Diffuse Toxic Goiter (Graves’ Disease) Although against it.

Polymorphisms of the cytotoxic T-

originally lymphocyte antigen
described by the Welsh physician Caleb Parry in a 4 (CTLA-4) gene also have been associated with
posthumous Graves’
article in 1825, this disorder is known as Graves’ disease development.3 Once initiated, the process
disease after causes sensitized
Robert Graves, an Irish physician who described T-helper lymphocytes to stimulate B
three patients lymphocytes, which
in 1835. Graves’ disease is by far the most produce antibodies directed against the thyroid
common cause hormone receptor.
of hyperthyroidism in North America, accounting TSIs or antibodies that stimulate the TSH-R, as
for 60% to well as
80% of cases. It is an autoimmune disease with a TSH-binding inhibiting immunoglobulins or
strong familial antibodies, have
predisposition, female preponderance (5:1), and been described. The thyroid-stimulating
peak incidence antibodies stimulate
between the ages of 40 and 60 years. Graves’ the thyrocytes to grow and synthesize excess
disease thyroid hormone,
is characterized by thyrotoxicosis, diffuse goiter, which is a hallmark of Graves’ disease. Graves’
and extrathyroidal disease also
conditions including ophthalmopathy, is associated with other autoimmune conditions
dermopathy such as type
(pretibial myxedema), thyroid acropachy, 1 diabetes mellitus, Addison’s disease, pernicious
gynecomastia, and anemia, and
other manifestations. myasthenia gravis.
Etiology, Pathogenesis, and Pathology. The exact Macroscopically, the thyroid gland in patients
etiology of with Graves’
the initiation of the autoimmune process in disease is diffusely and smoothly enlarged, with a
Graves’ disease is concomitant
not known. However, conditions such as the increase in vascularity. Microscopically, the gland
postpartum state, is hyperplastic,
iodine excess, lithium therapy, and bacterial and and the epithelium is columnar with minimal
viral infections colloid present.
have been suggested as possible triggers. The nuclei exhibit mitosis, and papillary
Genetic factors also projections of
play a role, as haplotyping studies indicate that hyperplastic epithelium are common. There may
Graves’ disease be aggregates
is associated with certain human leukocyte of lymphoid tissue, and vascularity is markedly
antigen (HLA) haplotypes, increased.
including HLA-B8, HLA-DR3, and HLADQA1*0501 Clinical Features. The clinical manifestations of
in Caucasian patients, whereas HLA-DRB1*0701 is Graves’ disease
protective
can be divided into those related to
hyperthyroidism and
those specific to Graves’ disease. Hyperthyroid
symptoms
include heat intolerance, increased sweating and
thirst, and
weight loss despite adequate caloric intake.
Symptoms of
increased adrenergic stimulation include
palpitations, nervousness,
fatigue, emotional lability, hyperkinesis, and
tremors.
The most common GI symptoms include
increased frequency
of bowel movements and diarrhea. Female
patients often
develop amenorrhea, decreased fertility, and an
increased
incidence of miscarriages. Children experience
rapid growth
with early bone maturation, whereas older
patients may present
with cardiovascular complications such as atrial
fibrillation
and congestive heart failure.
On physical examination, weight loss and facial
flushing
may be evident. The skin is warm and moist, and
African
American patients often note darkening of their
skin. Tachycardia
or atrial fibrillation is present, with cutaneous
vasodilation
leading to a widening of the pulse pressure and a
rapid falloff
in the transmitted pulse wave (collapsing pulse).
A fine tremor,
muscle wasting, and proximal muscle group
weakness with
hyperactive tendon reflexes often are present.
