hormone replacement therapy should have T3 triiodothyronine
TSH and free T4 serum concentrations in the normal range.18 !ose T4 thyroxine
who are being treated for thyroid cancer should have TSH sup- TBG thyroxine-binding globulin
pressed to low levels, with the appropriate TSH concentration being
TBII TSH binding inhibitor immunoglobulin
determined based on the patient’s risk of recurrence or progression,
and TG levels should be undetectable.74 Given the 7-day half-life TBPA thyroid-binding prealbumin
of T4 and the potential delayed response of the hypothalamus, the TcO4" pertechnetate

AL G r a w a n y
1264
18. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of
TG thyroglobulin
hypothyroidism: Prepared by the American !yroid Association task
TPOAb thyroid peroxidase antibodies force on thyroid hormone replacement. !yroid. 2014;24:1670–1751.
TR thyroid hormone receptor doi:10.1089/thy.2014.0028.
19. Ylli D, Wartofsky L, Burman KD. Evaluation and treatment of
TRH thyrotropin-releasing hormone amiodarone-induced thyroid disorders. J Clin Endocrinol Metab.
TRIAC triiodothyroacetic acid 2021;106:226–236. doi:10.1210/clinem/dgaa68.
20. Barbesino G. Misdiagnosis of Graves’ disease with apparent severe
SECTION

TSAb thyroid-stimulating antibody hyperthyroidism in a patient taking biotin megadoses. !yroid.

TSH thyroid-stimulating hormone 2016;26:860–863. doi:10.1089/thy.2015.0664.
21. Elston MS, Sehgal S, Du Toit S, et al. Factitious Graves’ disease due to
TT3 total triiodothyronine biotin immunoassay interference: A case and review of the literature.
TT4 total thyroxine J Clin Endocrinol Metab. 2016;101:3251–3255. doi:10.1210/jc.2016-1971.
22. Sundaresh V, Brito JP, Wang Z, et al. Comparative e"ectiveness of
TTR transthyretin
10 WBC white blood cell
therapies for Graves’ hyperthyroidism: A systematic review and
network meta-analysis. J Clin Endocrinol Metab. 2013;98(9):3671–3677.
doi:10.1210/jc.2013-1954.
23. Smith TJ, Hegedüs L. Graves’ disease. N Engl J Med. 2016;375:
Endocrinologic Disorders

