2929Thyroid Gland Physiology and Testing CHAPTER 382

may persist, however, in patients with underlying autoimmune thyroid

disease.

THYROID FUNCTION IN PREGNANCY

Five factors alter thyroid function in pregnancy: (1) the transient

increase in hCG during the first trimester, which weakly stimulates the

TSH-R; (2) the estrogen-induced rise in TBG during the first trimester,

which is sustained during pregnancy; (3) alterations in the immune

system, leading to the onset, exacerbation, or amelioration of an underlying autoimmune thyroid disease; (4) increased thyroid hormone

metabolism by the placental type III deiodinase; and (5) increased

urinary iodide excretion, which can cause impaired thyroid hormone

production in areas of marginal iodine sufficiency. Women with a

precarious iodine intake (<50 μg/d) are most at risk of developing a

goiter during pregnancy or giving birth to an infant with a goiter and

hypothyroidism. The World Health Organization recommends a daily

iodine intake of 250 μg during pregnancy and lactation, and prenatal

vitamins should contain 150 μg per tablet.

The rise in circulating hCG levels during the first trimester is

accompanied by a reciprocal fall in TSH that persists into the middle

of pregnancy. This reflects the weak binding of hCG, which is present

at very high levels, to the TSH-R. Rare individuals have variant TSH-R

sequences that enhance hCG binding and TSH-R activation. hCGinduced changes in thyroid function can result in transient gestational

hyperthyroidism that may be associated with hyperemesis gravidarum,

a condition characterized by severe nausea and vomiting and risk of

volume depletion. However, since the hyperthyroidism is not causal,

antithyroid drugs are not indicated unless concomitant Graves’ disease

is suspected. Parenteral fluid replacement usually suffices until the

condition resolves.

Normative values for most thyroid function tests differ during

pregnancy and, if available, trimester-specific reference ranges should

be used when diagnosing thyroid dysfunction during pregnancy. TSH

levels decrease at the end of the first trimester and then rise as gestation progresses so that the nonpregnant reference ranges can be used

from mid-gestation to delivery. Total T4

 and T3

 levels are ~1.5× higher

throughout pregnancy, but the free T4

, which is the same or slightly

higher at the end of the 1st trimester, then progressively decreases so

that third-trimester values in healthy pregnancies are often below the

nonpregnant lower reference cutoff.

During pregnancy, subclinical hypothyroidism occurs in 2% of

women, but overt hypothyroidism is present in only 1 in 500. Prospective randomized controlled trials have not shown a benefit for universal thyroid disease screening in pregnancy. Targeted TSH testing for

hypothyroidism is recommended for women planning a pregnancy if

they have a strong family history of autoimmune thyroid disease, other

autoimmune disorders (e.g., type 1 diabetes), infertility, prior preterm

delivery or recurrent miscarriage, or signs or symptoms of thyroid

disease, or are older than 30 years. Thyroid hormone requirements

are increased by up to 45% during pregnancy in levothyroxine-treated

hypothyroid women.

■ THYROID HORMONE TRANSPORT

AND METABOLISM

Serum-Binding Proteins T4

 is secreted from the thyroid gland

in about twentyfold excess over T3 (Table 382-1). Both hormones

are bound to plasma proteins, including thyroxine-binding globulin

(TBG), transthyretin (TTR, formerly known as thyroxine-binding prealbumin [TBPA]), and albumin. The plasma-binding proteins increase

the pool of circulating hormone, delay hormone clearance, and may

modulate hormone delivery to selected tissue sites. The concentration

of TBG is relatively low (1–2 mg/dL), but because of its high affinity for

thyroid hormones (T4

 > T3

), it carries ~80% of the bound hormones.

Albumin has relatively low affinity for thyroid hormones but has a high

plasma concentration (~3.5 g/dL), and it binds up to 10% of T4

 and

30% of T3

. TTR carries ~10% of T4

 but little T3

.

When the effects of the various binding proteins are combined,

~99.98% of T4

 and 99.7% of T3

 are protein-bound. Because T3

 is less

tightly bound than T4

, the fraction of unbound T3

 is greater than

unbound T4

, but there is less unbound T3

 in the circulation because it

is produced in smaller amounts and cleared more rapidly than T4

. The

unbound or “free” concentrations of the hormones are ~2 × 10–11 M for

T4

 and ~6 × 10–12 M for T3

, which roughly correspond to the thyroid

hormone receptor–binding constants for these hormones (see below).

The unbound hormone is thought to be biologically available to tissues.

The homeostatic mechanisms that regulate the thyroid axis are directed

toward maintenance of normal concentrations of unbound hormones.

Abnormalities of Thyroid Hormone–Binding Proteins

A number of inherited and acquired abnormalities affect thyroid

hormone–binding proteins. X-linked TBG deficiency is associated

with very low levels of total T4

 and T3

. However, because unbound

hormone levels are normal, patients are euthyroid and TSH levels are

normal. It is important to recognize this disorder to avoid efforts to

normalize total T4

 levels, because this leads to thyrotoxicosis and is

futile because of rapid hormone clearance in the absence of TBG. TBG

levels are elevated by estrogen, which increases sialylation and delays

TBG clearance. Consequently, in women who are pregnant or taking

estrogen-containing contraceptives, elevated TBG increases total T4

and T3

 levels; however, unbound T4

 and T3

 levels are normal. These features are part of the explanation for why women with hypothyroidism

require increased amounts of l-thyroxine replacement as TBG levels

are increased by pregnancy or estrogen treatment. Mutations in TBG,

TTR, and albumin may increase the binding affinity for T4

 and/or T3

and cause disorders known as euthyroid hyperthyroxinemia or familial

dysalbuminemic hyperthyroxinemia (FDH) (Table 382-2). These disorders result in increased total T4

 and/or T3

, but unbound hormone levels

are normal. The familial nature of the disorders, and the fact that TSH

levels are normal rather than suppressed, should suggest this diagnosis.

Unbound hormone levels (ideally measured by dialysis) are normal

in FDH. The diagnosis can be confirmed by using tests that measure

the affinities of radiolabeled hormone binding to specific transport

proteins or by performing DNA sequence analyses of the abnormal

transport protein genes.

Certain medications, such as salicylates and salsalate, can displace

thyroid hormones from circulating binding proteins. Although these

drugs transiently perturb the thyroid axis by increasing free thyroid

hormone levels, TSH is suppressed until a new steady state is reached,

thereby restoring euthyroidism. Circulating factors associated with

acute illness may also displace thyroid hormone from binding proteins

(Chap. 384).

Deiodinases T4

 may be thought of as a precursor for the more

potent T3

. T4

 is converted to T3

 by the deiodinase enzymes (Fig. 382-1).

Type I deiodinase, which is located primarily in thyroid, liver, and kidneys, has a relatively low affinity for T4

. Type II deiodinase has a higher

affinity for T4

 and is found primarily in the pituitary gland, brain,

brown fat, and thyroid gland. Expression of type II deiodinase allows it

to regulate T3

 concentrations locally, a property that may be important

in the context of levothyroxine (T4

) replacement. Type II deiodinase

TABLE 382-1 Characteristics of Circulating T4

 and T3

HORMONE PROPERTY T4 T3

Serum concentrations

Total hormone 8 μg/dL 0.14 μg/dL

 Fraction of total hormone in the

unbound form

0.02% 0.3%

Unbound (free) hormone 21 × 10–12M 6 × 10–12M

Serum half-life 7 d 2 d

Fraction directly from the thyroid 100% 20%

Production rate, including peripheral

conversion

90 μg/d 32 μg/d

Intracellular hormone fraction ~20% ~70%

Relative metabolic potency 0.3 1

Receptor binding 10–10M 10–11M

2930 PART 12 Endocrinology and Metabolism

TABLE 382-2 Conditions Associated with Euthyroid Hyperthyroxinemia

DISORDER CAUSE TRANSMISSION CHARACTERISTICS

Familial dysalbuminemic

hyperthyroxinemia (FDH)

Albumin mutations,

usually R218H

AD Increased T4

Normal unbound T4

Rarely increased T3

TBG

Familial excess Increased TBG production XL Increased total T4

, T3

Normal unbound T4

, T3

Acquired excess Medications (estrogen),

pregnancy, cirrhosis,

hepatitis

Acquired Increased total T4

, T3

Normal unbound T4

, T3

Transthyretina

Excess Islet tumors Acquired Usually normal T4

, T3

Mutations Increased affinity for T4

or T3

AD Increased total T4

, T3

Normal unbound T4

, T3

Medications: propranolol,

ipodate, iopanoic acid,

amiodarone

Decreased T4 → T3

conversion

Acquired Increased T4

Decreased T3

Normal or increased TSH

Resistance to thyroid

hormone (RTH)

Thyroid hormone receptor

β mutations

AD Increased unbound T4

, T3

Normal or increased TSH

Some patients clinically thyrotoxic

a

Also known as thyroxine-binding prealbumin (TBPA).

Abbreviations: AD, autosomal dominant; TBG, thyroxine-binding globulin; TSH, thyroid-stimulating hormone; XL, X-linked.

