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M. Sakr
Entrapment of the RLN, invasion of thyroid capsule, or spread into adjacent tissues can lead to
local pain in the neck or radiating to the jaw and
ear. Dysphagia, dysphonia, dyspnea, hoarseness,
or hemoptysis may all reect esophageal or tracheal involvement by a thyroid cancer. Nodules
associated with hyperthyroidism are usually
benign functioning adenomas, whereas a nodule
in a patient with hypothyroidism is often caused
by autoimmune thyroiditis.
A family history of thyroid disease, benign or
malignant, can be found in a signicant number
of patients with thyroid cancer and may help
determine which patients have an increased risk.
Fowler etal. found that a family history of thyroid disease was present in 41% of their patients
with thyroid nodules [145]. However, family history of thyroid disease also increases the risk of
autoimmune thyroiditis.
12.4.4.2 Physical Examination (Risk
Factors)
Careful examination of the neck reveals the
nature and location of the mass (Fig.12.23), tenderness, xation of the thyroid to surrounding tissue, and the presence of other cervical masses,
which can be metastases or lymphadenopathy.
Physical characteristics of a thyroid nodule
are poor predictors of malignancy; both malignant and benign STNs can be soft or rm, smooth
or irregular upon examination. In contrast, a
recent study by Uyar et al. indicated that
characteristics such as hard consistency, irregular
borders, micro-calcication, increased vascularity, and cervical lymphadenopathy are malignancy risk factors for STNs [146]. Hard nodules
may be due to calcications in benign adenomas,
however.
A nodule, xed to surrounding tissues such as
the trachea or strap muscles is most likely malignant. However, xation of the thyroid can also
occur with severe chronic thyroiditis. Vocal cord
paralysis strongly suggests an invasive cancer,
but again, benign conditions such as Hashimoto’s
thyroiditis or MNG can, rarely, affect vocal cord
function. The most signicant physical ndings
suggestive of malignancy are the unilateral, rm/
hard, non-tender, discrete LNs resulting from
metastatic thyroid cancer, most commonly papillary thyroid carcinoma (PTC) (Table12.12).
12.4.5 Laboratory Tests
12.4.5.1 Thyroid Function Tests
Thyroid function tests should be obtained as part
of the initial evaluation of STN; ndings are usually normal in patients with thyroid cancer. An
elevated TSH level may indicate agenesis of a
thyroid lobe or thyroiditis. A suppressed TSH
level is suggestive of benign pathology such as an
autonomously functioning adenoma or Hashi-
Fig. 12.23 (a) A 27-year-old lady with a midline solitary thyroid nodule (arrow). (b) A 32-year-old lady with a midline
solitary thyroid nodule (arrow)
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12 Benign Thyroid Disease
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Table 12.12
of thyroid cancer
History-taking Physical examination
– Family history
– Gender
– Age <20 or >60years
– History of head and neck
– Rapidity of growth
– Associated symptoms
– Growth on thyroid
Important clinical factors in the suspicion
– Solitary versus
multiple nodules
– A hard nodule
– Fixation to
irradiation
(pain, dysphagia,
dysphonia, dyspnea)
hormone suppression
adjacent structures
– Diameter 4cm or
more
– Cervical lympha-
denopathy
moto’s thyroiditis [147]. A strong association
exists between Hashimoto thyroiditis and primary thyroid lymphoma. Levels of free thyroxine
(T4), triiodothyronine (T3), and TSH are used to
direct medical therapy.
12.4.5.2 Serum Thyroglobulin (Tg)
Elevated serum Tg, thyroglobulin-antibody (TgAb), and TSH levels may be associated with a
higher risk of malignancy.
12.4.5.3 Serum Calcitonin
A series of prospective, non-randomized studies [148–152] suggested that the use of routine
serum calcitonin for screening may detect
C-cell hyperplasia and MTC at an earlier stage,
and overall survival consequently may be
improved.
The American Thyroid Association (ATA)
could not recommend for or against the routine
measurement of serum calcitonin as a screening
test in patients with thyroid nodules [153]. There
is emerging evidence that a calcitonin measurement from a thyroid nodule FNA washout may be
helpful in the preoperative evaluation of patients
with a modestly elevated basal serum calcitonin
(20–100 pg/mL) [154].