1552–1565. doi:10.1056/NEJMra1510030.
24. Burch HB, Cooper DS. Management of Graves’ disease: A review.
REFERENCES JAMA. 2015;314:2544–2554. doi:10.1001/jama.2015.16535.
25. Giuliani C, Cerrone D, Harii N, et al. A TSHR-LH/CGR chimera
1. Portulano C, Paroder-Belenitsky M, Carrasco N. !e Na+/I" symporter that measures functional thyroid-stimulating autoantibodies (TSAb)
(NIS): Mechanism and medical impact. Endocr Rev. 2014;35:106–149. can predict remission or recurrence in Graves’ patients undergoing
doi:10.1210/er.2012-1036. antithyroid drug (ATD) treatment. J Clin Endocrinol Metab.
2. Verloop H, Dekkers OM, Peeters RP, et al. Genetics in endocrinology— 2012;97(7):E1080–E1087. doi:10.1210/jc.2011-2897.
Genetic variation in deiodinases: A systematic review of potential 26. Bandai S, Okamura K, Fujikawa M, et al. !e long-term follow-up of
clinical e"ects in humans. Eur J Endocrinol. 2014;171:R123–R135. patients with thionamide-treated Graves’ hyperthyroidism. Endocrine J.
doi:10.1530/EJE-14-0302. 2019;66:535–545. doi:10.1507/endocrj.EJ18-0418.
3. Mendoza A, Hollenberg AN. New insights into thyroid hormone 27. Azizi F, Amouzegar A, Tohidi M, et al. Increased remission rates a$er
action. Pharmacol !er. 2017;173:135–145. doi:10.1016/ long-term methimazole therapy in patients with Graves’ disease:
j.pharmthera.2017.02.012. Results of a randomized clinical trial. !yroid. 2019;29:1192–1200.
4. Kleinau G, Biebermann H. Constitutive activities in the thyrotropin doi:10.1089/thy.2019.0180.
receptor: Regulation and signi&cance. Adv Pharmacol. 2014;70:81–119. 28. van Lieshout JM, Mooij CF, van Trotsenburg ASP, et al. Methimazole-
doi:10.1016/B978-0-12-417197-8.00003-1. induced remission rates in pediatric Graves’ disease: A systematic
5. Mackenzie LS. !yroid hormone receptor antagonists: From review. Eur J Endocrinol. 2021 Jun 1;EJE-21-0077.R1. doi:10.1530/
environmental pollution to novel small molecules. Vitam Horm. EJE-21-0077.
2018;106:147–162. doi:10.1016/bs.vh.2017.04.004. 29. Kahaly GJ, Bartalena L, Hegedüs L, et al. 2018 European !yroid
6. Ross DS, Burch HB, Cooper DS, et al. 2016 American !yroid Association Guideline for the management of Graves’ hyperthyroidism.
Association Guidelines for diagnosis and management of Eur !yroid J. 2018;7:167–186. doi:10.1159/00049038.
hyperthyroidism and other causes of thyrotoxicosis. !yroid. 30. Biondi B, Cooper DS. Subclinical hyperthyroidism. N Engl J Med.
2016;26:1343–421. doi:10.1089/thy.2016.0229. 2018;378:2411–9. doi:10.1056/NEJMcp1709318.
7. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), 31. Mazhari A, Emanuele MA, Espiritu B. Desensitization to methimazole.
and thyroid antibodies in the United States population (1988 to 1994): Endocr Pract. 2021;27(3):185–190. doi 10.1016/j.eprac.2020.10.019.
National Health and Nutrition Examination Survey (NHANES III). 32. Chen W-T, Chi CC. Associations of HLA genotypes with antithyroid
J Clin Endocrinol Metab. 2002;87:489–499. doi:10.1210/jcem.87.2.8182. drug-induced agranulocytosis: A systematic review and meta-analysis
8. Ylli D, Klubo-Gwiezdzinska J, Wartofsky L. !yroid emergencies. Pol of pharmacogenomics studies. Br J Clin Pharmacol. 2019;85:1878–1887.
Arch Intern Med. 2019;129:526–534. doi:10.20452/pamw.14876. doi:10.1111/bcp.13989.
9. Burch HB, Cooper DS. A young woman with palpitations, goitre 33. Vicente N, Cardoso L, Barros L, et al. Antithyroid drug-induced
and low thyroid-stimulating hormone. CMAJ. 2014;186:289–291. agranulocytosis: State of the art on diagnosis and management. Drugs
doi:10.1503/cmaj. R D. 2017;17:91–96. doi:10.1007/s40268-017-0172-1.
10. Chaudhry MA, Wayangankar S. !yrotoxic periodic paralysis: A 34. Brix TH, Lund LC, Henriksen DP, et al. Methimazole and risk of acute
concise review of the literature. Curr Rheumatol Rev. 2016;12:190–194. pancreatitis. Lancet Diabetes Endocrinol. 2020;8:187–189. doi:10.1016/
doi:10.2174/1573397112666160404124822. S2213-8587(20)30025-5.
11. Fan C, Kuhn M, Mbiol AP, et al. Kir2.2 p.!r140Met: a genetic 35. Glinoer D, Cooper DS. !e propylthiouracil dilemma. Curr Opin
susceptibility to sporadic periodic paralysis. Acta Myol. 2018;37: Endocrinol Diabetes Obes. 2012;19(5):402–407. doi:10.1097/
193–203. eCollection 2018 Sep. MED.0b013e3283565b49.
12. Ryodi E, Metso S, Jaatinen P, et al. Cancer incidence and mortality in 36. Andersen SL, Olsen J, Wu CS, et al. Birth defects a$er early pregnancy
patients treated with RAI or thyroidectomy for hyperthyroidism—A use of antithyroid drugs: A Danish nationwide study. J Clin Endocrinol
nation-wide cohort study with a long-term follow-up. J Clin Endocrinol Metab. 2013;98(11):4373–4381. doi:10.1210/jc.2013-2831.
Metab. 2015;100(10):3710–3717. doi:10.1210/jc.2015-1874. 37. Seo GH, Kim TH, Chung JH. Antithyroid drugs and congenital
13. Kitahara CM, Berrington de Gonzalez A, Bouville A, et al. Association malformations: A nationwide Korean cohort study. Ann Intern Med.
of radioactive iodine treatment with cancer mortality in patients with 2018;168:405–413. doi:10.7326/M17-1398.
hyperthyroidism. JAMA Intern Med. 2019;179:1034–1042. doi:10.1001/ 38. Alexander EK, Pearce EN, Brent GA, et al. 2017 guidelines of the
jamainternmed.2019.0981. American !yroid Association for the diagnosis and management
14. Kitahara CM, Preston DL, Sosa JA, et al. Association of radioactive of thyroid disease during pregnancy and the postpartum. !yroid.
iodine, antithyroid drug, and surgical treatments with solid cancer 2017;27(3):315–389. doi:10.1089/thy.2016.0457.
mortality in patients with hyperthyroidism. JAMA Netw Open. 39. Törring O, Watt T, Sjölin G, et al. Impaired quality of life a$er
2020;3(7):e209660. doi:10.1001/jamanetworkopen.2020.9660. radioiodine therapy compared to antithyroid drugs or surgical
15. Goichot B, Caron P, Landron F, et al. Clinical presentation of treatment for Graves’ hyperthyroidism: A long-term follow-up with the
hyperthyroidism in a large representative sample of outpatients in thyroid-related patient-reported outcome questionnaire and 36-item
France: Relationships with age, aetiology and hormonal parameters. short form health status survey. !yroid. 2019;29:322–331. doi 10.1089/
Clin Endocrinol (Oxf). 2016;84:445–451. doi:10.1111/cen.12816. thy.2018.0315.
16. Beck-Peccoz P, Giavoli C, Lania A. A 2019 update on TSH-secreting 40. Okamura K, Sato K, Fujikawa M, et al. J Clin Endocrinol Metab.
pituitary adenomas. Endocrinol Invest. 2019 Dec;42(12):1401–1406. 2014;99:3995–4002. doi:10.1210/jc.2013-4466.
doi:10.1007/s40618-019-01066-x. 41. Simsir IY, Ozdemir M, Duman S, et al. !erapeutic plasmapheresis in
17. Caron P. !yroiditis and SARS-CoV-2 pandemic: a review. Endocrine. thyrotoxic patients. Endocrine. 2018 Oct;62(1):144–148. doi:10.1007/
2021 May;72(2):326–331. doi:10.1007/s12020-021-02689-y. s12020-018-1661-x.
 1265
42. Hammond EN, Vangu M-D-T HW. E"ect of adjuvant lithium 59. Williams GR, Bassett JHD. !yroid diseases and bone health. J
on thyroxine (T4) concentration a$er radioactive iodine therapy. Endocrinol Invest. 2018;41:99–109. doi:10.1007/s40618-017-0753-4.
Eur J Nucl Med Mol Imaging. 2016;43:1980–7. doi:10.1007/ 60. Schneider R, Schneider M, Reiners C, et al. E"ects of levothyroxine
s00259-016-3388-3. on bone mineral density, muscle force, and bone turnover markers:
43. Dosiou C, Kossler AL. !yroid eye disease: Navigating the new A cohort study. J Clin Endocrinol Metab. 2012;97(11):3926–3934.
treatment landscape. J Endocrine Soc. 2021;5:1–13. doi:10.1210/jendso/ doi:10.1210/jc.2012-2570.
bvab034. 61. Virili C, Trimboli P, Romanelli F, et al. Liquid and so$gel levothyroxine
44. Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the treatment use in clinical practice: State of the art. Endocrine. 2016;54:3–14.