Nucleus

Cytoplasm

Gene expression

Gene TRE

RXR TR

CoR

T3

T3

T4

T3

CoA

1 2

3

4

FIGURE 382-4 Mechanism of thyroid hormone receptor action. The thyroid

hormone receptor (TR) and retinoid X receptor (RXR) form heterodimers that bind

specifically to thyroid hormone response elements (TRE) in the promoter regions

of target genes. In the absence of hormone, TR binds co-repressor (CoR) proteins

that silence gene expression. The numbers refer to a series of ordered reactions

that occur in response to thyroid hormone: (1) T4

 or T3

 enters the nucleus; (2) T3

binding dissociates CoR from TR; (3) co-activators (CoA) are recruited to the T3

-

bound receptor; and (4) gene expression is altered.

is also regulated by thyroid hormone; hypothyroidism induces the

enzyme, resulting in enhanced T4 → T3

 conversion in tissues such

as brain and pituitary. T4 → T3

 conversion is impaired by fasting,

systemic illness or acute trauma, oral contrast agents, and a variety of

medications (e.g., propylthiouracil, propranolol, amiodarone, glucocorticoids). Type III deiodinase inactivates T4

 and T3

 and is the most

important source of reverse T3

 (rT3

), including in the sick euthyroid

syndrome. This enzyme is expressed in the human placenta but is not

active in healthy individuals. In the sick euthyroid syndrome, especially

with hypoperfusion, the type III deiodinase is activated in muscle and

liver. Massive hemangiomas and other tumors that express type III

deiodinase are a rare cause of consumptive hypothyroidism.

■ THYROID HORMONE ACTION

Thyroid Hormone Transport Circulating thyroid hormones

enter cells by passive diffusion and via specific transporters such as

the monocarboxylate 8 transporter (MCT8), MCT10, and organic

anion-transporting polypeptide 1C1. Mutations in the MCT8 gene

have been identified in patients with X-linked psychomotor retardation

and thyroid function abnormalities (low T4

, high T3

, and high TSH).

After entering cells, thyroid hormones act primarily through nuclear

receptors, although they also have nongenomic actions through stimulating mitochondrial enzymatic responses and may act directly on

blood vessels and the heart through integrin receptors.

Nuclear Thyroid Hormone Receptors Thyroid hormones bind

with high affinity to nuclear TRs α and β. Both TRα and TRβ are

expressed in most tissues, but their relative expression levels vary

among organs; TRα is particularly abundant in brain, kidneys, gonads,

muscle, and heart, whereas TRβ expression is relatively high in the

pituitary and liver. Both receptors are variably spliced to form unique

isoforms. The TRβ2 isoform, which has a unique amino terminus, is

selectively expressed in the hypothalamus and pituitary, where it plays

a role in feedback control of the thyroid axis (see above). The TRα2

isoform contains a unique carboxy terminus that precludes thyroid

hormone binding; it may function to inhibit the action of other TR

isoforms.

The TRs contain a central DNA-binding domain and a C-terminal

ligand-binding domain. They bind to specific DNA sequences, termed

thyroid response elements (TREs), in target genes (Fig. 382-4). The

receptors bind as homodimers or, more commonly, as heterodimers

with retinoic acid X receptors (RXRs)

(Chap. 377). The activated receptor

can either stimulate gene transcription

(e.g., myosin heavy chain α) or inhibit

transcription (e.g., TSH β-subunit

gene), depending on the nature of the

regulatory elements in the target gene.

Thyroid hormones (T3

 and T4

)

bind with similar affinities to TRα

and TRβ. However, structural differences in the ligand-binding domains

provide the potential for developing

receptor-selective agonists or antagonists, and these are under investigation. T3

 is bound with 10–15 times

greater affinity than T4

, which explains

its increased potency. Although T4

 is

produced in excess of T3

, receptors are

occupied mainly by T3

, reflecting T4

→ T3

 conversion by peripheral tissues,

T3

 bioavailability in the plasma, and

the greater affinity of receptors for T3

.

After binding to TRs, thyroid hormone

induces conformational changes in the

receptors that modify its interactions

with accessory transcription factors.

Importantly, in the absence of thyroid

hormone binding, the aporeceptors

bind to co-repressor proteins that inhibit gene transcription. Hormone

binding dissociates the co-repressors and allows the recruitment of

co-activators that enhance transcription. The discovery of TR interactions with co-repressors explains the fact that TR silences gene expression in the absence of hormone binding. Consequently, hormone

deficiency has a profound effect on gene expression because it causes

gene repression as well as loss of hormone-induced stimulation. This

concept has been corroborated by the finding that targeted deletion

of the TR genes in mice has a less pronounced phenotypic effect than

hormone deficiency.

Thyroid Hormone Resistance Resistance to thyroid hormone

(RTH) is an autosomal dominant disorder characterized by elevated

thyroid hormone levels and inappropriately normal or elevated TSH.

2931Thyroid Gland Physiology and Testing CHAPTER 382

Individuals with RTH do not, in general, exhibit signs and symptoms

that are typical of hypothyroidism because hormone resistance is partial and is compensated by increased levels of thyroid hormone. The

clinical features of RTH can include goiter, attention deficit disorder,

mild reduction in IQ, delayed skeletal maturation, tachycardia, and

impaired metabolic responses to thyroid hormone.

Classical forms of RTH are caused by mutations in the TRβ gene.

These mutations, located in restricted regions of the ligand-binding

domain, cause loss of receptor function. However, because the mutant

receptors retain the capacity to dimerize with RXRs, bind to DNA,

and recruit co-repressor proteins, they function as antagonists of the

remaining normal TRβ and TRα receptors. This property, referred to as

“dominant negative” activity, explains the autosomal dominant mode

of transmission. The diagnosis is suspected when unbound thyroid

hormone levels are increased without suppression of TSH. Similar

hormonal abnormalities are found in other affected family members,

although the TRβ mutation arises de novo in ~20% of patients. DNA

sequence analysis of the TRβ gene provides a definitive diagnosis. RTH

must be distinguished from other causes of euthyroid hyperthyroxinemia (e.g., FDH) and inappropriate secretion of TSH by TSH-secreting

pituitary adenomas (Chap. 380). In most patients, no treatment is

indicated; the importance of making the diagnosis is to avoid inappropriate treatment of mistaken hyperthyroidism and to provide genetic

counseling.

A distinct form of RTH is caused by mutations in the TRα gene.

Affected patients have many clinical features of congenital hypothyroidism including growth retardation, skeletal dysplasia, and severe

constipation. In contrast to RTH caused by mutations in TRβ, thyroid

function tests include normal TSH, low or normal T4

, and normal

or elevated T3

 levels. These distinct clinical and laboratory features

underscore the different tissue distribution and functional roles of TRβ

and TRα. Thyroxine treatment appears to alleviate some of the clinical

manifestations of patients with RTH caused by TRα mutations.

■ PHYSICAL EXAMINATION

In addition to the examination of the thyroid itself, the physical examination should include a search for signs of abnormal thyroid function

and the extrathyroidal features of ophthalmopathy and dermopathy

(Chap. 384). Examination of the neck begins by inspecting the seated

patient from the front and side and noting any surgical scars, obvious

masses, or distended veins. The thyroid can be palpated with both

hands from behind or while facing the patient, using the thumbs to

palpate each lobe. It is best to use a combination of these methods,

especially when nodules are small. The patient’s neck should be slightly

flexed to relax the neck muscles. After locating the cricoid cartilage,

the isthmus, which is attached to the lower one-third of the thyroid

lobes, can be identified and then followed laterally to locate either

lobe (normally, the right lobe is slightly larger than the left). By asking

the patient to swallow sips of water, thyroid consistency can be better

appreciated as the gland moves beneath the examiner’s fingers.

Features to be noted include thyroid size, consistency, nodularity,

and any tenderness or fixation. An estimate of thyroid size (normally

12–20 g) should be made, and a drawing is often the best way to record

findings. Ultrasound imaging provides the most accurate measurement

of thyroid volume and nodularity and is useful for assessment of goiter

prevalence in iodine-deficient regions. However, ultrasound is not

indicated if the thyroid physical examination is normal. The size, location, and consistency of any nodules should also be defined. A bruit

or thrill over the gland, located over the insertion of the superior and

inferior thyroid arteries (supero- or inferolaterally), indicates increased

vascularity, associated with turbulent rather than laminar blood flow,

as occurs in hyperthyroidism. If the lower borders of the thyroid lobes

are not clearly felt, a goiter may be retrosternal. Large retrosternal

goiters can cause venous distention over the neck and difficulty breathing, especially when the arms are raised (Pemberton’s sign). With any

central mass above the thyroid, the tongue should be extended, as

thyroglossal cysts then move upward. The thyroid examination is not

complete without assessment for lymphadenopathy in the supraclavicular and cervical regions of the neck.

■ LABORATORY EVALUATION

Measurement of Thyroid Hormones The enhanced sensitivity

and specificity of TSH assays have greatly improved laboratory assessment of thyroid function. Because TSH levels change dynamically in

response to alterations of T4

 and T3

, a logical approach to thyroid testing

is to first determine whether TSH is suppressed, normal, or elevated.

With rare exceptions (see below), a normal TSH level excludes a primary

abnormality of thyroid function. This strategy depends on the use of

immunochemiluminometric assays (ICMAs) for TSH that are sensitive

enough to discriminate between the lower limit of the reference interval

and the suppressed values that occur with thyrotoxicosis. Extremely

sensitive assays can detect TSH levels ≤0.004 mIU/L, but, for practical

purposes, assays sensitive to ≤0.1 mIU/L are sufficient. The widespread

availability of the TSH ICMA has rendered the TRH stimulation test

obsolete, because the failure of TSH to rise after an intravenous bolus

of 200–400 μg TRH has the same implications as a suppressed basal

TSH measured by ICMA. Because the antibodies used in the ICMA are

biotinylated, biotin supplements, including biotin in multivitamins, can

interfere with TSH measurement, resulting in falsely low TSH values

and falsely high T4

 or T3

 levels. Therefore, patients should be advised

to stop taking biotin for at least 2 days prior to thyroid function testing.