12.4.5.4 Complete Blood Count (CBC)
andSerum Calcium (Ca) Levels
If a thyroid “abscess” is suspected, CBC may
be obtained. Serum Ca levels should be monitored immediately postoperatively to assess
parathyroid function and the need for
supplementation.
12.4.6 Imaging Studies
12.4.6.1 Ultrasonography (US)
Ultrasonography is considered the “imaging
study of choice” for thyroid nodules; however,
alone, the sensitivity, specicity, and positive
predictive value of US is quite low. US is a safe
and effective method of determining the size and
the presence of solid or cystic components within
a thyroid nodule (cystic, solid, or mixed) [155].
High-resolution US can determine non-palpable
nodules as small as 1mm. It can also identify the
presence of other nodules that indicate MNG,
and central or lateral neck lymphadenopathy predictive of malignant involvement, as well as provide accurate measurements of nodule diameter
allowing serial scans and better assessment of
growth. Additionally, it allows characterization
of nodules by sonographic features that suggest
malignancy [18], which is helpful when planning
FNAB (Table 12.13) [156–158]. Ultrasoundguided FNA is recommended for cervical LNs
that are sonographically suspicious for thyroid
cancer.
12.4.6.2 Doppler Scan
Color ow patterns on Doppler scan are categorized as follows: (a) Type 1: no blood ow, (b)
Type 2: perinodular ow, and (c) Type 3: intranodular blood ow (peri-nodular vessels may or
may not be present). Although nonspecic,
benign nodules may have peripheral vascularization, whereas thyroid cancers may have internal
hypervascularity. However, type 3 vascularization can be found in both benign and malignant
nodules [99]. Completely avascular nodules are
more likely to be benign.
12.4.6.3 Ultrasound-Elastography
(Elasto-sonography)
The addition of US-elastography (elastosonography) in combination with high-resolution
US has signicantly improved the diagnostic
accuracy of US in STNs. A thyroid nodule with
rm or hard consistency is associated with an
increased risk of malignancy. The predictive
value of US-elastographic measurement seems to
be independent of nodule size [148, 149]. Cystic
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Table 12.13
Highly suggestive Moderately suggestive Minimally suggestive
– Extra- capsular extension
– Suspicious cervical LNs
– Taller than wider nodule
– Micro- calcication
– Irregular ill-dened margins
– Markedly hypoechoic
Ultrasound features of thyroid nodule suggestive of malignancy
– Elastography
– Texture (>50% solid)
– Increased intra-nodular vascularity.
– Absence of halo
– Hypoechoic
– Macro- calcication
– Isoechoic, hyperechoic
– Complex nodules
– Peripheral calcication
(Egg-shell)
– Spongyiform nodules
nodules and those with a calcied shell (by US)
are not suitable for US-elastographic evaluation.
Larger prospective studies are needed to establish
the diagnostic accuracy of this technique.
12.4.6.6 Positron Emission
Tomography (PET)
18F-2-uoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) and PET-CT are a
12.4.6.4 Radionuclide Imaging
(Thyroid Scintigraphy)
Radioisotopes of iodine (
99m
(
Tc) are based on the assumption that malig-
123
I) or technetium
nant thyroid tissue neither traps nor incorporates
iodine and therefore should appear nonfunctioning or “cold” on uptake scan. Normally
functioning nodules are “warm”, and hyperfunctioning nodules appear as “hot” on the scan. The
incidence of malignancy is higher in cold nodules
as compared with warm or hot nodules. Thyroid
scans have generally been replaced as a rst-line
test by FNAB [159].
nuclear medicine imaging test that uses a small
amount of radiolabeled glucose to identify cancer.
Since cancer cells are more metabolically active
than normal cells, they take up more of the radiolabeled glucose than normal cells and show up on
the FDG-PET scan, which may be combined with
CT scans (i.e., PET-CT) to accurately identify
where in the body a cancer may be located.
A recent meta-analysis conrmed that approx-
imately one in three (⁓35%) 18FDG-PET positive
thyroid nodules proved to be cancerous [162].
The role of PET in the preoperative evaluation of
follicular or indeterminate nodules remains
unclear due to problems with accuracy. Routine
12.4.6.5 Computed Tomography (CT)
andMagnetic Resonance
use of PET scans in the evaluation of STNs is not
recommended at the present time [163].