CHAPTER
of active thyroid eye disease. N Engl J Med. 2020;382:341–52. doi:10.1007/s12020-016-1035-1.
doi:10.1056/NEJMoa1910434. 62. Pirola I, Da#ni L, Gandossi E, et al. Comparison between liquid and
45. Francis N, Francis T, Lazarus JH, et al. Current controversies in the tablet levothyroxine formulations in patients treated through enteral
management of Graves’ hyperthyroidism. Expert Rev Endocrinol Metab. feeding tube. J Endocrinol Invest. 2014;37:583–587. doi:10.1007/
2020;15:159–169. doi:10.1080/17446651.2020.1754192. s40618-014-0082-9.
46. Chaker L, Bianco AC, Jonklaas J, et al. Hypothyroidism. Lancet. 63. Vita R, Saraceno G, Trimarchi F, et al. Switching levothyroxine from the
2017;390(10101):1550–1562. doi:10.1016/S0140-6736(17)30703-1. tablet to the oral solution formulation corrects the impaired absorption
47. Beck-Peccoz P, Rodari G, Giavoli C, et al. Central hypothyroidism - a of levothyroxine induced by proton-pump inhibitors. J Clin Endocrinol
96
neglected thyroid disorder. Nat Rev Endocrinol. 2017;13:588–598. Metab. 2014;99:4481–4486. doi:10.1210/jc.2014-2684.
doi:10.1038/nrendo.2017.47. 64. Santaguida MG, Virili C, Del Duca SC, et al. !yroxine so$gel