The finding of an abnormal TSH level must be followed by measurements of circulating thyroid hormone levels to confirm the diagnosis of

hyperthyroidism (suppressed TSH) or hypothyroidism (elevated TSH).

Automated immunoassays are widely available for serum total T4

 and

total T3

. T4

 and T3

 are highly protein-bound, and numerous factors

(illness, medications, genetic factors) can influence protein binding. It

is useful, therefore, to measure the free, or unbound, hormone levels,

which correspond to the biologically available hormone pool. Two direct

methods are used to measure unbound thyroid hormones: (1) unbound

thyroid hormone competition with radiolabeled T4

 (or an analogue)

for binding to a solid-phase antibody, and (2) physical separation of

the unbound hormone fraction by ultracentrifugation or equilibrium

dialysis. Although early unbound hormone immunoassays suffered

from artifacts, newer assays correlate well with the results of the more

technically demanding and expensive physical separation methods. An

indirect method that is now less commonly used to estimate unbound

thyroid hormone levels is to calculate the free T3

 or free T4

 index from

the total T4

 or T3

 concentration and the thyroid hormone binding ratio

(THBR). The latter is derived from the T3

-resin uptake test, which determines the distribution of radiolabeled T3

 between an absorbent resin

and the unoccupied thyroid hormone–binding proteins in the sample.

The binding of the labeled T3

 to the resin is increased when there is

reduced unoccupied protein binding sites (e.g., TBG deficiency) or

increased total thyroid hormone in the sample; it is decreased under the

opposite circumstances. The product of THBR and total T3

 or T4

 provides the free T3

 or T4

 index. In effect, the index corrects for anomalous

total hormone values caused by variations in hormone-protein binding.

Total thyroid hormone levels are elevated when TBG is increased

due to estrogens (pregnancy, oral contraceptives, hormone therapy,

tamoxifen, selective estrogen receptor modulators, inflammatory liver

disease) and decreased when TBG binding is reduced (androgens,

nephrotic syndrome). Genetic disorders and acute illness can also

cause abnormalities in thyroid hormone–binding proteins, and various

drugs (phenytoin, carbamazepine, salicylates, and nonsteroidal antiinflammatory drugs [NSAIDs]) can interfere with thyroid hormone

binding. Because unbound thyroid hormone levels are normal and the

patient is euthyroid in all of these circumstances, assays that measure

unbound hormone are preferable to those for total thyroid hormones.

For most purposes, the unbound T4

 level is sufficient to confirm

thyrotoxicosis, but 2–5% of patients have only an elevated T3

 level

(T3

 toxicosis). Thus, unbound T3

 levels should be measured in patients

with a suppressed TSH but normal unbound T4

 levels.

There are several clinical conditions in which the use of TSH as a

screening test may be misleading, particularly without simultaneous

unbound T4

 determinations. Any severe nonthyroidal illness can cause

abnormal TSH levels. Although hypothyroidism is the most common

cause of an elevated TSH level, rare causes include a TSH-secreting

2932 PART 12 Endocrinology and Metabolism

pituitary tumor (Chap. 380), thyroid hormone resistance, and assay

artifact. Conversely, a suppressed TSH level, particularly <0.01 mIU/L,

usually indicates thyrotoxicosis. However, subnormal TSH levels

between 0.01 and 0.1 mIU/L may be seen during the first trimester of

pregnancy (due to hCG secretion), after treatment of hyperthyroidism

(because TSH can remain suppressed for several months), and in

response to certain medications (e.g., high doses of glucocorticoids

or dopamine). TSH levels measured by immunoassay may also be

suppressed in patients ingesting biotin supplements <18 h prior to a

blood draw because the TSH capture antibodies are biotinylated and

the exogenous biotin can interfere with the subsequent streptavidin

capture. Importantly, secondary hypothyroidism, caused by hypothalamic-pituitary disease, is associated with a variable (low to highnormal) TSH level, which is inappropriate for the low T4

 level. Thus, TSH

should not be used as an isolated laboratory test to assess thyroid function

in patients with suspected or known hypothalamic or pituitary disease.

Tests for the end-organ effects of thyroid hormone excess or depletion, such as estimation of basal metabolic rate, tendon reflex relaxation rates, or serum cholesterol, are relatively insensitive and are not

useful as clinical determinants of thyroid function.

Tests to Determine the Etiology of Thyroid Dysfunction

Autoimmune thyroid disease is detected most easily by measuring

circulating antibodies against TPO and Tg. Because antibodies to Tg

alone are less common, it is reasonable to measure only TPO antibodies. About 5–15% of euthyroid women and up to 2% of euthyroid

men have thyroid antibodies; such individuals are at increased risk of

developing thyroid dysfunction. Almost all patients with autoimmune

hypothyroidism, and up to 80% of those with Graves’ disease, have

TPO antibodies, usually at high levels.

TSIs are antibodies that stimulate the TSH-R in Graves’ disease.

They are most commonly measured by commercially available tracer

displacement assays called TRAb (TSH receptor antibody) with the

assumption that elevated levels in the setting of clinical hyperthyroidism reflect stimulatory effects on the TSH receptor. A bioassay is less

commonly used. Remission rates in patients with Graves’ disease after

antithyroid drug cessation are higher with disappearance rather than

persistence of TRAb. Furthermore, the TRAb assay is used to predict

both fetal and neonatal thyrotoxicosis caused by transplacental passage

of high maternal levels of TRAb or TSI (>3× upper limit of normal) in

the last trimester of pregnancy.

Serum Tg levels are increased in all types of thyrotoxicosis except

thyrotoxicosis factitia caused by self-administration of thyroid hormone. Tg levels are particularly increased in thyroiditis, reflecting

thyroid tissue destruction and release of Tg. The main role for Tg

measurement, however, is in the follow-up of thyroid cancer patients.

After total thyroidectomy and radioablation, Tg levels should be

<0.2 ng/mL in the absence of anti-Tg antibodies; measurable levels

indicate incomplete ablation or recurrent cancer.

Radioiodine Uptake and Thyroid Scanning The thyroid gland

selectively transports radioisotopes of iodine (123I, 125I, 131I) and 99mTc

pertechnetate, allowing thyroid imaging and quantitation of radioactive tracer fractional uptake.

Nuclear imaging of Graves’ disease is characterized by an enlarged

gland and increased tracer uptake that is distributed homogeneously.

Toxic adenomas appear as focal areas of increased uptake, with

suppressed tracer uptake in the remainder of the gland (reflecting

suppressed TSH). In toxic MNG, the gland is enlarged—often with distorted architecture—and there are multiple areas of relatively increased

(functioning nodules) or decreased tracer uptake (suppressed thyroid

parenchyma or nonfunctioning nodules). Subacute, viral, and postpartum thyroiditis are associated with very low uptake because of follicular

cell damage and TSH suppression. Thyrotoxicosis factitia is also associated with low uptake because exogenous hormone suppresses TSH. In

addition, if there is excessive circulating exogenous iodine (e.g., from

dietary sources of iodinated contrast dye), the radionuclide uptake is

low even in the presence of increased thyroid hormone production.

Thyroid scintigraphy is not used in the routine evaluation of patients

with thyroid nodules but should be performed if the serum TSH level

is subnormal to determine if functioning thyroid nodules are present. Functioning or “hot” nodules are almost never malignant, and

fine-needle aspiration (FNA) biopsy is not indicated. The vast majority

of thyroid nodules do not produce thyroid hormone (“cold” nodules),

and these are more likely to be malignant (~5–10%). Whole-body and

thyroid scanning is also used in the treatment and, now less frequently,

in the surveillance of thyroid cancer. After thyroidectomy for thyroid

cancer, the TSH level is raised by either using a thyroid hormone withdrawal protocol or recombinant human TSH injection (Chap. 385).

Administration of either 131I or 123I (in higher activities than used to

image the thyroid gland alone) allows whole-body scanning (WBS)

to detect the thyroid remnant. WBS imaging is also performed after

therapeutic administration of 131I, which confirms remnant ablation

and may reveal iodine-avid metastases.

Thyroid Ultrasound Ultrasonography is the most valuable tool

for the diagnosis and evaluation of patients with nodular thyroid

disease (Chap. 385). Evidence-based guidelines recommend thyroid

ultrasonography for all patients suspected of having thyroid nodules

by either physical examination or another imaging study. Using 10- to

12-MHz linear transducers, resolution and image quality are excellent,

allowing the characterization of nodules and cysts >3 mm. Sonographic

patterns that combine suspicious sonographic features are highly suggestive of malignancy (e.g., hypoechoic solid nodules with infiltrative

borders and microcalcifications, >90% cancer risk), whereas other

patterns correlate with a lower likelihood of cancer (isoechoic solid

nodules, 5–10% cancer risk). Some patterns suggest benignity (e.g.,

spongiform nodules, defined as those with multiple small internal cystic areas, or simple cysts, <3% cancer risk) (see Chap. 385, Fig. 385-2).

These patterns have been incorporated into validated risk stratification

systems (RSSs) for sonographic imaging of thyroid nodules (American

College of Radiology [ACR] Thyroid Imaging Reporting and Data

System [TI-RADS], American Thyroid Association, European Thyroid

Association [EU-TIRADS] and others) (see Chap. 385, Fig. 385-1).

These systems are relatively concordant in the classification of thyroid

nodules; they differ in size cutoff recommendations for FNA. Not surprisingly, the RSSs with lower size cutoffs have higher sensitivity and

lower specificity for thyroid cancer diagnosis than those with higher

cutoffs. Nevertheless, all have been shown to reduce unnecessary FNAs

by at least 45%, in part due to the recommendation not to perform

FNA of spongiform nodules.