Imaging (MRI)
Indications for these imaging techniques include
(1) suspected involvement, either by invasion or
12.4.7 Biopsy (Cytology/Histology)
compression of the larynx, pharynx, trachea,
esophagus, or major blood vessels [160], (2)
extension into the mediastinum, (3) recurrent disease, (4) presence of cervical LNs, and (5)
hemoptysis indicating pulmonary metastasis.
Both, CT scan and MRI are relatively expensive and have a limited role in the initial evaluation of a STN as they have a limited ability in
distinguishing between benign and malignant
lesions. However, they are necessary in some
cases to determine the staging (in case of malignancy), and in planning surgery [161]. Unlike
contrast media used with CT, contrast media used
in MRI does not inuence thyroid function
(Gadolinium-enhanced MRI scan).
12.4.7.1 Fine Needle Aspiration
Cytology (FNAC): Free-Hand or
US-Guided
Fine needle aspiration biopsy (FNAB) is a simple
outpatient procedure with rare complications
such as hematoma or infection. It has become the
diagnostic procedure of choice of STNs as it has
been shown repeatedly to be a better predictor of
malignancy than other preoperative tests and has
substantially decreased the number of patients
requiring surgery for benign disease in adults
[164–166]. However, clinical suspicion of cancer
because of a history of ionizing radiation, a family history of thyroid cancer, or clinical features
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12 Benign Thyroid Disease
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of malignancy also should preclude the use of
FNAC in favor of “excisional biopsy”.
The use of US-guided FNA can improve the
diagnostic accuracy of palpation-guided FNA and
should be considered in a patient whose thyroid
nodule is difcult to palpate or in whom the initial
FNA was nondiagnostic [4]. Retrospective studies
have reported lower rates of both nondiagnostic
and false-negative cytology using US-guided
FNA compared to palpation-guided FNA [167,
168]. Still, however, interpretation of the aspirate
for denitive diagnosis may still not be possible.
In cases of follicular neoplasia, FNA may not be
able to distinguish malignant from benign disease, since the diagnosis of follicular carcinoma is
histological, by identication of capsular or vascular invasion. The same applies when dealing
with Hürthle cell neoplasms where pathology
reports may be suspicious for malignancy of
which nearly 20% will actually be malignant
Hürthle or follicular neoplasms [167, 169].
Table 12.14 Diagnostic FNA categories and recommended actions (BTA guidelines) [21]
Category Description Recommended action
Thy 1 Nondiagnostic, insufcient sample, or cyst
containing colloid or histiocytes only, in the
absence of epithelial cells
Thy 2 Benign, nonneoplastic, or cyst containing benign
epithelial cells
Thy 3 Follicular or Hurthle cell lesion/suspected folic,
or Hurthle tumor
Thy 4 Suspicious of malignancy MDT discussion—TT
Thy 5 Diagnostic of malignancy MDT discussion—TT
MDT multidisciplinary team; TT total thyroidectomy
Cytology results can be placed in ve diagnostic categories (Thy 1–Thy 5) as indicated by
the British Thyroid Association (BTA) Guidelines
[21]. This will help with subsequent management
as summarized in Table12.14. The probability of
a benign thyroid nodule being accurately diagnosed as benign from a single FNAC is 90%.
However, the accuracy of diagnosis increases signicantly to 98% if two separate aspirates are
performed on separate occasions. As such, having two aspirates reduces the false negative rate
to only 1.2% [160].
The recently issued Bethesda System for
Reporting Thyroid Cytopathology (BSRTC)
based on an NCI-sponsored conference (2007) is
currently considered to be the most suitable for
communicating ndings from thyroid smears.
The cyto-diagnostic categories of Besthesda
Classication [23], with the corresponding estimated risk of malignancy, are listed in
Table12.15.
