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ENDOCRINE SURGERY
80
the identification of the recurrent laryngeal
nerve and preservation of the parathyroid
glands. Once the nerve is encountered the entire
cervical course can be exposed and de-roofed
from the Zuckerkandl tubercle downward.
Proye described the ‘‘toboggan technique’’
used to expose the recurrent laryngeal nerve
along its course before any attempt of dissection
and mobilization of the substernal goiter [59].
Although stretching of the recurrent laryngeal
nerve as a cause of vocal cord paralysis is rare, it
is commonly associated with large substernal
goiters [60]. Thus with the nerve in sight and
protected, the fascial attachments and capsular
plane of the thyroid are freed with the finger
above the nerve reaching downward and sweeping it toward the anterior surface. This will
release the negative pressure while applying
gentle upward traction to the thyroid with the
other hand. The thoracic inlet is the most narrowed portion, and it is important to be in the
right plane and avoid any resistance which may
cause torrential bleeding on the gland especially
between the gland and the posterior aspect of
the manubrium and sternum. Successful delivery of the secondary anterior substernal goiter
almost invariably can be achieved. Even a large
goiter can be pulled out and removed without
resorting to splitting of the sternum. Nonetheless
if difficulty is encountered despite careful dissection, additional maneuvers should be considered.
The surgeon’s finger should be used to sweep
around the lower end of the goiter again with
simultaneous continuous traction, to confirm
that all palpable adhesions have been divided
[61]. A goiter extending down to the level of
theaorticarchorevenfurthersometimesmay
not be fully accessible with the tip of the finger.
A sterile soup spoon can be used to reach further
than the finger, and it may be slipped down
alongside the anterolateral aspect of the thyroid,
further breaking the negative intrathoracic pressure and in most instances leading to an immediate and satisfying delivery of the gland [62].
However one must be careful when using the
spoon technique of the loss of tactile sensation
and dexterity when reaching for the lower end of
the goiter. Not infrequently Lahey’s morcellation
technique may be used to release the pressure in
the thoracic inlet by breaching the capsule of the
goiter and scooping out the content to draw the
goiter out of the thorax [63]. This technique however may result in torrential venous bleeding and
tumor spillage in unsuspected malignancy [56].
Failing this the collar incision can be extended
by splitting the sternum with a partial sternotomy or full sternotomy to give a wider exposure
of the thoracic inlet, but this is often not necessary. A sternal split should only be considered
in large substernal goiter with mediastinal fixation associated with severe venous obstruction
and suspected of malignancy. In addition
crossed-over anterior substernal goiter either
to the opposite side (Fig. 5.3) or to the posterior
compartment (Fig. 5.5) and those with isthmus
below the level of the manubrial notch should be
best approached through a combined cervical
and sternal split. This approach will allow direct
visualization of the blunt finger dissection along
the tissue plane toward the other compartment
and avoid vital structures particularly the major
vessels such as the brachiocephalic vein, superior vena cava, and the aortic arch.
Posterior Mediastinal Goiter
Posteriormediastinal goiter exclusivelyoccurs in
the right side since the brachiocephalic vein and
aortic arch prevent the goiter from descending
on the left. Most patients are asymptomatic but
when symptomatic they are usually related to
direct tracheal or esophageal compression and
stretching of recurrent laryngeal nerve. Primary
isolated posterior mediastinal goiter is extremely
rare and in such circumstances is often necessary
to have a preoperative thyroid scan to confirm
the truly isolated goiter and exclude other mediastinalmass. This isimportant to allow adequate
anatomical and functional assessment to decide
on the best possible approach.
To achieve complete removal of a true primary
isolated posterior mediastinal goiter, it is best
approached through a primary thoracic incision
either through a posterolateral or antero-lateral
incision. This is because the posterior goiter may
have an aberrant blood supply directly from the
mediastinal. Furthermore this approach is crucial
to allow visualization of the parietal pleural and
protects the vital structures such as the superior
vena cava and azygos vein especially toward the
posterior medial region of the right thorax. On
the other hand secondary posterior mediastinal
goiter should be first approached through the
cervical incision. As with the anterior substernal
goiter a substantial portion of the blood supply
comes from the inferior thyroid vessels and
81
MULTINODULAR GOITER
hence, it is imperative to control the proximal
blood vessels before exploring the mediastinal
goiter. One should be careful not to attempt
removal through the thoracotomy alone except
only for the primary isolated posterior mediastinal goiter.