In addition to evaluating thyroid nodules, ultrasound is useful for

monitoring nodule size and for the aspiration of nodules or cystic

lesions. Ultrasound-guided FNA biopsy of thyroid lesions lowers the

rate of inadequate sampling and decreases sample error, thereby reducing both the nondiagnostic and false-negative rates of FNA cytology.

Ultrasonography of the central and lateral cervical lymph node compartments is indispensable in the evaluation of thyroid cancer patients,

preoperatively and during follow-up. In addition, the ACR recommends a survey of the cervical lymph nodes as part of every diagnostic

thyroid sonographic examination.

■ FURTHER READING

Alexander EK et al: 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during

pregnancy and postpartum. Thyroid 27:315, 2017.

Braun D, Schweizer U: Thyroid hormone transport and transporters. Vitam Horm 106:19, 2018.

Ortiga-Cavalho TM et al: Thyroid hormone receptors and resistance

to thyroid hormone disorders. Nat Rev Endocrinol 10:582, 2014.

Rugge JB et al: Screening and treatment of thyroid dysfunction: An

evidence review for the U.S. Preventive Services Task Force. Ann

Intern Med 162:35, 2015.

Stoupa A et al: Update of thyroid developmental genes. Endocrinol

Metab Clin North Am 45:243, 2016.

Tessler FN et al: ACR Thyroid Imaging Reporting and Data System

(TI-RADS): White paper of the ACR TI-RADS Committee. J Am

Coll Radiol 14:587 2017.

Zimmermann MB, Boelaert K: Iodine deficiency and thyroid disorders. Lancet Diabetes Endocrinol 3:286, 2015.

2933Hypothyroidism CHAPTER 383

HYPOTHYROIDISM

Iodine deficiency remains a common cause of hypothyroidism worldwide. In areas of iodine sufficiency, autoimmune disease (Hashimoto’s

thyroiditis) and iatrogenic causes (treatment of hyperthyroidism) are

most common (Table 383-1).

■ CONGENITAL HYPOTHYROIDISM

Prevalence Hypothyroidism occurs in about 1 in 2000–4000 newborns, and neonatal screening is performed in most industrialized

countries. It may be transient, especially if the mother has thyroidstimulating hormone (TSH) receptor (TSH-R)–blocking antibodies or

has received antithyroid drugs, but permanent hypothyroidism occurs

in the majority. The causes of neonatal hypothyroidism include thyroid

gland dysgenesis in 65%, inborn errors of thyroid hormone synthesis in

30%, and TSH-R antibody mediated in 5% of affected newborns. The

developmental abnormalities are twice as common in girls. Mutations

that cause congenital hypothyroidism are being increasingly identified, but most remain idiopathic. These can be broadly categorized as

mutations causing (1) central hypothyroidism because of abnormal

hypothalamic-pituitary development or the loss of specific components of the thyrotropin-releasing hormone (TRH)/TSH hormonal

pathways; (2) abnormal thyroid gland development or dysgenesis;

or (3) abnormal thyroid hormone synthesis and processing, or dyshormonogenesis (Table 383-2). Transplacental passage of maternal

thyroid hormone occurs before the fetal thyroid gland begins to function and provides partial hormone support to a fetus with congenital

hypothyroidism.

383 Hypothyroidism

J. Larry Jameson, Susan J. Mandel,

Anthony P. Weetman

Clinical Manifestations The majority of infants appear normal

at birth, and with the use of biochemical screening, few cases are

now diagnosed based on clinical features, which include prolonged

jaundice, feeding problems, hypotonia, enlarged tongue, delayed bone

maturation, and umbilical hernia. Importantly, permanent neurologic damage results if treatment is delayed. Typical features of adult

hypothyroidism may also be present (Table 383-3). Other congenital

malformations, especially cardiac, are four times more common in

congenital hypothyroidism.

Diagnosis and Treatment Because of the severe neurologic consequences of untreated congenital hypothyroidism, neonatal screening

programs have been established. These are generally based on measurement of TSH or T4

 levels in heel-prick blood specimens. When the

diagnosis is confirmed, T4

 is instituted at a dose of 10–15 μg/kg per d,

and the dose is adjusted by close monitoring of TSH levels. T4

 requirements are relatively great during the first year of life, and a high circulating T4

 level is usually needed to normalize TSH. Early treatment

with T4

 results in normal IQ levels, but subtle neurodevelopmental

abnormalities may occur in those with the most severe hypothyroidism

at diagnosis or when treatment is delayed or suboptimal. If transient

hypothyroidism is suspected, or the diagnosis is unclear, treatment can

be stopped safely after the age of 3 years followed by further evaluation.

■ AUTOIMMUNE HYPOTHYROIDISM

Classification Autoimmune hypothyroidism may be associated

with a goiter (Hashimoto’s, or goitrous thyroiditis) or minimal residual

thyroid tissue (atrophic thyroiditis). Because the autoimmune process

gradually reduces thyroid function, there is a phase of compensation

when normal thyroid hormone levels are maintained by a rise in TSH.

Although some patients may have minor symptoms, this state is called

subclinical hypothyroidism. Later, unbound T4

 levels fall and TSH levels

rise further; symptoms become more readily apparent at this stage

(usually TSH >10 mIU/L), which is referred to as clinical hypothyroidism or overt hypothyroidism.

Prevalence The mean annual incidence rate of autoimmune hypothyroidism is up to 4 per 1000 women and 1 per 1000 men. It is more

common in certain populations, such as the Japanese, probably because

of genetic factors and chronic exposure to a high-iodine diet. The

mean age at diagnosis is 60 years, and the prevalence of overt hypothyroidism increases with age. Subclinical hypothyroidism is found in

6–8% of women (10% over the age of 60) and 3% of men. The annual

risk of developing clinical hypothyroidism is ~4% when subclinical

hypothyroidism is associated with positive thyroid peroxidase (TPO)

antibodies.

Pathogenesis In Hashimoto’s thyroiditis, there is a marked lymphocytic infiltration of the thyroid with germinal center formation,

atrophy of the thyroid follicles accompanied by oxyphil metaplasia,

absence of colloid, and mild to moderate fibrosis. In atrophic thyroiditis, the fibrosis is much more extensive, lymphocyte infiltration

is less pronounced, and thyroid follicles are almost completely absent.

Atrophic thyroiditis usually represents the end stage of Hashimoto’s

thyroiditis rather than a separate disorder, although a distinct form

of marked fibrosis occurs in which the gland is infiltrated with IgG4-

positive plasma cells.

As with most autoimmune disorders, susceptibility to autoimmune

hypothyroidism is determined by a combination of genetic and environmental factors, and the risk of either autoimmune hypothyroidism

or Graves’ disease is increased among siblings. HLA-DR polymorphisms are the best documented genetic risk factors for autoimmune

hypothyroidism, especially HLA-DR3, DR4, and DR5 in Caucasians.

A weak association also exists between polymorphisms in CTLA-4,

a T cell–regulatory gene, and autoimmune hypothyroidism. Both of

these genetic associations are shared by other autoimmune diseases,

which may explain the relationship between autoimmune hypothyroidism and other autoimmune diseases, especially type 1 diabetes

mellitus, Addison’s disease, pernicious anemia, and vitiligo. HLA-DR

and CTLA-4 polymorphisms account for approximately half of the

TABLE 383-1 Causes of Hypothyroidism

Primary

Autoimmune hypothyroidism: Hashimoto’s thyroiditis, atrophic thyroiditis

Iatrogenic: 131I treatment, subtotal or total thyroidectomy, external irradiation of

neck for lymphoma or cancer

Drugs: iodine excess (including iodine-containing contrast media), amiodarone,

lithium, antithyroid drugs, p-aminosalicylic acid, interferon α and other

cytokines, aminoglutethimide, tyrosine kinase inhibitors (e.g., sunitinib), immune

checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembrolizumab)

Congenital hypothyroidism: absent or ectopic thyroid gland, dyshormonogenesis,

TSH-R mutation

Iodine deficiency

Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis, scleroderma,

cystinosis, Riedel’s thyroiditis

Overexpression of type 3 deiodinase in infantile hemangioma and other tumors

Transient

Silent thyroiditis, including postpartum thyroiditis

Subacute thyroiditis

Withdrawal of supraphysiologic thyroxine treatment in individuals with an intact

thyroid

After 131I treatment or subtotal thyroidectomy for Graves’ disease

Secondary

Hypopituitarism: tumors, pituitary surgery or irradiation, infiltrative disorders,

Sheehan’s syndrome, trauma, genetic forms of combined pituitary hormone

deficiencies

Isolated TSH deficiency or inactivity

Bexarotene treatment

Hypothalamic disease: tumors, trauma, infiltrative disorders, idiopathic

Abbreviations: TSH, thyroid-stimulating hormone; TSH-R, TSH receptor.

2934 PART 12 Endocrinology and Metabolism

genetic susceptibility to autoimmune hypothyroidism, and the role

of other contributory loci remains to be clarified. A gene on chromosome 21 may be responsible for the association between autoimmune

hypothyroidism and Down’s syndrome. The female preponderance of

thyroid autoimmunity is most likely due to sex steroid effects on the

immune response, but an X chromosome–related genetic factor is also

possible and may account for the high frequency of autoimmune hypothyroidism in Turner’s syndrome. Environmental susceptibility factors

are poorly defined at present. A high iodine or low selenium intake

and decreased exposure to microorganisms in childhood increase the

risk of autoimmune hypothyroidism. Smoking cessation transiently

increases incidence, whereas alcohol intake seems protective. These

factors may account for the increase in prevalence over the past two

to three decades.

