Toxic Nodular Goiter

John H. Boey

ABSTRACT
Toxic nodular goiters comprise toxic multinodular goiter (TMNG) and the solitary autonomously functioning thyroid nodule
(AFTN). Preferential growth of actively secreting, TSH-independent thyroid follicles gives rise to palpable nodules. Although most
patients remain euthyroid, some gradually develop biochemical, and later clinical, toxicity. The latter is more common with enlarging
thyroid mass and advancing age, and in endemic goiter areas. The declining incidence of toxic goiters parallels the overall reduction
in goiters, especially in endemic regions. AFTN and TMNG presently account for about 10% to 20% of all cases of hyperthyroidism.
Definitive therapy is indicated for frank toxicity, obstructive symptoms, and suspicion of malignancy. The choice between surgery
and radio iodine ablation should be individualized according to the general health and age of the patient, the severity of toxicity, the goiter
size andpresence of obstruction, the possibility of malignancy, and prior treatment. Radioiodine ispreferredin patients who are medically
unfit or elderly, especially if they have mild toxicity or a small gland, and in those who relapse after thyroidectomy. Despite the relatively
high dosages administered, hyperthyroidism may not be controlled for many months, and repeat applications are necessary in about a
quarter of patients. Late hypothyroidism occurs quite commonly after radioiodine ablation of solitary AFTNs but less often after treatment
for TMNG.
Subtotal thyroidectomy for TMNG and lobectomyfor AFTN rapidly alleviate toxic symptoms and remove the goiter. It is most suitable
in healthy and young individuals, those with obstructing goiters and possibly malignant nodules. Most patients are rendered euthyroid
but an increasing incidence of late hypothyroidism has been recognized following surgery for TMNG. Primary operations are very safe
but higher complication rates attend reexplorations.

Nodular goiters that produce hyperthyroidism are broadly

categorized as toxic nodular goiters.' The term encompasses
the solitary autonomously functioning thyroid nodule (AFTN)
(toxic adenoma) as well as toxic multinodular goiter (TMNG)
(Plummer's disease). The pathogenesis, clinical presentation
and treatment of these conditions differ from Graves disease:
an autoimmune mechanism is hardly ever implicated; toxicity
develops gradually over many years; patients tend to be older,
and present more often with cardiac symptoms; exophthalmos
is absent; nodules, either single or multiple, are characteristic
findings; and the radionuclide scan appearance seldom shows
diffuse uptake in both lobes.
PATHOGENESIS AND EVOLUTION OF NODULES
Toxic nodular goiter is not known to have an autoimmune
basis. Highly specific thyroid-stimulating immunoglobulin
(TSI) is found almost exclusively in patients with Graves'
disease (1). Reports of TSI in other hyperthyroid patients seem
to represent Graves' disease co-existing with Hashimoto's
disease (1) or a variant of TMNG (2). Toxic nodular goiters
have TSH receptors and adenylate cyclase systems similar to
that in normal thyroid tissue (3). This implies a more distal

Room 1206, Melbourne Plaza, 33 Queen's Road Central, Hong Kong

John H. Boey, Dip. Am. Board of Surgery, private practice
Correspondence to: Dr. John H. Boey

166

level of metabolic alteration whose cause and development is

as yet unknown.
Nodule formation is a prominent feature of the condition.
These apparently develop in response to intermittent TSH
stimulation due to dietary iodine deficiency in endemic goiter
regions, or to other growth factors, such as goitrogens, growthstimulating immunoglobulins (4) or external radiation. Studer
and colleagues (5,6) argue that there is a dissociation between
follicular replication and hormonal secretory function. They
postulate that clones of cells with varying secretory ability
develop from different mother follicles. Preferential multiplication of growth-prone daughter follicles gives rise initially to
pathologically demonstrable, and later clinically evident, nodules.
I-131 autoradiographic studies of surgical specimens by
Taylor (7), Miller (8) and Studer (5,6) helped to elucidate the
heterogeneous patterns of autonomous nodule development.
Individual follicles may be scattered either haphazardly
throughout or clustered together within the gland (5). Some
follicles may combine to form microadenomas segregated
from the surrounding normal or hypofunctioning parenchyma,
or progress to involve the entire thyroid. Combinations of these
basic patterns may co-exist in different parts of TMNG. Macroscopic nodules evolve from polyclonal daughter follicles that
grow within a confining lattice of fibrous scars produced by
follicular necrosis (6). Under a unifying hypothesis of toxic
goiters (6), the solitary AFTN, at one end of a broad spectrum,
originates from a single clone of follicles that has supranormal
secretory as well as growth capacity.