To repeat FNAC (US guidance may help). If the
cyst is aspirated to dryness with no residual
swelling, clinical/US follow-up alone may be
sufcient
Repeat FNAC in 3–6months. Two nonneoplastic
results 3–6months apart should exclude
neoplasia
MDT discussion—diagnostic lobectomy
Table 12.15
Category Description Risk of cancer
I Nondiagnostic or unsatisfactory: Cyst uid only—virtually acellular specimen,
II Benign: Consistent with a benign follicular nodule, Hashimoto’s thyroiditis, or
III Atypia of undetermined signicance (AUS ) or follicular lesion of undetermined
IV Follicular neoplasm (FN) or suspicious for a follicular neoplasm (SFN) 15–30%
V Suspicious for malignancy (SUSP) 60–75%
VI Malignant 97–99%
Bethesda system for reporting thyroid cytopathology [23]
1–4%
other (obscuring blood, clotting artifact)
0–3%
granulomatous thyroiditis
5–15%
signicance (FLUS)
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12.4.7.2 Large-Needle Biopsy (LNB)
andCore-Needle Biopsy (CNB)
A core-needle biopsy (CNB), performed under
“US-guidance” with a 20- to 21-gauge cutting
needle by experienced operators, may offer
additional information to FNAB in selected
cases of thyroid or neck masses when two aspiration procedures show a nondiagnostic specimen (Thy 1) [170]. In patients with suspicious
anaplastic tumor, thyroid lymphoma, pathological LNs, or other malignant neck disease, CNB
should be considered as it frequently provides
critical information for nodule management
[171]. However, CNB offers no additional diag-
nostic value in distinguishing a cellular hyperplastic nodule from a follicular adenoma or
carcinoma [172]. Hence, US-guided CNB
should not be regarded as an alternative to
FNAB but as a complementary investigational
tool [171].
Both, LNB or CNB, performed without US
guidance with a large-bore needle, is not recommended for thyroid nodules because of local pain
and risk of cervical bleeding. It also does not add
any further diagnostic information to FNAB in
nodules with follicular cytological characteristics
[173].
12.4.7.3 Intra-Operative Frozen-
Section Biopsy
Intra-operative frozen-section analysis of thyroid nodules requires excisional biopsy in the
form of thyroidectomy and may provide no
additional information. Some authors report a
high degree of accuracy with intra-operative
frozen-section; however, its contribution to
the management of STNs remains
controversial.
12.4.8 Management
The management of a STN depends on several
factors such as demographic, clinical, biochemical, and imaging as well as on the results of
FNAC.
12.4.8.1 Clinically Non-Palpable
Incidental Nodule <1cm
(Incidentalloma)
Non-palpable nodules <1cm that are either noted
during surgery or imaging performed for another
purpose have a very low risk of cancer and should
be “observed” [24]. In addition, there is no evidence to show that treatment of sub-centimeter
micro-carcinomas improves outcome [68, 174].
The exception to the above is an “incidentalloma” identied by “FDG-PET scan.” These
carry a 50% chance of malignancy and should be
managed as STN or ‘incidentalloma’ >1cm [68].
The patient with incidentaloma should be closely
monitored for any change in size and the development of symptoms.
12.4.8.2 Benign Simple Nodule
If FNAB indicates a benign nodule, there are
three options for treatment: (1) surgery (hemithyroidectomy), (2) observation, and (3) hormone
(L-T4) suppression, in addition to the “novel”
US-guided minimally-invasive procedures that is
percutaneous ethanol injection (PEI) and thermal
ablation using radio-frequency ablation (RFA)
and percutaneous laser ablation (PLA).
Surgery (Hemithyroidectomy)
Surgery (Hemithyroidectomy) may be considered if the nodule is causing symptoms or disgurement and also in those patients who are at
increased risk of thyroid cancer despite a benign
FNA.Complications with this surgery are generally low. In such an individual, full thyroid suppression also is recommended as lifetime
postoperative therapy.
Observation
If the patient does not require surgery, the nodule
may either be “observed” or suppressed with
Levothyroxine (L-T4) as the initial treatment
modality.
Levothyroxine (L-T4) Suppression Therapy
Suppression (L-T4) therapy should either reduce
the size of the nodule or prevent its further growth
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12 Benign Thyroid Disease
311
when administered for 6–12 months, otherwise
cancer should be suspected and surgery considered. Several studies reported the lack of efcacy
of suppression therapy for STN.There has also
been some concern that the use of thyroxin, especially in postmenopausal women, may lead to
osteoporosis [175].
Ultrasound-Guided Minimally Invasive
Procedures
Minimally invasive thyroid surgery may be performed with minimum surgical risk in patients
with small nodules [176, 177]. In recent years,
percutaneous, image-guided, minimally invasive
therapeutic procedures have been proposed for
the nonsurgical management of thyroid nodules
in selected cases [178, 179].
Percutaneous Ethanol Injection (PEI)
Percutaneous uid drainage may cure thyroid
cysts; however, recurrences are common and surgery is often the nal treatment of large relapsing
lesions [180]. Prospective randomized trials and
long-term studies have shown that PEI is signicantly superior to aspiration alone for inducing
volume reduction in cysts and complex nodules
with a dominant uid component [181–184].