The thyroid lymphocytic infiltrate in autoimmune hypothyroidism is composed of activated T cells as well as B cells. Thyroid cell

destruction is primarily mediated by the CD8+ cytotoxic T cells, but

local production of cytokines, such as tumor necrosis factor (TNF),

interleukin-1 (IL-1), and interferon γ (IFN-γ), derived from the

inflammatory infiltrate may render thyroid cells more susceptible to

apoptosis mediated by death receptors, such as Fas, and by oxidative

stress. These cytokines also impair thyroid cell function directly and

induce the expression of other proinflammatory molecules by the thyroid cells themselves, such as cytokines, HLA class I and class II molecules, adhesion molecules, CD40, and nitric oxide. Administration of

high concentrations of cytokines for therapeutic purposes (especially

IFN-α) is associated with increased autoimmune thyroid disease, possibly through mechanisms similar to those in sporadic disease. Novel

anticancer and immunomodulatory treatments, such as tyrosine kinase

inhibitors, immune checkpoint inhibitors, and alemtuzumab, can also

induce thyroiditis via their effects on T-cell regulation.

Antibodies to TPO and thyroglobulin (Tg) are clinically useful

markers of thyroid autoimmunity, but any pathogenic effect is restricted

to a secondary role in amplifying an ongoing autoimmune response.

TPO antibodies fix complement, and complement membrane-attack

complexes are present in the thyroid in autoimmune hypothyroidism.

However, transplacental passage of Tg or TPO antibodies has no effect

on the fetal thyroid, which suggests that T cell–mediated injury is

required to initiate autoimmune damage to the thyroid.

Up to 20% of patients with autoimmune hypothyroidism have antibodies against the TSH-R, which, in contrast to thyroid-stimulating

immunoglobulin (TSI), do not stimulate the receptor but prevent the

TABLE 383-2 Examples of Genetic Causes of Congenital Hypothyroidism

DEFECTIVE GENE PROTEIN TYPE OF HYPOTHYROIDISM INHERITANCE CONSEQUENCES

PROP-1 Central, hypothyroidism Homozygous recessive Combined pituitary hormone deficiencies,

including thyroid-stimulating hormone (TSH), with

preservation of adrenocorticotropic hormone

PIT-1 Central, hypothyroidism Homozygous or Heterozygous loss of

function

Combined deficiencies of growth hormone,

prolactin, TSH

IGSF1 Central, hypothyroidism X-linked loss of function Loss of TSH receptor (TSH-R) expression, testicular

enlargement

TSHβ Central, hypothyroidism Heterozygous loss of function TSH deficiency

TTF-1 (TITF-1) Primary, thyroid dysgenesis Heterozygous loss of function Variable thyroid hypoplasia, choreoathetosis,

pulmonary problems

TTF-2 (FOXE-1) Primary, thyroid dysgenesis Homozygous recessive Thyroid agenesis, choanal atresia, spiky hair

PAX-8 Primary, thyroid dysgenesis Heterozygous loss of function Thyroid dysgenesis, kidney abnormalities

NKX2-1 Primary, thyroid dysgenesis Heterozygous loss of function Thyroid dysgenesis, brain, lung abnormalities

NKX2-5 Primary, thyroid dysgenesis Heterozygous loss of function Thyroid dysgenesis, heart abnormalities

GLIS3 Primary, thyroid dysgenesis Homozygous recessive Thyroid dysgenesis, neonatal diabetes, facial

abnormalities

JAG-1 Primary, thyroid dysgenesis Heterozygous loss of function Thyroid dysgenesis, Alagille syndrome type 1,

heart abnormalities

TSH receptor Primary, thyroid dysgenesis

and dyshormonogenesis

Homozygous recessive Resistance to TSH

GS

α (Albright hereditary

osteodystrophy)

Primary, thyroid dyshormonogenesis Heterozygous loss of function,

imprinting

Resistance to TSH

Na+

/I–

 symporter (SLC5A5) Primary, thyroid dyshormonogenesis Homozygous recessive Inability to transport iodide

DUOX2 (THOX2) Primary, thyroid dyshormonogenesis Heterozygous loss of function Organification defect

DUOXA2 Primary, thyroid dyshormonogenesis Homozygous recessive Organification defect

Thyroid peroxidase Primary, thyroid dyshormonogenesis Homozygous recessive Defective organification of iodide

Thyroglobulin Primary, thyroid dyshormonogenesis Homozygous recessive Defective synthesis of thyroid hormone

Pendrin (SLC26A4) Primary, thyroid dyshormonogenesis Homozygous recessive Pendred syndrome: sensorineural deafness and

partial organification defect in thyroid

Dehalogenase 1 (IYD) Primary, thyroid dyshormonogenesis Homozygous recessive Loss of iodide reutilization

TABLE 383-3 Signs and Symptoms of Hypothyroidism

(Descending Order of Frequency)

SYMPTOMS SIGNS

Tiredness, weakness

Dry skin

Feeling cold

Hair loss

Difficulty concentrating and poor

memory

Constipation

Weight gain with poor appetite

Dyspnea

Hoarse voice

Menorrhagia (later oligomenorrhea or

amenorrhea)

Paresthesia

Impaired hearing

Dry coarse skin; cool peripheral

extremities

Puffy face, hands, and feet (myxedema)

Diffuse alopecia

Bradycardia

Peripheral edema

Delayed tendon reflex relaxation

Carpal tunnel syndrome

Serous cavity effusions

2935Hypothyroidism CHAPTER 383

binding of TSH. These TSH-R-blocking antibodies, therefore, cause

hypothyroidism and, especially in Asian patients, thyroid atrophy.

Their transplacental passage may induce transient neonatal hypothyroidism. Rarely, patients have a mixture of TSI and TSH-R-blocking

antibodies, and thyroid function can oscillate between hyperthyroidism and hypothyroidism as one or the other antibody becomes dominant. Predicting the course of disease in such individuals is difficult,

and they require close monitoring of thyroid function. Bioassays can

be used to document that TSH-R-blocking antibodies reduce the cyclic

AMP–inducing effect of TSH on cultured TSH-R-expressing cells, but

these assays are difficult to perform. Thyrotropin-binding inhibitory

immunoglobulin (TBII) assays that measure the binding of antibodies

to the receptor by competition with labeled TSH do not distinguish

between TSI and TSH-R-blocking antibodies, but a positive result in

a patient with spontaneous hypothyroidism is strong evidence for the

presence of blocking antibodies. The use of these assays does not generally alter clinical management, although it may be useful to confirm

the cause of transient neonatal hypothyroidism.

Clinical Manifestations The main clinical features of hypothyroidism are summarized in Table 383-3. The onset is usually insidious,

and the patient may become aware of symptoms only when euthyroidism is restored. Patients with Hashimoto’s thyroiditis may present

because of goiter rather than symptoms of hypothyroidism. The goiter

may not be large, but it is usually irregular and firm in consistency.

Rarely, uncomplicated Hashimoto’s thyroiditis is associated with pain.

Patients with atrophic thyroiditis or the later stage of Hashimoto’s

thyroiditis present with symptoms and signs of hypothyroidism. The

skin is dry, and there is decreased sweating, thinning of the epidermis, and hyperkeratosis of the stratum corneum. Increased dermal

glycosaminoglycan content traps water, giving rise to skin thickening

without pitting (myxedema). Typical features include a puffy face with

edematous eyelids and nonpitting pretibial edema (Fig. 383-1). There

is pallor, often with a yellow tinge to the skin due to carotene accumulation. Nail growth is retarded, and hair is dry, brittle, difficult to manage,

and falls out easily. In addition to diffuse alopecia, there is thinning of

the outer third of the eyebrows, although this is not a specific sign of

hypothyroidism.

Other common features include constipation and weight gain

(despite a poor appetite). In contrast to popular perception, the weight

gain is usually modest and due mainly to fluid retention in the myxedematous tissues. Libido is decreased in both sexes, and there may be

oligomenorrhea or amenorrhea in long-standing disease, but menorrhagia may occur at an early stage. Fertility is reduced, and the incidence of miscarriage is increased. Prolactin levels are often modestly

increased (Chap. 380) and may contribute to alterations in libido and

fertility and cause galactorrhea.

Myocardial contractility and pulse rate are reduced, leading to a

reduced stroke volume and bradycardia. Increased peripheral resistance may be accompanied by hypertension, particularly diastolic.

Blood flow is diverted from the skin, producing cool extremities. Pericardial effusions occur in up to 30% of patients but rarely compromise

cardiac function. Although alterations in myosin heavy chain isoform

expression have been documented, cardiomyopathy is rare. Fluid may

also accumulate in other serous cavities and in the middle ear, giving

rise to conductive deafness; sensorineural deafness may also occur.

Pulmonary function is generally normal, but dyspnea may be caused

by pleural effusion, impaired respiratory muscle function, diminished

ventilatory drive, or sleep apnea.

Carpal tunnel and other entrapment syndromes are common, as is

impairment of muscle function with stiffness, cramps, and pain. On

examination, there may be slow relaxation of tendon reflexes and pseudomyotonia. Memory and concentration are impaired. Experimentally,

positron emission tomography (PET) scans examining glucose metabolism in hypothyroid subjects show lower regional activity in the amygdala, hippocampus, and perigenual anterior cingulate cortex, among

other regions, and this activity corrects after thyroxine replacement.