Review Articles: Toxic Nodular Goiter

AUTONOMOUS ACTIVITY AND TOXICITY
Functional autonomy designates independence of follicular secretory activity from TSH regulation. This is characterized by a radioisotope scan demonstrating increased uptake by
one or more nodules that is not reduced (or may even be
relatively enhanced) after TSH suppression by exogenous
thyroxine. Following TSH stimulation, there is augmented
uptake in extranodular parenchyma, which may or may not
have been completely suppressed by thyroid hormone secreted by the hyperfunctioning nodule (s). Not all hyperfunctioning nodules are autonomous. Some have normal or relatively low thyroid function, and may precede complete TSH
autonomy (9,10).
Morphologically uniform areas may appear functionally
heterogeneous on radioisotope scanning. More sensitive than
scintigraphy, autoradiography can disclose follicles that possess
active iodine metabolism but appear "cold" on conventional
scans. A seemingly single AFTN may be surrounded by other
autonomous but metabolically less active follicles.
The unit hormonal secretory activity in autonomous nodules is quite variable, often subnormal (11,12), but usually
remains stable even with increase in nodule size (13). Since
growth capacity and hormonal activity are dissociated in autonomous glands (8), large but poorly functioning multinodular
goiters may not manifest clinical or even biochemical
hyperthyroidism. Toxicity occurs when the product of the
mass of active follicles and their secretory activity exceeds
normal levels. A transitional phase of preclinical (or subclinical)
hyperthyroidism can be identified by normal circulating hormone levels present in conjunction with a suppressed TSH
level that is unresponsive to exogenous TRH stimulation
(11,14,15). Preferential secretion of T3 over T4 under TSH
stimulation may be reversed by propanolol leading to partial
improvement of the impaired TSH response to TRH (16).
Selective resection of autonomous nodules in endemic goiter
areas can re-establish a euthyroid state with full recovery of
TSH responsiveness to TRH (15,17).
The propensity of autonomous nodules to produce
hyperthyroidism varies according to the mass of autonomous
tissue, which in turn varies with the age of the patient, number
of functioning nodules, and geographical area.
The risk of developing hyperthyroidism increases with the
functioning mass (11,13,18). About two-thirds of nodular
goiters exceeding 75 grams in weight become autonomous
(12). In sporadic TMNG, Jensen and his colleagues (19) found
that 28% of their patients had resected gland weights below 50
grams even though the average weight for their 442 patients
was 113 grams. In one endemic goiter area (11), the resected
specimen weight averaged 48 grams in patients with nontoxic
multinodular goiter, 103 grams in those with preclinical
hyperthyroidism, and 130 grams in TMNG (11). A similar
relationship between size and toxicity holds true for AFTN.
Among 48 patients with AFTN,
euthyroid patients had smaller
nodules (mean area 5 cm2) than hyperthyroid patients (mean
area 8.9 cm2) (20). Based on planimetry measurements of
nodule size on scans, toxic nodules have a mass volume three
times greater than nontoxic lesions (13, 21). In general, solitary
nodules smaller than 2.5 cm hardly ever produce
hyperthyroidism whereas most lesions larger than 4 cm are
either toxic or completely suppress the extranodular thyroid
tissue (22,23).
A gradual increase in goiter size accounts for the higher
incidence of hyperthyroidism in elderly patients. Most studies
document a 12 to 16 years interval between the onset of a goiter
and the development of clinical hyperthyroidism (18,19). Swiss