Thyroid Disorders
48. Peters C, van Trotsenburg ASP, Schoenmakers N. Diagnosis of capsule in patients with gastric-related T4 malabsorption. Endocrine.
endocrine disease: Congentital hypothyroidism: update and 2015;49(1):51–57. doi:10.1007/s12020-014-0476-7.
perspectives. Eur J Endocrinol. 2018;179:R297–R317. doi:10.1530/ 65. Fallahi P, Ferrari SM, Antonelli A. Oral l-thyroxine liquid versus tablets
EJE-18-0383. in patients with hypothyroidism without malabsorption: A prospective
49. Esfandiari NH, Papaleontiou M. Biochemical testing in thyroid study. Endocrine. 2016;52:597–601. doi:10.1007/s12020-015-0836-y.
disorders. Endocrinol Metab Clin North Am. 2017;46:631–648. 66. Pang X, Pu T, Xu L, et al. E"ect of l-thyroxine administration before
doi:10.1016/j.ecl.2017.04.002. breakfast vs at bedtime on hypothyroidism: A meta-analysis. Clin
50. O’Malley G, Lee HJ, Parekh S, et al. Rapid evolution of thyroid Endocrinol (Oxf). 2020;92:475–481. doi:10.1111/cen.14172.
dysfunction in patients treated with nivolumab. Endocr Pract. 67. Wartofsky L, Dickey RA. !e evidence for a narrower thyrotropin
2017;23:1223–1231. doi:10.4158/EP171832.OR. reference range is compelling. J Clin Endocrinol Metab.
51. Yeliosof O, Gangat M. Diagnosis and management of 2005;90(9):5483–5488. doi:10.1210/jc.2005-0455.
hypopituitarism. Curr Opin Pediatr. 2019;31:531–536. doi:10.1097/ 68. Surks MI, Goswami G, Daniels GH. !e thyrotropin reference range
MOP.0000000000000779. should remain unchanged. J Clin Endocrinol Metabol. 2005;90(9):
52. Makita N, Manaka K, Sato J, et al. Bexarotene-induced hypothyroidism: 5489–5496. doi 10.1210/jc.2005-0170.
Characteristics and therapeutic strategies. Clin Endocrinol (Oxf). 69. Cappola AR. !e thyrotropin reference range should be changed
2019;91:195–200. doi:10.1111/cen.13975. in older patients. JAMA. 2019;322(20):61–62. doi 10.1001/
53. Jonklaas J, Cappola AR, Celi FS. Editorial: Combination therapy for jama.2019.14728.
hypothyroidism: !e journey from bench to bedside. Front Endocrinol 70. Biondi B, Cappola AR, Cooper DS. Subclinical hypothyroidism: A
(Lausanne). 2020;11:422. doi:10.3389/fendo.2020.00422. Review. JAMA. 2019;322(2):153–160. doi 10.1001/jama.2019.9052.
54. Jonklaas J, Bianco AC, Cappola AR, et al. Evidence-based use of 71. Mooijaart SP, Du Puy RS, Stott DJ, et al. Association between
levothyroxine/liothyronine combinations in treating hypothyroidism: levothyroxine treatment and thyroid-related symptoms among adults
A consensus document. !yroid. 2021;31(2):156–182. doi:10.1089/ aged 80 years and older with subclinical hypothyroidism. JAMA.
thy.2020.0720. 2019;322(20):1977–1986. doi:10.1001/jama.2019.17274.
55. Werneck de Castro JP, Fonseca TL, Ueta CB, et al. Di"erences in 72. Feller M, Snel M, Moutzouri E, et al. Association of thyroid hormone
hypothalamic type 2 deiodinase ubiquitination explain localized therapy with quality of life and thyroid-related symptoms in patients
sensitivity to thyroxine. J Clin Invest. 2015;125(2):769–781. doi:10.1172/ with subclinical hypothyroidism A systematic review and meta-
JCI77588. analysis. JAMA. 2018;320:1349–1359. doi:10.1001/jama.2018.13770.
56. Santini F, Giannetti M, Ricco I, et al. Steady-state serum T3 73. Centanni M, Benvenga A, Sachmechi I. Diagnosis and management
concentrations for 48 hours following the oral administration of a of treatment-refractory hypothyroidism: An expert consensus
single dose of 3,5,3’-triiodothyronine sulfate (T3S). Endocr Pract. report. J Endocrinol Invest. 2017;40(12):1289–1301. doi:10.1007/
2014;20(7):680–689. doi:10.4158/EP13331.OR. s40618-017-0706-y.
57. Benvenga S, Carlé A. Levothyroxine formulations: Pharmacological and 74. Haugen BR, Alexander EK, Bible KC, et al. 2015 American !yroid
clinical implications of generic substitution. Adv !er. 2019;36(Suppl 2): Association Management Guidelines for adult patients with thyroid
S59–S71. doi.org/10.1007/s12325-019-01079-1. nodules and di"erentiated thyroid cancer. !yroid. 2016;26(1):1–133.
58. Dew R, Okosieme O, Dayan C, et al. Clinical, behavioural and doi 10.1089/thy.2015.0020.
pharmacogenomic factors in'uencing the response to levothyroxine
therapy in patients with primary hypothyroidism-protocol for a
systematic review. Syst Rev. 2017;6:60. doi:10.1186/s13643-017-0457-z.

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