Rare neurologic problems include reversible cerebellar ataxia, dementia, psychosis, and myxedema coma. Hashimoto’s encephalopathy has

been defined as a steroid-responsive syndrome associated with TPO

antibodies, myoclonus, and slow-wave activity on electroencephalography, but the relationship with thyroid autoimmunity or hypothyroidism is not established, and if a patient is euthyroid, levothyroxine (LT4)

therapy has not been shown to be efficacious in treatment. The hoarse

voice and occasionally clumsy speech of hypothyroidism reflect fluid

accumulation in the vocal cords and tongue.

The features described above are the consequence of thyroid hormone deficiency. However, autoimmune hypothyroidism may be

associated with signs or symptoms of other autoimmune diseases,

particularly vitiligo, pernicious anemia, Addison’s disease (Schmidt’s

syndrome), alopecia areata, and type 1 diabetes mellitus (T1DM). In

the polygenic disorder autoimmune polyendocrine syndrome type 2,

autoimmune thyroid disease is present in 70–75%, T1DM in 40–60%,

and Addison’s disease in 40–50%. Less common associations include

celiac disease, dermatitis herpetiformis, chronic active hepatitis, rheumatoid arthritis, systemic lupus erythematosus (SLE), myasthenia

gravis, autoimmune hypoparathyroidism, primary hypogonadism,

and Sjögren’s syndrome. Thyroid-associated ophthalmopathy usually

occurs in Graves’ disease (see below), but in ~5% of patients, it is associated with autoimmune hypothyroidism.

Autoimmune hypothyroidism is uncommon in children and usually

presents with slow growth and delayed facial and dental maturation.

The pituitary may be enlarged due to thyrotroph hyperplasia. Myopathy, with muscle swelling, is more common in children than in adults.

In most cases, puberty is delayed, but precocious puberty sometimes

occurs. There may be intellectual impairment if the onset is before 3

years and the hormone deficiency is severe.

Laboratory Evaluation A summary of the investigations used to

determine the existence and cause of hypothyroidism is provided in

Fig. 383-2. A normal TSH level excludes primary (but not secondary)

hypothyroidism. If the TSH is elevated, a free or unbound T4

 level (FT4

)

is needed to confirm the presence of clinical hypothyroidism, but T4

 is

inferior to TSH when used as a screening test because it will not detect

subclinical hypothyroidism. Circulating unbound T3

 levels are normal

in ~25% of patients, reflecting adaptive deiodinase responses to hypothyroidism. T3

 measurements are, therefore, not indicated.

FIGURE 383-1 Facial appearance in hypothyroidism. Note puffy eyes and thickened

skin.

2936 PART 12 Endocrinology and Metabolism

Once clinical or subclinical hypothyroidism is confirmed, the

etiology is usually easily established by demonstrating the presence

of TPO and Tg antibodies, which are present in >95% of patients

with autoimmune hypothyroidism. TBII can be found in 10–20% of

patients, but measurement is not needed routinely. Other abnormal

laboratory findings in hypothyroidism may include increased creatine

phosphokinase, elevated cholesterol and triglycerides, and anemia

(usually normocytic or macrocytic). Except when accompanied by iron

deficiency, the anemia and other abnormalities gradually resolve with

thyroxine replacement.

Differential Diagnosis An asymmetric goiter in Hashimoto’s

thyroiditis may be confused with a multinodular goiter (MNG) or

thyroid carcinoma, in which thyroid antibodies may also be present.

Ultrasound can be used to show the presence of a solitary lesion or

an MNG rather than the thyroid enlargement with heterogeneous

echogenicity typical of Hashimoto’s thyroiditis. Fine-needle aspiration

biopsy is useful in the investigation of focal nodules. Other causes

of hypothyroidism are discussed below and in Table 383-1 but rarely

cause diagnostic confusion.

■ OTHER CAUSES OF HYPOTHYROIDISM

Iatrogenic hypothyroidism is a common cause of hypothyroidism and

can often be detected by screening before symptoms develop. In the

first 3–4 months after radioiodine treatment for Graves’ disease, transient hypothyroidism may occur due to reversible radiation damage.

Low-dose thyroxine treatment can be withdrawn if recovery occurs.

Because TSH levels are suppressed by hyperthyroidism, unbound T4

levels are a better measure of thyroid function than TSH in the months

following radioiodine treatment. Mild hypothyroidism after subtotal

thyroidectomy may also resolve after several months, as the gland

remnant is stimulated by increased TSH levels.

Iodine deficiency is responsible for endemic goiter and cretinism

but is an uncommon cause of adult hypothyroidism unless the iodine

intake is very low or there are complicating factors, such as the consumption of thiocyanates in cassava or selenium deficiency. Although

hypothyroidism due to iodine deficiency can be treated with thyroxine,

public health measures to improve iodine intake should be advocated

to eliminate this problem. Iodized salt or bread or a single bolus of oral

or intramuscular iodized oil have all been used successfully.

Paradoxically, chronic iodine excess can also induce goiter and

hypothyroidism. The intracellular events that account for this effect

are unclear, but individuals with autoimmune thyroiditis are especially

susceptible. Iodine excess is responsible for the hypothyroidism that

occurs in patients treated with amiodarone (Chap. 384). Other drugs,

particularly lithium, may also cause hypothyroidism. Transient hypothyroidism caused by thyroiditis is discussed below.

Secondary or central hypothyroidism is usually diagnosed in the

context of other anterior pituitary hormone deficiencies; isolated TSH

deficiency is very rare (Chap. 379). TSH levels may be low, normal,

or even slightly increased in secondary hypothyroidism; the latter is

due to secretion of immunoactive but bioinactive forms of TSH. The

diagnosis is confirmed by detecting a low unbound T4

 level. The goal

of treatment is to maintain T4

 levels in the upper half of the reference

interval because TSH levels cannot be used to monitor therapy.

TREATMENT

Hypothyroidism

CLINICAL HYPOTHYROIDISM

If there is no residual thyroid function, the daily replacement dose

of LT4 is usually 1.6 μg/kg body weight (typically 100–150 μg), ideally taken at least 30 min before breakfast. In many patients, however, lower doses suffice until residual thyroid tissue is destroyed. In

patients who develop hypothyroidism after the treatment of Graves’

disease, there is often underlying autonomous function, necessitating lower replacement doses (typically 75–125 μg/d).

Adult patients under 60 years old without evidence of heart

disease may be started on 50–100 μg of LT4 daily. The dose is

adjusted on the basis of TSH levels, with the goal of treatment

being a normal TSH, ideally in the lower half of the reference

range. TSH responses are gradual and should be measured about 2

months after instituting treatment or after any subsequent change

in LT4 dosage. The clinical effects of LT4 replacement are slow to

appear. Patients may not experience full relief from symptoms until

3–6 months after normal TSH levels are restored. Adjustment of

LT4 dosage is made in 12.5- or 25-μg increments if the TSH is high;

decrements of the same magnitude should be made if the TSH is

suppressed. Patients with a suppressed TSH of any cause, including

LT4 overtreatment, have an increased risk of atrial fibrillation and

reduced bone density.

About 10–15% of patients may have persistent symptoms despite

restoration of euthyroidism with LT4 for reasons that remain

unclear. Although desiccated animal thyroid preparations (thyroid

extract USP) are available, they are not recommended because the

Measure unbound T4

Mild Measure unbound T4

 hypothyroidism

Measure TSH

Elevated

Normal

Normal

Primary

 hypothyroidism

Low

Autoimmune

 hypothyroidism

Rule out other

 causes of

 hypothyroidism

Consider T4

treatment

TPOAb+ or

 symptomatic

TPOAb–, no

symptoms

Annual follow-up T4 treatment

TPOAb+ TPOAb–

Pituitary disease suspected?

No further

 tests

Normal

Yes

Rule out drug effects, sick

 euthyroid syndrome,

 then evaluate anterior

 pituitary function

No further

 tests

No

Low

FIGURE 383-2 Evaluation of hypothyroidism. TPOAb+

, thyroid peroxidase antibodies present; TPOAb–

, thyroid peroxidase antibodies not present; TSH, thyroid-stimulating

hormone.

2937Hypothyroidism CHAPTER 383

ratio of T3

 to T4

 is nonphysiologic. The use of LT4 combined with

liothyronine (triiodothyronine, T3

) has been investigated, but benefit has not been confirmed in prospective studies. There is no place

for liothyronine alone as long-term replacement, because the short

half-life necessitates three or four daily doses and is associated with

fluctuating T3

 levels.

Once full replacement is achieved and TSH levels are stable,

follow-up measurement of TSH is recommended at annual intervals. It is important to ensure ongoing adherence as patients do not

feel any symptomatic difference after missing a few doses of LT4,

and this sometimes leads to self-discontinuation.

In patients of normal body weight who are taking ≥200 μg of

LT4 per d, an elevated TSH level is often a sign of poor adherence

to treatment. This is also the likely explanation for fluctuating TSH

levels, despite a constant LT4 dosage. Such patients often have normal or high unbound T4

 levels, despite an elevated TSH, because

they remember to take medication for a few days before testing;

this is sufficient to normalize T4

, but not TSH levels. It is important

to consider variable adherence, because this pattern of thyroid

function tests is otherwise suggestive of disorders associated with

inappropriate TSH secretion (Chap. 382). Because T4

 has a long

half-life (7 days), patients who miss a dose can be advised to take

two doses of the skipped tablets at once. Other causes of increased

LT4 requirements must be excluded, particularly malabsorption

(e.g., celiac disease, small-bowel surgery, atrophic or Helicobacter

pylori–related gastritis), oral estrogen-containing medications or

selective estrogen receptor modulator therapy, ingestion with a

meal, and drugs that interfere with T4

 absorption or metabolism

such as bile acid sequestrants, ferrous sulfate, calcium supplements,

sevelamer, sucralfate, proton pump inhibitors, lovastatin, aluminum

hydroxide, rifampicin, amiodarone, carbamazepine, phenytoin, and

tyrosine kinase inhibitors.