Fortunately likewise with anterior substernal
goiter most secondary posterior mediastinal goiter, either an ipsilateral descend or a crossed-over
goiter, can be easily removed through the cervical
incision [64, 65]. The crucial step in surgery is
to expose the prevertebral avascular space to
facilitate optimal extraction of the goiter out of
the thoracic inlet. The extracapsular blunt digital
dissection of the mediastinal goiter from the
surrounding structures can be performed safely
from behind along this prevertebral space.
As described earlier with the course of recurrent laryngeal nerve in sight, the gentle blunt
finger dissection releases the attachment and
removes the extra-capsular pressure off the
surrounding structure. At the same time continuous traction is applied with the other hand
coupled with slow tugging from side to side to
facilitate the removal of goiter out of the thorax.
One must be extremely careful not to use any
force or aggressive traction in the presence of
fixation. If all these measures fail to extract the
goiter, Lahey’s morcellation technique should
be considered (Fig. 5.4B). This internal scooping of the goiter content not only provides additional space but deflates the goiter further and
removes the negative pressure of the surrounding structures to allow easy extraction out of the
thorax [63]. A combined approach with initial
cervical incision and thoracotomy is desirable
when dealing with a fixed and adherent posterior mediastinal goiter, especially in reoperative
recurrence goiter, large posterior goiter, goiter
with deep extension below the aortic arch, and
malignancy [64]. Occasionally sternal split has
been used to remove the posterior mediastinal
goiter. However this is not the ideal approach as
sternal split will only widen the thoracic inlet
but the lower end of the goiter in the posterior
mediastinal is still far from accessible. The
worst unaccepted scenario is to have all three
approaches of cervical, sternal split, and thoracotomy in an attempt to remove the secondary
posterior mediastinal goiter. Before closure the
substernal space is routinely filled with saline
and the lungs hyperinflated to check for any
pleural leak. A suction catheter is routinely left
in place for drainage of the large dead space
and mandatory to insert chest drain in the
respective side when there is a pneumothorax.
The presence of substernal goiter is an indication for removal in view of the potential risk
of airway compression and high incidence of
malignancy. In the majority of cases substernal
goiters can be removed through a standard cervical incision. However a sternal split is inevitable especially in those patients diagnosed with
primary isolated intrathoracic goiter and recurrent anterior substernal goiter. On the other
hand thoracotomy is indicated for primary isolated posterior mediastinal goiter. However for
large or recurrence posterior ipsilateral and
contralateral mediastinal goiter the best surgical
approach is through a combined cervical and
right posterolateral thoracotomy.
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6
Thyrotoxicosis and Thyroiditis: Causes, Investigation, and Management
Johnathan G.H. Hubbard and Paul V. Carroll
Introduction
Thyrotoxicosis represents the clinical syndrome
that results from exposure to elevated levels of
circulating thyroid hormones. Hyperthyroidism
is used to describe thyrotoxicosis resulting
from overproduction of thyroid hormones by
thyrocytes, with Graves’ disease the commonest
cause. Less frequently thyrotoxicosis occurs in
the absence of hyperthyroidism, for example, a
short-term thyrotoxicosis can occur when stored
hormones are released in a destructive thyroiditis. The causes of thyrotoxicosis are listed in
Table 6.1. Graves’ disease, toxic multinodular
goiter, and solitary toxic nodule account for
95% of cases and are commonly encountered in
surgical practice. Causes such as Hashimoto’s
thyroiditis or drug-related thyrotoxicosis are
uncommon but may require surgical evaluation.