Approximately 50% of patients with Graves’
disease also
develop clinically evident ophthalmopathy, and
dermopathy
occurs in 1% to 2% of patients. It is characterized
by deposition
of glycosaminoglycans, leading to thickened skin
in the pretibial
region and dorsum of the foot (Fig. 38-12). Eye
symptoms
include lid lag (von Graefe’s sign), spasm of the
upper eyelid
revealing the sclera above the corneoscleral
limbus (Dalrymple’s
sign), and a prominent stare, due to
catecholamine excess. True
infiltrative eye disease results in periorbital
edema, conjunctival
swelling and congestion (chemosis), proptosis,
limitation of
upward and lateral gaze (from involvement of the
inferior and
medial rectus muscles, respectively), keratitis, and
even blindness
due to optic nerve involvement. The etiology of
Graves’
ophthalmopathy is not completely known;
however, orbital
fibroblasts and muscles are thought to share a
common antigen,
the TSH-R. Ophthalmopathy is thought to result
from inflammation
caused by cytokines released from sensitized
killer
T lymphocytes and cytotoxic antibodies.
Gynecomastia is common
in young men. Rare bony involvement leads to
subperiosteal
bone formation and swelling in the metacarpals
(thyroid
acropachy). Onycholysis, or separation of
fingernails from their
beds, is a commonly observed finding. On
physical examination,
the thyroid usually is diffusely and symmetrically of the orbits are useful in evaluating Graves’
enlarged, ophthalmopathy.
as evidenced by an enlarged pyramidal lobe. Treatment. Graves’ disease may be treated by any
There may be an of three treatment
overlying bruit or thrill over the thyroid gland modalities: antithyroid drugs, thyroid ablation
and a loud venous with radioactive
hum in the supraclavicular space. 131 I, and thyroidectomy. The choice of treatment
Diagnostic Tests. The diagnosis of depends
hyperthyroidism is made on several factors, as discussed in the following
by a suppressed TSH with or without an elevated sections.
free T4 or Antithyroid Drugs. Antithyroid medications
T3 level. If eye signs are present, other tests are generally are administered
generally not in preparation for RAI ablation or surgery. The
needed. However, in the absence of eye findings, drugs
an 123I uptake commonly used are propylthiouracil (PTU, 100 to
and scan should be performed. An elevated 300 mg three
uptake, with a times daily) and methimazole (10 to 30 mg three
diffusely enlarged gland, confirms the diagnosis times daily,
of Graves’ then once daily). Methimazole has a longer half-
disease and helps to differentiate it from other life and can be
causes of hyperthyroidism. dosed once daily. Both drugs reduce thyroid
Technetium scintigraphy (using pertechnetate, hormone production
which is trapped by the thyroid, but not by inhibiting the organic binding of iodine and
organified) can also the coupling
be used to determine etiology. While technetium of iodotyrosines (mediated by TPO). In addition,
scans results PTU
in low range of normal uptake and high also inhibits the peripheral conversion of T4 to T3,
background activity, total-body radiation making it
exposure is less than that of 123 I scans. If useful for the treatment of thyroid storm. Both
free T4 levels are normal, free T3 levels should be drugs can cross
determined, as the placenta, inhibiting fetal thyroid function, and
they often are elevated in early Graves’ disease or are excreted
toxic nodules in breast milk, although PTU has a lower risk of
(T3 toxicosis). Anti-Tg and anti-TPO antibodies are transplacental
elevated in transfer. Methimazole also has been associated
up to 75% of patients but are not specific. with congenital
Elevated TSH-R or aplasia; therefore, PTU is preferred in pregnant
thyroid-stimulating antibodies (TSAb) are and breastfeeding
diagnostic of Graves’ women. Side effects of treatment include
disease and are increased in about 90% of reversible
patients. MRI scans granulocytopenia, skin rashes, fever, peripheral
neuritis, polyarteritis,
vasculitis, hepatitis, and, rarely, agranulocytosis
and
aplastic anemia. Patients should be monitored for
these possible
complications and should always be warned to
stop PTU
or methimazole immediately and seek medical
advice should
they develop a sore throat or fever. Treatment of
agranulocytosis
involves admission to the hospital,
discontinuation of the
drug, and broad-spectrum antibiotic therapy.
Surgery should be
postponed until the granulocyte count reaches
1000 cells/mm3.