SUBCLINICAL HYPOTHYROIDISM

By definition, subclinical hypothyroidism refers to biochemical evidence of thyroid hormone deficiency in patients who have few or no

apparent clinical features of hypothyroidism. There are no universally accepted recommendations for the management of subclinical

hypothyroidism, but LT4 is recommended if the patient is a woman

who wishes to conceive or is pregnant or when TSH levels are

>10 mIU/L. Most other patients can simply be monitored annually.

A trial of treatment may be considered when young or middle-aged

patients have symptoms of hypothyroidism or risk of heart disease.

It is important to confirm that any elevation of TSH is sustained

over a 3-month period before treatment is given. Treatment is

administered by starting with a low dose of LT4 (25–50 μg/d) with

the goal of normalizing TSH.

SPECIAL TREATMENT CONSIDERATIONS

Rarely, LT4 replacement is associated with pseudotumor cerebri

in children. Presentation appears to be idiosyncratic and occurs

months after treatment has begun.

Because maternal hypothyroidism may both adversely affect

fetal neural development and be associated with adverse gestational

outcomes (miscarriage, preterm delivery), thyroid function should

be monitored to preserve euthyroidism in women with a history or

high risk of hypothyroidism. Although epidemiologic studies have

demonstrated the association of miscarriage and preterm delivery

with the presence of thyroid autoantibodies detected either during or prior to gestation, randomized controlled trails evaluating

LT4 therapy in this population have not demonstrated benefit.

Because of the known increase in thyroid hormone requirements

during pregnancy in hypothyroid women, LT4 therapy should

be targeted to maintain a serum TSH in the normal range but

<2.5 mIU/L prior to conception. Subsequently, thyroid function

should be evaluated immediately after pregnancy is confirmed and

every 4 weeks during the first half of the pregnancy, with less frequent testing after 20 weeks’ gestation (every 6–8 weeks depending

on whether LT4 dose adjustment is ongoing). The increment of

LT4 dosage increase depends upon the etiology of hypothyroidism,

with athyreotic women requiring more (~45%) than those with

Hashimoto’s who may have some residual thyroid function. Women

should increase LT4 from once-daily dosing to nine doses per week

as soon as pregnancy is confirmed to anticipate this change. Thereafter dosage should be closely monitored with a goal TSH in the

lower half of the trimester-specific normative range, if available, or

<2.5 mIU/L which allows for reserve if additional LT4 dosage

increases are required as pregnancy progresses. However, it is

important to recognize that the normal TSH range in pregnancy

for the second and third trimesters is not significantly different

from the nonpregnancy reference range. However, serum TSH

decreases in the late first trimester, and if trimester-specific ranges

are not available, an appropriate range for 7–12 weeks’ gestation can

be approximated by decreasing the upper limit of the nonpregnant

reference range by 0.5 mIU/L (~4.0 mIU/L) and the lower limit by

0.4 mIU/L (~0.1 mIU/L).

After delivery, LT4 doses typically return to prepregnancy levels.

Pregnant women should be counseled to separate ingestion of prenatal vitamins and iron supplements from LT4.

Elderly patients may require 20% less thyroxine than younger

patients. In the elderly, especially patients with known coronary

artery disease, the starting dose of LT4 is 12.5–25 μg/d with similar

increments every 2–3 months until TSH is normalized. In some

patients, it may be impossible to achieve full replacement despite

optimal antianginal treatment. Emergency surgery is generally safe

in patients with untreated hypothyroidism, although routine surgery in a hypothyroid patient should be deferred until euthyroidism

is achieved.

Myxedema coma still has a 20–40% mortality rate, despite intensive treatment, and outcomes are independent of the T4

 and TSH

levels. Clinical manifestations include reduced level of consciousness, sometimes associated with seizures, as well as the other

features of hypothyroidism (Table 383-3). Hypothermia can reach

23°C (74°F). There may be a history of treated hypothyroidism with

poor compliance, or the patient may be previously undiagnosed.

Myxedema coma almost always occurs in the elderly and is usually precipitated by factors that impair respiration, such as drugs

(especially sedatives, anesthetics, and antidepressants), pneumonia, congestive heart failure, myocardial infarction, gastrointestinal

bleeding, or cerebrovascular accidents. Sepsis should also be suspected. Exposure to cold may also be a risk factor. Hypoventilation,

leading to hypoxia and hypercapnia, plays a major role in pathogenesis; hypoglycemia and dilutional hyponatremia also contribute to

the development of myxedema coma.

LT4 can initially be administered as a single IV bolus of

200–400 μg, which serves as a loading dose, followed by a daily

oral dose of 1.6 μg/kg per d, reduced by 25% if administered IV.

If suitable IV preparation is not available, the same initial dose of

LT4 can be given by nasogastric tube (although absorption may be

impaired in myxedema). Because T4 → T3

 conversion is impaired

in myxedema coma, there is a rationale for adding liothyronine (T3

)

intravenously or via nasogastric tube to LT4 treatment, although

excess liothyronine has the potential to provoke arrhythmias. An

initial loading dose of 5–20 μg liothyronine should be followed by

2.5–10 μg every 8 h, with lower doses chosen for smaller or older

patients and those at cardiovascular risk.

Supportive therapy should be provided to correct any associated

metabolic disturbances. External warming is indicated only if the

temperature is <30°C, as it can result in cardiovascular collapse

(Chap. 464). Space blankets should be used to prevent further

heat loss. Parenteral hydrocortisone (50 mg every 6 h) should be

administered because there is impaired adrenal reserve in profound hypothyroidism. Any precipitating factors should be treated,

including the early use of broad-spectrum antibiotics, pending the

exclusion of infection. Ventilatory support with regular blood gas

analysis is usually needed during the first 48 h. Hypertonic saline

or IV glucose may be needed if there is severe hyponatremia or

hypoglycemia; hypotonic IV fluids should be avoided because they

2938 PART 12 Endocrinology and Metabolism

may exacerbate water retention secondary to reduced renal perfusion and inappropriate vasopressin secretion. The metabolism of

most medications is impaired, and sedatives should be avoided if

possible or used in reduced doses. Medication blood levels should

be monitored, when available, to guide dosage.

■ FURTHER READING

Alexander EK et al: 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during

pregnancy and postpartum. Thyroid 27:315, 2017.

Biondi B et al: Subclinical hypothyroidism: A review. JAMA 322:153,

2019.

Chaker L et al: Hypothyroidism. Lancet 390:1550, 2017.

Ettleson MD et al: Individualized therapy for hypothyroidism: Is T4

enough for everyone? J Clin Endocrinol Metab 105:e3090, 2020.

Jonklaas J et al: Guidelines for the treatment of hypothyroidism: Prepared by the American Thyroid Association Task Force on thyroid

hormone replacement. Thyroid 24:1670, 2014.

Wassner AJ: Congenital hypothyroidism. Clin Perinatol 45:1, 2018.

THYROTOXICOSIS

Thyrotoxicosis is defined as the state of thyroid hormone excess and is

not synonymous with hyperthyroidism, which is the result of excessive

thyroid function. However, the major etiologies of thyrotoxicosis are

hyperthyroidism caused by Graves’ disease, toxic multinodular goiter

(MNG), and toxic adenomas. Other causes are listed in Table 384-1.

■ GRAVES’ DISEASE

Epidemiology Graves’ disease accounts for 60–80% of thyrotoxicosis. The prevalence varies among populations, reflecting genetic

factors and iodine intake (high iodine intake is associated with an

increased prevalence of Graves’ disease). Graves’ disease occurs in up

to 2% of women but is one-tenth as frequent in men. The disorder

rarely begins before adolescence and typically occurs between 20 and

50 years of age; it also occurs in the elderly.

Pathogenesis As in autoimmune hypothyroidism, a combination

of environmental and genetic factors, including polymorphisms in

HLA-DR, the immunoregulatory genes CTLA-4, CD25, PTPN22,

FCRL3, and CD226, as well as the gene encoding the thyroid-stimulating hormone (TSH) receptor (TSH-R), contributes to Graves’

disease susceptibility. The concordance for Graves’ disease in monozygotic twins is 20–30%, compared to <5% in dizygotic twins. Indirect

evidence suggests that stress is an important environmental factor,

presumably operating through neuroendocrine effects on the immune

system. Smoking is a minor risk factor for Graves’ disease and a major

risk factor for the development of ophthalmopathy. Sudden increases

in iodine intake may precipitate Graves’ disease, and there is a threefold

increase in the occurrence of Graves’ disease in the postpartum period.

Graves’ disease may occur during the immune reconstitution phase

after highly active antiretroviral therapy (HAART) or alemtuzumab

treatment and following treatment with immune checkpoint inhibitors

(e.g., nivolumab, pembrolizumab).