Volume reduction is followed by the disappearance of local pressure symptoms [181–185]. The
recurrence rate (RR) of cystic lesions successfully treated with PEI is low, but in large or multilocular thyroid cysts several injections may be
necessary [181]. Clinically signicant decreases
in nodule size after PEI are reported in solid thyroid nodules that are cold on scintigraphy [186,
187]. The response, however, is less impressive
than in cysts, more treatments are needed, and
adverse effects are more frequent [181].
Thermal Ablation withRadio Frequency
Radiofrequency ablation (RFA) has been proposed for the debulking of a large benign thyroid
nodule [188, 189]. It is based on the percutaneous
insertion of large needle electrodes (14–18
gauge) or hook needles under local anesthesia or
conscious sedation. A high-frequency electrical
current moves from the electrodes into the tissues, and the alternate movement of ions results
in frictional heating of the target tissue.
Monopolar probes produce heat by ionic agitation within a 2-mm radius; tissue heating beyond
this zone is due to heat conduction. Because of
some disadvantages (cost of the device and cumbersome technique) and the absence of prospective randomized trials, RFA is currently not
recommended in the routine management of
benign thyroid nodules.
US-Guided Thermal Ablation withLaser
Percutaneous laser ablation (PLA) is a minimally
invasive procedure proposed as an alternative to
surgical ablation of benign thyroid nodules causing compressive symptoms or cosmetic concerns
in patients who decline surgery or are at surgical
risk. Beginning the day after PLA, patients
receive prednisone 25mg for 3days and 5mg for
4 days. Proton-pump inhibitors (Lansoprazole
30 mg) are simultaneously administered for
10 days. Adverse effects include pain, intranodular bleeding, subcapsular hematoma, swelling, and reversible (within 4–6 weeks) vocal
palsy due to nodule swelling and pressure on the
RLN (rare).
In most patients with thyroid nodules, one to
three sessions of PLA or a single treatment with
multiple bers induces a clinically signicant
decrease in nodule volume and amelioration of
local symptoms [190]. Two randomized trials
have conrmed the safety and clinical efcacy of
PLA [191, 192]; however, because of the novelty
of the PLA technique, long-term follow-up studies are lacking [193].
12.4.8.3 Benign Toxic Nodule
Observation
Patients with a hyperfunctioning “asymptomatic”
STN can be observed. Treatment is recommended
in the presence of “subclinical hyperthyroidism”
for patients at high risk of cardiac side effects, for
postmenopausal women with decreased bone
mineral density, and those with a hyperfunctioning nodule >3 cm in diameter. Both RAI (
131
I)
and surgery (hemithyroidectomy) have been
reported to be effective in the treatment of solitary toxic nodules.
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M. Sakr
Surgical Treatment
Surgical treatment (hemithyroidectomy) has the
advantages of immediate symptomatic relief,
avoidance of radiation exposure to the normal
thyroid tissue, and the low risk of complications.
A hot toxic nodule may require medical therapy
with anti-thyroid drugs (ATDs) before surgical
removal to allow for operative stability. Both
postoperative hypothyroidism and recurrence of
hyperthyroidism are uncommon.
All toxic nodules in “children” should be
removed. After thyroidectomy, thyroid hormone
replacement is necessary. This therapy is continued for the child’s lifetime with close monitoring
so that adequate therapy is maintained during
growth and changing needs.
Radio-active Iodine (RAI)
Radioactive iodine (RAI) treatment usually
requires higher doses of
131
I than are normally
used for the treatment of Graves’ disease.
Disadvantages include delay in symptomatic
relief, exposure of normal thyroid tissue to radiation, which may result in hypothyroidism in up to
35% of patients, and concerns related to the persistence of the nodule [194].
because of the high RR and availability of other
successful treatment options.
12.4.8.4 Indeterminate Lesion
(Follicular or Hurthle Cell
Neoplasm)
The principal surgical approach to solitary undetermined nodule is ipsilateral lobectomy (hemithy-
roidectomy). When FNAC demonstrates follicular
or Hurthle cell neoplasm, “surgery” is indicated to
reach a denite diagnosis. At surgical intervention,
about 20–30% of such specimens are determined
to be malignant lesions [195, 196]. If the nodule is
hyperfunctioning, a thyroid scintiscan may be
appropriate. A “hot’ nodule may be observed,
treated with
131
I, or surgically excised. If the plan is
to treat a hyperfunctioning nodule with surgery,
the thyroid scan may be omitted.