The dose of antithyroid medication is titrated as
needed
in accordance with TSH and T4 levels. Most
patients have
improved symptoms in 2 weeks and become
euthyroid in about
6 weeks. Some physicians use the block-replace
regimen, by
adding T4 (0.05 to 0.10 mg) to prevent
hypothyroidism and
suppress TSH secretion, because some, but not
all, studies suggest
that this reduces recurrence rates. The length of
therapy is
debated. Treatment with antithyroid medications
is associated
with a high relapse rate when these drugs are
discontinued, with
40% to 80% of patients developing recurrent
disease after a 1- to
2-year course. Patients with small glands are less
likely to recur
so that treatment for curative intent is reserved
for patients with
(a) small, nontoxic goiters less than 40 g; (b)
mildly elevated
thyroid hormone levels; (c) negative or low or
titers of thyroid
hormone receptor antibodies; and (d) rapid
decrease in gland
size with antithyroid medications. The
catecholamine response
of thyrotoxicosis can be alleviated by
administering -blocking
agents. -Blockade should be considered in all
patients with
symptomatic thyrotoxicosis and is recommended
for elderly
patients, those with coexistent cardiac disease,
and patients
with resting heart rates >90 bpm. These drugs
have the added
effect of decreasing the peripheral conversion of
T4 to T3. Propranolol
is the most commonly prescribed medication in
doses
of about 20 to 40 mg four times daily. Higher
doses are sometimes
required due to increased clearance of the
medication.
Caution should be exercised in patients with
asthma. Calcium
channel blockers are useful for rate control in
patients in whom
-blockers are contraindicated.
Radioactive Iodine Therapy (131I). RAI forms the
mainstay of
Graves’ disease treatment in North America. The
major advantages
of this treatment are the avoidance of a surgical
procedure
and its concomitant risks, reduced overall
treatment costs, and
ease of treatment. Antithyroid drugs are given
until the patient is euthyroid and then
discontinued to maximize drug uptake.
The 131I dose is calculated after a preliminary scan
and usually
consists of 8 to 12 mCi administered orally. After
standard treatment
with RAI, most patients become euthyroid within
2 months.
However, only about 50% of patients treated with
RAI are
euthyroid 6 months after treatment, and the
remaining are still
hyperthyroid or already hypothyroid.4 After 1
year, about 2.5%
of patients develop hypothyroidism each year.
RAI also has been
documented to lead to progression of Graves’
ophthalmopathy
(33% after RAI compared to 16% after surgery),
and ophthalmopathy
is more common in smokers. Although there is
no evidence
of long-term problems with infertility, and overall
cancer
incidence rates are unchanged, there is a small
increased risk of
nodular goiter, thyroid cancer,5 and
hyperparathyroidism (HPT)6
in patients who have been treated with RAI.
Patients treated with
RAI have an unexplained increase in their overall
and cardiovascular
mortality rates when compared to the general
population.
RAI therapy is therefore most often used in older
patients
with small or moderate-sized goiters, those who
have relapsed
after medical or surgical therapy, and those in
whom antithyroid
drugs or surgery are contraindicated. Absolute
contraindications
to RAI include women who are pregnant (or
planning pregnancy
within 6 months of treatment) or breastfeeding.
Relative contraindications
include young patients (i.e., especially children
and
adolescents), those with thyroid nodules, and
those with ophthalmopathy.
Lack of access to a high-volume thyroid surgeon
is also a consideration. The higher the initial dose
of 131I, the
earlier the onset and the higher the incidence of
hypothyroidism.
Surgical Treatment. In North America, surgery is
recommended
when RAI is contraindicated as in patients who (a)
have confirmed
cancer or suspicious thyroid nodules, (b) are
young, (c)
desire to conceive soon (<6 months) after
treatment, (d) have
had severe reactions to antithyroid medications,
(e) have large
goiters (>80 g) causing compressive symptoms,
and (f) are
reluctant to undergo RAI therapy. Relative
indications for thyroidectomy
include patients, particularly smokers, with
moderate
to severe Graves’ ophthalmopathy, those desiring
rapid
control of hyperthyroidism with a chance of
being euthyroid,
and those demonstrating poor compliance to
antithyroid medications.