Clinical Presentation
and Systemic Manifestation
of Thyrotoxicosis
The clinical features of thyrotoxicosis depend on
the severity and duration of the disease, the age of
the patient, extrathyroidal manifestations, and the
specific cause of the thyrotoxicosis. Thyroid hormone excess affects almost all organ systems, and
thesymptomsandsignsofthyrotoxicosisare
similar regardless of etiology. Widespread effects
occur due to the stimulation of metabolicprocesses
and sensitization of the sympathetic nervous system (Table 6.2). In the elderly the symptoms may
be more subtle than in younger patients. Apathetic
thyrotoxicosis [1] occurs in elderly patients when
features of sympathetic reactivity are absent, and
patients may present with severe depression,
weight loss, occult atrial rhythm disturbance, and
a small goiter. Graves’ disease has additional features, due to the immunological nature of the condition, in particular thyroid eye disease (Table 6.2).
Eye Manifestations of Thyrotoxicosis
Retraction of the upper eye lid resulting in a
bright-eyed stare is common in all forms of thyrotoxicosis and is related to sympathetic overactivity. Similarly lid lag (when the upper lids move
more slowly than the globe) is a general finding
in the thyrotoxic individual. It is important to
distinguish these features from the specific ocular manifestations of infiltrative ophthalmopathy
that is characteristic of Graves’ disease.
Thyroid Gland
Both Graves’ disease and toxic nodular goiter
are usually associated with enlargement of the
thyroid gland. Toxic adenoma and multinodular goiter commonly result in an asymmetric
gland. The goiter of Graves’ disease is typically
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_6, Ó Springer-Verlag London Limited 2009
85
ENDOCRINE SURGERY
Table 6.1. Cause of thyrotoxicosis
Group Disease Relative frequency
Thyrotoxicosis of thyroidal origin Graves’ disease 70%
Toxic adenoma 5%
Multinodular toxic goiter 20%
Iodine-induced thyrotoxicosis <1%
TSH-secreting adenomas <1%
Neonatal thyrotoxicosis <1%
Associated with thyroid destruction Subacute thyroiditis 3%
Silent thyroiditis 3%
Amiodarone-induced thyrotoxicosis (type 2) <1%
Thyrotoxicosis of nonthyroidal origin Factitious thyrotoxicosis Very rare
Thyroid hormone poisoning Very rare
Struma ovarii Very rare
Metastatic thyroid cancer Very rare
86
Table 6.2. Systemic effects of thyrotoxicosis
System Effects
General Weight reduction, nervousness, irritability, heat intolerance, fatigue, poor sleep
Skin Warm, moist palms, hyperhidrosis, urticaria, itching, exacerbation of eczema
*Dermopathy: violaceous, nonpitting induration of pretibial skin (pretibial myxoedema)
*Acropachy: clubbing
Eye Lid lag and retraction
*Periorbital edema, chemosis, exophthalmos, ophthalmoplegia, redness, loss of vision
CNS Irritability, worsening of psychiatric conditions, stupor, coma
CVS Tachycardia, cardiomegaly, heart failure, rhythm disturbance
Respiratory Dyspnoea
Bone Reduced bone mineral density
Fertility/reproduction Gynecomastia, infertility, light or absent menstrual periods
Metabolic Hyperglycemia, hypercalcemia
Gastrointestinal Diarrhoea/hyperdefecation
Neuromuscular Tremor, myopathy, paralysis
*Features specific to Graves’.
visible, diffusely enlarged, smooth, and may be
associated with a bruit or thrill.
associated suppression of thyroid-stimulating
hormone (TSH). Thyroxine (T4) and triiodothyronine (T3) are most commonly measured in their
respective free states (free T4 and free T3 [2]).
Laboratory Diagnosis
of Thyrotoxicosis
TSH is suppressed in the vast majority of thyrotoxic individuals due to negative feedback of
thyroid hormones on the anterior pituitary, but
canbenormalorelevatedwhenaTSH-secreting
The biochemical diagnosis of thyrotoxicosis is
confirmed on blood tests demonstrating elevated
levels of circulating thyroid hormone levels with
pituitary tumor is present or with thyroid hor-
mone resistance [3]. Subclinical thyrotoxicosis
exists when TSH is suppressed without overt
87
THYROTOXICOSIS AND THYROIDITIS
elevation of free T4/T3 [4]. Once the diagnosis of
thyrotoxicosis is confirmed the cause should be
established. The presence of extra-thyroidal signs
and the size and shape of a goiter are informative
as to the likely cause, although in 30% a goiter
may not be palpable [3].