Patients with follicular STN can be treated with
hemithyroidectomy or TT, depending on the clinical situation and patient preference. Frozen- section
biopsy is usually not recommended [195, 197] but
may be useful in nodules with an ill- dened capsule, or in case of non-total thyroidectomy to
decrease the risk of completion thyroidectomy in
the scenario of cancer diagnosis.
Anti-thyroid Drugs (ATDs)
The ATDs are not curative and must be given
life- long to avoid the recurrence of hyperthyroidism. Their use is limited to preparing
patients for surgical or RAI treatment but may
also be considered in elderly patients with
medical problems that preclude surgery or RAI
therapy. They include Methimazole (caution
should be taken during pregnancy because it
can cause fetal hypothyroidism and has been
associated with fetal aplasia cutis) and
Propylthiouracil (documented in pregnancyassociated thyrotoxicosis but should be used in
lowest effective dose because of risk of hypothyroidism to fetus).
Percutaneous Ethanol Injection (PEI)
Ultrasound-guided PEI is effective in reversing
hyperthyroidism, but it requires multiple painful
injections and can be complicated by transient
RLN paresis. It is not highly recommended
12.4.8.5 Suspicious Nodule
Suspicious STNs should be treated with TT to
avoid missing a thyroid cancer. This category
includes samples characterized by cytological features that suggest malignancy but do not fulll the
criteria for a denite diagnosis. It also includes
samples with inadequate cellularity but with cellular features strongly suggestive of malignancy
[197, 198]. The rate of histologically conrmed
malignancy in these cases is about 60–75% [199].
Most of these cases are determined to be PTC on
denitive histological examination [154, 200].
Surgery (TT) with intra-operative histological
examination has been recommended [201].
Frozen-section may be performed to help guide
surgical decision-making [200, 202].
12.4.8.6 Nondiagnostic Biopsies
The results of FNAB, even with US-guidance,
may be repeatedly nondiagnostic. This particularly occurs with cystic nodules. The rate of
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12 Benign Thyroid Disease
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malignancy in these nodules is extremely low
and “observation” may be appropriate. However,
diagnostic lobectomy should be performed after
a repeat nondiagnostic FNAB.The routine use of
frozen-section is excessively costly and falsepositive results could lead to unnecessary thyroidectomies. The decision to do a more extensive
resection should be based on the patient’s history
or characteristics of the nodule [203].
12.5 Thyrotoxicosis
12.5.1 Denitions
“Thyrotoxicosis” refers to a syndrome characterized by signs and symptoms of sympathetic overactivity and hyper-metabolism due to excessive
amounts of thyroid hormone. It is often incorrectly
used interchangeably with “hyperthyroidism,”
which is dened as excess synthesis or secretion of
thyroid hormone by the thyroid gland [204].
12.5.2 Epidemiology
The prevalence of thyrotoxicosis in the United
States is 1.2%, including 0.5% overt thyrotoxicosis and 0.7% subclinical. The peak incidence is
between ages 20 and 50years. Graves’ disease is
the most common cause with an incidence of
20–50 cases/100,000 persons followed by toxic
MNG and toxic adenoma. Graves’ disease most
commonly affects women aged 30–50years with
a male-to-female ratio of 5:1 but can occur at any
age in both genders. Toxic nodular goiter increases
with age and in iodine-decient regions.
Thyroiditis accounts for 10% of cases. Only about
1–2% of patients with thyrotoxicosis develop the
serious complication of thyroid storm [205].
12.5.3 Etiology
The causes of thyrotoxicosis are summarized in
Table12.16. The most common cause is Graves’
disease, followed by toxic MNG, and toxic adenoma [204]. Other causes include thyroiditis,
Table 12.16 Causes of thyrotoxicosis
Associated with
hyperthyroidism
– Graves’ disease
– Toxic multinodular
goiter
– Solitary toxic
adenoma
– Iodine-induced
– Hashimoto’s
thyroiditis
– Thyrotropin-
producing pituitary
tumor
– Thyroid hormone
resistance
syndromes
Not associated with
hyperthyroidism
– Subacute thyroiditis
– Radiation thyroiditis
– Excess thyroid hormone
ingestion (iatrogenic,
thyrotoxicosis factitia)
– Struma ovari
– Functioning metastatic
thyroid cancer
subacute thyroiditis, painless thyroiditis, and gestational hyperthyroidism. Drug-induced thyrotoxicosis has been associated with amiodarone
and iodinated contrast.