384 Hyperthyroidism and

Other Causes of

Thyrotoxicosis

J. Larry Jameson, Susan J. Mandel,

Anthony P. Weetman

TABLE 384-1 Causes of Thyrotoxicosis

Primary Hyperthyroidism

Graves’ disease

Toxic multinodular goiter

Toxic adenoma

Functioning thyroid carcinoma metastases

Activating mutation of the TSH receptor

Activating mutation of GS

α (McCune-Albright syndrome)

Struma ovarii

Drugs: iodine excess (Jod-Basedow phenomenon)

Thyrotoxicosis without Hyperthyroidism

Subacute thyroiditis

Silent thyroiditis

Other causes of thyroid destruction: amiodarone, radiation, infarction of

adenoma

Ingestion of excess thyroid hormone (thyrotoxicosis factitia) or thyroid tissue

Secondary Hyperthyroidism

TSH-secreting pituitary adenoma

Thyroid hormone resistance syndrome: occasional patients may have features of

thyrotoxicosis

Chorionic gonadotropin-secreting tumorsa

Gestational thyrotoxicosisa

a

Circulating TSH levels are low in these forms of secondary hyperthyroidism.

Abbreviation: TSH, thyroid-stimulating hormone.

The hyperthyroidism of Graves’ disease is caused by thyroidstimulating immunoglobulins (TSIs) that are synthesized by lymphocytes in the thyroid gland as well as in bone marrow and lymph nodes.

Such antibodies can be detected by bioassays or by using the more

widely available immunoassays (TSH receptor antibody [TRAb]) that

measure whether the patient’s serum contains an antibody that can

displace either labeled TSH or a monoclonal TSH receptor antibody

from the TSH receptor. The presence of TRAb in a patient with thyrotoxicosis implies the existence of TSI, and these assays are useful in

monitoring pregnant Graves’ patients in whom high levels of TSI can

cross the placenta and cause neonatal thyrotoxicosis. Other thyroid

autoimmune responses, similar to those in autoimmune hypothyroidism (see above), occur concurrently in patients with Graves’ disease. In

particular, thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies occur in up to 80% of cases. Because the coexisting thyroiditis can

also affect thyroid function, there is no direct correlation between the

level of TSI and thyroid hormone levels in Graves’ disease.

Cytokines appear to play a major role in thyroid-associated ophthalmopathy. There is infiltration of the extraocular muscles by activated

T cells; the release of cytokines such as interferon γ (IFN-γ), tumor

necrosis factor (TNF), and interleukin 1 (IL-1) results in fibroblast

activation and increased synthesis of glycosaminoglycans that trap

water, thereby leading to characteristic muscle swelling. Late in the

disease, there is irreversible fibrosis of the muscles. Increased fat is an

additional cause of retrobulbar tissue expansion. The increase in intraorbital pressure can lead to proptosis, diplopia, and optic neuropathy.

Although the pathogenesis of thyroid-associated ophthalmopathy is

incompletely understood, the TSH-R is a thyroid autoantigen and is

expressed in orbital tissues. In addition, aberrant signaling via insulinlike growth factor 1 receptors (IGF-1R) on orbital fibroblasts has also

been implicated. These mechanisms are the basis for new monoclonal

antibody treatments (e.g., teprotumumab) that reduce the levels of

TSH-R/IGF-1R complexes and attenuate signaling.

Clinical Manifestations Signs and symptoms include features

that are common to any cause of thyrotoxicosis (Table 384-2) as well

as those specific for Graves’ disease. The clinical presentation depends

on the severity of thyrotoxicosis, the duration of disease, individual

susceptibility to excess thyroid hormone, and the patient’s age. In the

2939Hyperthyroidism and Other Causes of Thyrotoxicosis CHAPTER 384

of Graves’ ophthalmopathy occurs within the year before or after

the diagnosis of thyrotoxicosis in 75% of patients but can sometimes

precede or follow thyrotoxicosis by several years, accounting for some

cases of euthyroid ophthalmopathy.

About one-third of patients with Graves’ disease have clinical evidence of ophthalmopathy. However, the enlarged extraocular muscles

typical of the disease, and other subtle features, can be detected in most

patients when investigated by ultrasound or computed tomography

(CT) imaging of the orbits. Unilateral signs are found in up to 10% of

ophthalmopathy patients. The earliest manifestations of ophthalmopathy are usually a sensation of grittiness, eye discomfort, and excess

tearing. About one-third of patients have proptosis, best detected by

visualization of the sclera between the lower border of the iris and the

lower eyelid, with the eyes in the primary position. Proptosis can be

measured using an exophthalmometer. In severe cases, proptosis may

cause corneal exposure and damage, especially if the lids fail to close

during sleep. Periorbital edema, scleral injection, and chemosis are also

frequent. In 5–10% of patients, the muscle swelling is so severe that

diplopia results, typically, but not exclusively, when the patient looks

up and laterally. The most serious manifestation is compression of the

optic nerve at the apex of the orbit, leading to papilledema; peripheral

field defects; and, if left untreated, permanent loss of vision.

The “NO SPECS” scoring system to evaluate ophthalmopathy is an

acronym derived from the following changes:

0 = No signs or symptoms

1 = Only signs (lid retraction or lag), no symptoms

2 = Soft tissue involvement (periorbital edema)

3 = Proptosis (>22 mm)

4 = Extraocular muscle involvement (diplopia)

5 = Corneal involvement

6 = Sight loss

Although useful as a mnemonic, the NO SPECS scheme is inadequate to describe the eye disease fully, and patients do not necessarily

progress from one class to another; alternative scoring systems (e.g.,

the EUGOGO system developed by the European Group on Graves’

Orbitopathy) that assess disease activity are preferable for monitoring

and treatment purposes. When Graves’ eye disease is active and severe,

referral to an ophthalmologist is indicated and objective measurements

are needed, such as lid-fissure width; corneal staining with fluorescein;

TABLE 384-2 Signs and Symptoms of Thyrotoxicosis

(Descending Order of Frequency)

SYMPTOMS SIGNSa

Hyperactivity, irritability, dysphoria

Heat intolerance and sweating

Palpitations

Fatigue and weakness

Weight loss with increased appetite

Diarrhea

Polyuria

Oligomenorrhea, loss of libido

Tachycardia; atrial fibrillation in the

elderly

Tremor

Goiter

Warm, moist skin

Muscle weakness, proximal myopathy

Lid retraction or lag

Gynecomastia

a

Excludes the signs of ophthalmopathy and dermopathy specific for Graves’

disease.

elderly, features of thyrotoxicosis may be subtle or masked, and patients

may present mainly with fatigue and weight loss, a condition known as

apathetic thyrotoxicosis.

Thyrotoxicosis may cause unexplained weight loss, despite an

enhanced appetite, due to the increased metabolic rate. Weight gain

occurs in 5% of patients, however, because of increased food intake.

Other prominent features include hyperactivity, nervousness, and

irritability, ultimately leading to a sense of easy fatigability in some

patients. Insomnia and impaired concentration are common; apathetic

thyrotoxicosis may be mistaken for depression in the elderly. Fine

tremor is a frequent finding, best elicited by having patients stretch

out their fingers while feeling the fingertips with the palm. Common

neurologic manifestations include hyperreflexia, muscle wasting, and

proximal myopathy without fasciculation. Chorea is rare. Thyrotoxicosis is sometimes associated with a form of hypokalemic periodic

paralysis; this disorder is particularly common in Asian males with

thyrotoxicosis, but it occurs in other ethnic groups as well.

The most common cardiovascular manifestation is sinus tachycardia,

often associated with palpitations, occasionally caused by supraventricular tachycardia. The high cardiac output produces a bounding pulse,

widened pulse pressure, and an aortic systolic murmur and can lead to

worsening of angina or heart failure in the elderly or those with preexisting heart disease. Atrial fibrillation is more common in patients

>50 years of age. Treatment of the thyrotoxic state alone converts atrial

fibrillation to normal sinus rhythm in about half of patients, suggesting

the existence of an underlying cardiac problem in the remainder.

The skin is usually warm and moist, and the patient may complain

of sweating and heat intolerance, particularly during warm weather.

Palmar erythema, onycholysis, and, less commonly, pruritus, urticaria,

and diffuse hyperpigmentation may be evident. Hair texture may

become fine, and a diffuse alopecia occurs in up to 40% of patients,

persisting for months after restoration of euthyroidism. Gastrointestinal transit time is decreased, leading to increased stool frequency, often

with diarrhea and occasionally mild steatorrhea. Women frequently

experience oligomenorrhea or amenorrhea; in men, there may be

impaired sexual function and, rarely, gynecomastia. The direct effect

of thyroid hormones on bone resorption leads to osteopenia in longstanding thyrotoxicosis; mild hypercalcemia occurs in up to 20% of

patients, but hypercalciuria is more common. There is a small increase

in fracture rate in patients with a previous history of thyrotoxicosis.

In Graves’ disease, the thyroid is usually diffusely enlarged to two to

three times its normal size. The consistency is firm, but not nodular.

There may be a thrill or bruit, best detected at the inferolateral margins

of the thyroid lobes, due to the increased vascularity of the gland and

the hyperdynamic circulation.

Lid retraction, causing a staring appearance, can occur in any form

of thyrotoxicosis and is the result of sympathetic overactivity. However, Graves’ disease is associated with specific eye signs that comprise

Graves’ ophthalmopathy (Fig. 384-1A). This condition is also called

thyroid-associated ophthalmopathy, because it occurs in the absence

of hyperthyroidism in 10% of patients. Most of these individuals

have autoimmune hypothyroidism or thyroid antibodies. The onset

A

C

B

FIGURE 384-1 Features of Graves’ disease. A. Ophthalmopathy in Graves’ disease;

lid retraction, periorbital edema, conjunctival injection, and proptosis are marked.

B. Thyroid dermopathy over the lateral aspects of the shins. C. Thyroid acropachy.