Antithyroid Antibody
Detection of TSH-receptor antibodies (TRAb) in
the blood of the thyrotoxic patient is useful in
confirming Graves’ disease as the cause. Most
laboratories usein vitromethodology thatassesses
TSH-binding-inhibiting immunoglobulins (TBII).
Positive TBII tests are found in approximately
90% percent of patients with Graves’ disease with
99% specificity. TBII is usually used when the
clinical picture is unclear or in cases of pregnancy
to guide on the risk of neonatal thyrotoxicosis.
Antithyroid peroxidase and antithyroglobulin
antibodies are commonly measured in the thyrotoxic patient to determine underlying autoimmune thyroid disease. They can be found in up
to 90% of patients with Graves’ disease but may be
present in patients with thyroiditis.
Table 6.3. Diagnosis and pattern of radioiodine uptake in
thyrotoxicosis (with suppressed TSH)
Low uptake
Silent/postpartum thyroiditis
Nontender thyroid, + antithyroid antibodies
subacute/de Quervain
Recent URT viral infection, tender thyroid, fever, High ESR
Struma ovari
Abdominal uptake
Iodine induced (e.g., IV radiological contrast, amioderone)
Usually on background of MNG
Thyrotoxicosis factitia
High uptake
Graves’ disease
Diffuse uptake
Toxic MNG
Nodular/patchy uptake
Toxic Nodule
Uptake in nodule with suppressed normal thyroid
Trophoblastic tumor
Raised b HCG
Lymphocytic thyroiditis
Positive thyroid autoantibodies
Nuclear Medicine Imaging
(Thyroid Scintigraphy)
The pattern of uptake ona nuclear medicinescan
(radioiodine or technetium-99m) can be useful
in establishing the cause but is not necessary in
all cases of thyrotoxicosis (Table 6.3). Any
patient with a dominant nodule should be considered for thyroid fine needle aspiration cytology (FNA) to exclude malignancy. However, the
cytological interpretation of FNAs taken from
toxic nodules is problematic due to their hyperplastic nature. This causes an increased yield of
atypical cells (Thy3), making it difficult to
exclude malignancy, despite the fact that most
nodules are benign. Therefore care should be
taken in the selection of such patients for FNA.
Graves’ Disease
Exophthalmic goiter is the most common cause
of thyrotoxicosis, accounting for approximately
70% of cases. It was first described in 1786 by
Parry, an English physician from Bath, but he
did not publish his findings during his lifetime.
In the English-speaking world it has become
known as Graves’ disease after Robert Graves,
an Irish physician who described it in the early
nineteenth century, while in mainland Europe it
is known as Basedow’s disease following von
Basedow’s description in Germany in 1840.
Graves affects 2% of women, with a female to
male ratio of 10:1 [5, 6]. It is an autoimmune
disease that can occur at any age, although it
typically affects young women between 20 and
40 years of age. Geographical variations are
reported, with peak incidence occurring in
older patients in Iceland and Sweden [7]. Graves’
disease is more common in tobacco users [8].
Pathogenesis
Geneticfactorsare thought to be importantin the
development of Graves’disease.Studies in monozygotic twins have shown higher concordance
ENDOCRINE SURGERY
88
rates (30–50%) compared with dizygotic twins
(5%) suggesting a genetic component is involved
[9], although environmental factors have an
important role. Graves’ disease is more common
in Caucasians and has been liked to certain major
histocompatibility complex-human leukocyte
antigens (MHC-HLA) class II gene polymorphisms, most notably, DRB3 [9, 10]. Polymorphisms
of the CTLA-4 gene (cytotoxic T-lymphocyte-
associated-4) are more common in individuals
with Graves’ disease. CTLA-4 is a T-cell-surface
molecule important in T-cell activation, alongside
HLA class II antigen presentation [10]. Polymorphisms to such genes may have a role in
susceptibility to both autoimmune and infectious
diseases. Other autoimmune conditions are associated with Graves’ disease and these are listed in
Table 6.3. Debated triggers for Graves’ disease
include stress [11], smoking [7], and antibodies
to infections including Yersinia enterocolitica [12,
13] which may cross-react with TSH receptors.