Rare causes of thyrotoxicosis include TSHproducing adenomas, struma ovarii, gestational
trophoblastic neoplasia, thyrotoxicosis factitia,
activation mutations of the TSH receptor, and
functional thyroid cancer metastases [206]. Some
patients with thyrotoxicosis, such as those with
subacute thyroiditis or excess thyroxin-intake, do
not have hyperthyroidism.
12.5.4 Clinical Manifestations
The clinical manifestations of thyrotoxicosis
are diverse and result from increased thyroid
hormone levels that sensitize nerve cells to catecholamines and cause the symptoms of
increased sympathetic nervous system activity.
Older patients usually have fewer and more
subtle symptoms (apathetic hyperthyroidism).
They are also more frequently present with cardiovascular manifestations such as atrial brillation, angina, or congestive heart failure [205].
12.5.4.1 Symptoms
Patients complain of a neck swelling of variable
size in addition to symptoms of toxicity, which
include nervousness, anxiety, irritability,
weight loss despite increased appetite, palpita-
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M. Sakr
tions, heat intolerance, excessive sweating,
insomnia or sleep disturbances, fatigue, weakness, hair loss, brittle nails, dyspnea on effort,
increased frequency of bowel movements,
reduced libido, impaired fertility, and menstrual disturbances.
12.5.4.2 Local Examination
The thyroid gland becomes diffusely enlarged
with a smooth surface and eshy consistency. In
moderate and severe cases, pulsations due to
increased vascularity could be seen (inspection),
a thrill may be felt (palpation), and a bruit may be
heard (auscultation). The skin overlying may
show dilated veins.
12.5.4.3 General Examination
Findings of general examination depend on the
severity of the condition and age of the patient.
They are summarized in Table12.17.
Table 12.17 General examination ndings in
thyrotoxicosis
Systems/organs Manifestations
Body
metabolism
Nails The junction of the nail with its
Digestive system Diarrhea, nausea, and vomiting
Respiratory
system
Nervous system Increased irritability, nervousness,
Cardiovascular
system
Increased metabolism leads to
excessive sweating, loss of weight
in spite of good appetite, and
intolerance to hot weather
bed becomes straight or concave
(thyroid acropathy) and
onycholysis
(thyrotoxic crisis), abdominal
distention, increased glucose
intolerance, and glycosuria
(polyphagia and polydepsia).
Dyspnea on effort
easy excitability, ne tremors,
choreiform movement of the hands
and arms, and frank psychosis (in
severe cases)
Attacks of palpitation on exertion
or rest, tachycardia, cardiac
arrhythmias superimposed on a
sinus tachycardia (as the disease
progresses) in the form of multiple
extrasystoles, paroxysmal atrial
tachycardia, paroxysmal atrial
brillation, persistent atrial utter
not responsive to digoxin and
congestive heart failure (CHF)
Table 12.17
Systems/organs Manifestations
Musculoskeletal
system
Eye manifestations
Lid retraction
(Dalrymple’s
sign)
Lid lag (Von
Graefe’s sign)
Stellwag’s sign Staring look due to infrequent
Joffroy’s sign No wrinkling of the forehead on
Moebius sign Lack of convergence on looking at
Giffod’s sign Difculty in passive eversion of
Rosenbach’s
sign
Backer’s sign Abnormal pulsation of the retinal
Thyrotoxic
exophthalmos
Malignant
exophthalmos
(continued)
Myopathy (weakness),
osteoporosis (vertebral collapse or
fractures), and peri-tibial
myxedema (localized, bilateral
leathery thickening of the skin of
the fronts of the legs)
Spasm of the involuntary part of
the levator palpebrae superioris
muscle (Muller’s muscles) causes
widening of the palpebral ssure,
so a band of white sclera appears
between the margin of the upper
eyelid and the cornea (no
proptosis)
Lack of harmony between
movement of the upper eyelid and
the eyeball. The eyelid lags behind
the eyeball as the patient looks
down following the examiner’s
nger
blinking, a mild degree of lid
retraction or exophthalmos
looking upwards due to weakness
of the frontalis muscle
a near object for a long time due to
easy fatigability of skeletal
muscles of the eye
the eye
Involuntary spasm of the eyelids
when closed
vessels
Abnormal protrusion of the
eyeball, usually bilateral but may
be unilateral
Edema and pigmentation of
eyelids, diplopia and squint from
ophthalmoplegia, edema and
chemosis of conjunctiva, and
corneal, which may end in
panophthalmitis and blindness
12.5.5 Diagnosis
The TSH level is low in all patients with thyrotoxicosis except in rare cases of TSH-secreting
pituitary tumors or pituitary resistance to thyroid
hormone. When TSH level is low, T3 and T4 levels should be obtained. In patients with a sup-
t.me/Dr_Mouayyad_AlbtousH
12 Benign Thyroid Disease
315
pressed TSH and a normal FT4 level, T3 levels
are important to make a diagnosis of T3 toxicosis. The measurement of thyroid-stimulating
immunoglobulins and anti-thyroid antibodies is
useful for diagnosing Graves’ disease or thyroiditis in selected patients. A thyroid scintiscan can
differentiate a hypo-functioning nodule in a
patient with Graves’ disease from a solitary toxic
nodule.