Pregnancy is also a relative contraindication, and
surgery
should be used only when rapid control is
needed and antithyroid
medications cannot be used. Surgery is best
performed in
the second trimester. The goal of thyroidectomy
for Graves’
disease should be the complete and permanent
control of the
disease with minimal morbidity. Patients should
be rendered
euthyroid before operation with antithyroid
drugs that should be
continued up to the day of surgery. Lugol’s
iodide solution or
saturated potassium iodide generally is
administered beginning
7 to 10 days preoperatively (three drops twice
daily) to reduce
vascularity of the gland and decrease the risk of
precipitating
thyroid storm. The major action of iodine in this
situation is to
inhibit release of thyroid hormone. If it is not
possible to render
the patient euthyroid prior to surgery (if the
surgery is urgent
or the patient is allergic to antithyroid
medications), the patient
can be prepared with -blockade and potassium
iodide alone.
Steroids can be a useful adjunct in this situation.
The extent of thyroidectomy to be performed
used to be
determined by the desired outcome (risk of
recurrence vs.
euthyroidism) and surgeon experience. In
patients with coexistent
thyroid cancer and those who refused RAI
therapy or had
severe ophthalmopathy or life-threatening
reactions to antithyroid
medications (vasculitis, agranulocytosis, or liver
failure),
total or near-total thyroidectomy was
recommended. Ophthalmopathy
has been demonstrated to stabilize or improve in
most
patients after total thyroidectomy, presumably
from removal of
the antigenic stimulus. A subtotal thyroidectomy,
leaving a 4-
to 7-g remnant, was recommended for all
remaining patients.
During subtotal thyroidectomy, remnant tissue
may be left on
each side (bilateral subtotal thyroidectomy), or a
total lobectomy
can be performed on one side with a subtotal
thyroidectomy
on the other side (Hartley-Dunhill procedure).
Results
were similar with either procedure,7 but the latter
procedure
was theoretically associated with fewer
complications and
requires re-entering only one side of the neck
should recurrence
require reoperation. Most studies, however, show
no difference
in the rates of complications with either
approach, although
patients undergoing a total resection had higher
rates of temporary
hypoparathyroidism. However, patients treated
with subtotal
thyroidectomy are prone to recurrence, the rates
of which
are dependent on remnant size. Based on the
current evidence,
recently published guidelines from the American
Thyroid
Association (ATA) and the American Association
of Clinical
Endocrinologists (AACE) recommend total or
near-total thyroidectomy
as the procedure of choice for the surgical
management
of Graves’ disease.8 Recurrent thyrotoxicosis
usually
is managed by radioiodine treatment. Toxic complication rates with repeat surgery. Care must
Multinodular Goiter Toxic multinodular goiters be taken in
usually identifying the RLN, which may be found laterally
occur in older individuals, who often have a prior on the thyroid
history (rather than posterior) or stretched anteriorly
of a nontoxic multinodular goiter. Over several over a nodule.
years, enough RAI therapy is reserved for elderly patients who
thyroid nodules become autonomous to cause represent very
hyperthyroidism. poor operative risks, provided there is no airway
The presentation often is insidious in that compression
hyperthyroidism may from the goiter and thyroid cancer is not a
only become apparent when patients are placed concern. However,
on low doses of because uptake is less than in Graves’ disease,
thyroid hormone suppression for the goiter. larger doses of
Some patients have RAI often are needed to treat the
T3 toxicosis, whereas others may present only hyperthyroidism. Furthermore,
with atrial fibrillation RAI-induced thyroiditis has the potential to cause
or congestive heart failure. Hyperthyroidism also swelling and
can be acute airway compromise and leaves the goiter
precipitated by iodide-containing drugs such as intact, with the
contrast media possibility of recurrent hyperthyroidism.
and the antiarrhythmic agent amiodarone (Jod-
Basedow hyperthyroidism).
Symptoms and signs of hyperthyroidism are
similar
to Graves’ disease, but extrathyroidal
manifestations are absent.
Diagnostic Studies. Blood tests are similar to
Graves’ disease
with a suppressed TSH level and elevated free T4
or T3 levels.
RAI uptake also is increased, showing multiple
nodules with
increased uptake and suppression of the
remaining gland. Treatment. Hyperthyroidism
must be adequately controlled.
Both RAI and surgical resection may be used for
treatment.
When surgery is performed, near-total or total
thyroidectomy is
recommended to avoid recurrence and the
consequent increased