The pathogenesis of Graves’ disease has not
been fully elucidated. Key in the process are antibodies acting against the TSH receptor (TSHstimulating antibodies are found in the sera of
>90% of untreated cases [3]). Patients with
Graves’ have been found to have three classes of
antibodies (neutral, blocking, and stimulatory)
[14]. The clinical picture depends on the balance
of these antibodies [15]. In classical Graves’
hyperthyroidism the preponderance of stimulatory antibodies results in the overproduction of
thyroidhormone inan unregulated fashion. Antibodies to other thyroid antigens are frequently
present (antithyroperoxidase and antithyroglobulin). Inflammatory cells infiltrate the thyroid
with the production of cytokines. There is associated hyperplasia and hypertrophy of thyroid
follicles resulting in goiter formation. The combination of both stimulatory and destructive thyroid antibodies may explain the variable course of
Graves following medical treatment, with remissions and hypothyroidism in some patients.
Diagnosis
The diagnosis of Graves is confirmed clinically
when thyrotoxicosis is present in a patient with
a diffuse goiter, with extra thyroidal signs such
as ophthalmopathy or dermopathy. Antithyroglobulin and antithyroid peroxidase antibodies
are elevated in 80%. Thyroid-stimulating antibodies are measured in cases where the diagnosis is uncertain. Thyroid scintigraphy shows
diffuse uptake in the thyroid and can be used
to distinguish Graves from other causes of thyrotoxicosis (e.g., toxic multinodular goiter and a
solitary toxic nodule).
Thyroid Eye Disease (Thyroid
Ophthalmopathy, Graves’
Ophthalmopathy)
Eyelid retraction and lag are common nonspecific eye signs which can occur in all causes of
thyrotoxicosis. They are caused by the sympathetic innervation of levator palpebrae superioris carried via the third cranial nerve. Specific
Graves’ ophthalmopathy is clinically evident in
30% of patients [3]. Eye signs include eye discomfort and grittiness, proptosis (30%), and
extraocular muscle involvement (10%), while
corneal involvement and optic nerve compression are uncommon.
The cause of ophthalmopathy remains
under investigation but is thought to be due
to an immune response to antigens present in
retroorbital tissues that are shared with the
thyroid, or antigens which can cross-react
with the TSH receptor. Orbital adipocytes and
fibroblasts have been shown to express TSH
receptors [16, 17]. The results are edema, glycosaminoglycan deposition, and fibrosis of retroorbital tissue and extraocular muscles.
Ophthalmopathy is more common in smokers
[18, 19], and rarely the signs can be unilateral
(10%). CT and MRI of the orbit are useful in
determining degree of extraocular muscle
enlargement. Treatment for milder forms is
directed at symptom control and includes
lubricating eye drops, elevation of the head of
the bed, and occasionally diuretics. Active
inflammation may respond to immunosuppressive treatments including corticosteroids (used as
a first-line treatment) and azathioprine (Figs. 6.1
and 6.2). External beam radiotherapy is commonly used to reduce inflammation and enlargement of extraocular muscles. In cases where the
optic nerve is threatened and acuity reduced orbital decompression by an experienced surgeon
may be necessary.
89
THYROTOXICOSIS AND THYROIDITIS
Fig. 6.1. Eye movements (A) pretreatment and (B) day 6 after initiation of treatment with methylprednisolone.
Fig. 6.2. Orbital MRI demonstrating bilateral proptosis, enlarged ocular muscles, and compressive optic neuropathy. (A) Axial
view; (B) coronal view.
Identifying the Etiology
of Thyrotoxicosis
Commonly the etiology is clinically evident and
the treatment choice straightforward. The presence of thyroid eye disease and a diffuse goiter
with a bruit are classical features of Graves’ disease. Distinguishing between Graves’ disease and
toxic nodular disease in the middle-aged individual without extra-thyroidal manifestations may
be more difficult. In addition to clinical assessment, measurement of thyroid antibodies, highresolution ultrasonography, and nuclear medicine