12.5.6 Histopathology
Toxic multinodular goiter and toxic adenomas
are follicular adenomas, which are usually a nonmalignant proliferation of follicles encased in a
brous capsule. It is usually a benign, nonfunctional adenoma that usually does not secrete
thyroid hormone [205].
12.5.7 Dierential Diagnosis
Thyrotoxicosis should be considered in children
with a growth spurt, behavior problems or myopathy, and in elderly patients with tachycardia or
arrhythmias, unexplained diarrhea, and loss of
weight. It should be differentiated from anxiety
neurosis, organic diseases, which cause heart diseases, anemia, or gastrointestinal diseases, myasthenia gravis or other muscular disorders,
menopausal syndrome, pheochromocytoma, and
other causes of exophthalmos and primary
opthalmopathy.
12.5.8 Graves’ Disease
Graves’ disease (Basedow’s or Parry’s disease), is an autoimmune disorder with a genetic
predisposition that typically affects young
individuals between 20 and 40 years of age,
with a female to male ratio that varies from 4:1
to 10:1. It is the most common cause of spontaneously occurring thyrotoxicosis, accounting
for 60–90% of all cases, and frequently occurs
in association with other autoimmune
diseases.
12.5.8.1 Pathogenesis
Reduced activation of suppressor T-lymphocytes
by specic antigen that occurs due to an inherited
abnormality in antigen presentation encoded for
by histocompatibility genes has been postulated
to be the main defect behind the development of
thyrotoxicosis [207]. The autoimmune dysfunction may be precipitated by environmental factors such as stress, infection, or trauma. The
defect in suppressor T-cell function allows for
thyroid-directed B-lymphocytes, which are normally suppressed, to produce thyroid antibodies
directed against the TSH receptor, which stimulates the follicular cells in a manner similar to
TSH [208].
Graves’ disease is also characterized by thyroid autoantibodies to other antigens including
thyroglobulin (Tg) and thyroid peroxidase (TPO).
12.5.8.2 Pathology
Macroscopically, the gland is smooth and diffusely enlarged, reddish brown and friable. The
cut-surface shows a varying picture depending on
the colloid content, vascularity, and the amount
of brous stroma. Microscopically, the gland
shows marked vascularity, epithelial proliferation
of the cells lining the follicles, and lymphocytic
inltration of the stroma.
12.5.8.3 Clinical Presentation
Patients with Grave’s disease typically have a diffuse symmetric goiter (Fig.12.24) often with an
audible bruit in addition to the variable presence
of ophthalmopathy, dermopathy, and acropachy.
Extra-thyroidal manifestations of Graves’ disease result from tissue deposition of glycosaminoglycans in response to the immune reaction
against tissue antigens shared with the thyroid
gland or antigens that cross-react with the TSH
receptor.
Ophthalmopathy occurs more in patients with
higher levels of thyroid receptor antibodies
[209]. Eyelid retraction, lid lag, and stare look
may occur with thyrotoxicosis regardless of its
cause; however, peri-orbital edema, chemosis,
exophthalmos (Fig. 12.25a, b), diplopia, and
decreased visual acuity are more specic for
Graves’ disease and occur as a result of edema,
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