patients with nontoxic goiters had an average age of 45 years as

compared with 52 years in those with preclinical
hyperthyroidism, and 58 years in hyperthyroid patients with
TMNG (11). Similarly, in Germany, goiters are common before
the age of 40 but clinical toxicity more likely above 60 years
(18). In sporadic goiter areas, there is a similar interval
between the development of a goiter and the onset of
hyperthyroidism (12).
In solitary AFTN, older patients tend to have larger nodules
and a greater risk of toxicity (21). In one large series (22),
hyperthyroidism was present in 56.5% of patients 60 years or
older but in only 12.5% of those younger than 60 years. Somewhat
unexpectedly, young individuals (under 20 years) did not have
a higher proportion of toxicity than those between 20 and 60
years of age (22). As pointed out by Thomas and co-workers
(23), although functional activity in AFTN increases with age,
it is not a strictly linear relationship. An inherent tendency of
many AFTNs to undergo degenerative involution (10,21,24)
lowers the expected incidence of toxicity in older individuals
(22).
Endemic goiters are more apt to develop hyperthyroidism
than sporadic lesions. An estimated 50% to 60% of older patients
with autonomous nodules in endemic areas eventually develop
hyperthyroidism (25,26). Of the 93 patients operated upon for
endemic goiters that contained autonomously functioning
follicles, only one-quarter had clinical hyperthyroidism (11).
Sporadic autonomous goiters pursue a more indolent course:
only six of 52 patients (11.5%) developed mild toxicity during a
four years followup period (27).
Hyperthyroidism develops less frequently in solitary AFTNs
(32%) than multinodular lesions (66%) in endemic areas (18). In
a collective series of 288 AFTNs, 96 (42%) were judged to be
hyperthyroid while another 21 (9%) had only biochemical
(preclinical) hyperthyroidism (28). None of 48 euthyroid
patients with AFTNs became hyperthyroid during a two years
followup period (28); in fact, nodule degeneration, occurred in
two of them. In Hamburger's extensive series (22), only 14 of
142 (10%) euthyroid patients with AFTNs who were followed
for up to six years actually developed hyperthyroidism. Depending upon the length of followup, the incidence of
hyperthyroidism among AFTNs ranged from 0% to 15%
(10,21,24,28).
PATHOLOGY
Thyroid follicles in TMNG vary from medium to large in
size with epithelium composed of flat, low cuboidal cells. By
contrast, the hyperactive follicles in a Graves' gland, consisting
of high or columnar epithelium, are homogeneous and diffusely scattered throughout both lobes. A diffuse form of
TMNG can be distinguished from Graves' disease by the
variable follicular size, abundance of connective tissue and
absence of lymphocytic permeation (5). The solitary AFTN is
characterized by a large encapsulated hyperactive follicle
surrounded by normal but suppressed parenchyma. Twothirds of AFTNs are of the cellular microfollicular or simple
adenoma variety (24).
INCIDENCE OF TOXIC NODULAR GOITER
Over the past several decades, the incidence of TMNG has
decreased dramatically in comparison with Graves' disease
and AFTN. When Plummer at the Mayo Clinic first described
TMNG in 1913,it accounted for about 20% of their hyperthyroid
cases. Paralleling the declining incidence of nontoxic goiters,
only 59 cases of TMNG were treated at that same institution
between 1970 and 1974 compared with 334 cases between 1950
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Journal of the Hong Kong Medical Association Vol. 42, No.3, 1990
and 1954 (19). In iodine-sufficient areas, TMNG now accounts
for about 4% to 15% of hyperthyroidism (29,30). In a recent
survey of 201 hyperthyroid patients in New Zealand (31), 170
had Graves' disease, 21 TMNG, and only 10 had AFTN. On the
other hand, in iodine-deficient areas such as South America,
Iran and parts of Europe (25), TMNG still accounts for up to
one-half of hyperthyroid conditions. In a series of 630 surgical
patients, the relative incidence of Graves' disease, TMNG and
solitary AFTN was 58.2%, 36.2% and 5.6% respectively (24). This
epidemiological data supports the major promoting role of
iodine insufficiency and TSH stimulation in its pathogenesis,
and suggests that the recent declining incidence of toxic
goiters in endemic areas is related to increased dietary iodine
intake.
Solitary AFTN is seen inroughly 5% of patients with dominant
sporadic nodules (22,32). However, most lesions are nontoxic,
and Hamburger (22) encountered only one toxic AFTN for
every 50 Graves' lesions. In endemic goiter areas, toxic AFTNs
can account for up to one third of hyperthyroid cases (18).
CLINICAL PRESENTATION
Because a TMNG evolves from a preexisting nontoxic
goiter, sporadic TMNG, unlike other forms of hyperthyroidism,
is more prevalent among patients in the seventh and later
decades of life (19). Given the earlier onset of TMNG in
endemic goiter areas, toxicity appears about a decade earlier
but still only after a 13 to 15 years period of evolution (18).
Women are affected in about 80% of cases (19).
Unlike Graves' disease, hyperthyroidism in TMNG develops insidiously. Seldom is the condition ushered in by a
dramatic flurry of thyrotoxic symptoms. Only after the diagnosis
is made are mild toxic symptoms retrospectively ascribed to
this indolent condition. As sporadic cases occur mainly in
elderly patients, cardiac symptoms (atrial fibrillation or congestive heart failure) predominate. Non-specific symptoms
such as weight loss, increasingly labile control of diabetes
mellitus or delayed recovery from acute illnesses might raise
this diagnostic possibility to the astute physician. Less commonly, impaired swallowing or stridor reflects tracheal compression by a large goiter or one in a retrosternal location.
Toxic AFTNs, although frequently existing by the fourth
and fifth decades of life, usually become symptomatic only a
decade later (19,22). Whereas the female to male sex ratio in
sporadic nontoxic autonomous nodules is about 14.9:1, a lower
ratio of 5.9:1 is observed in toxic AFTNs (22). A larger
proportion of men (33%) are affected (22), and this is even more
so in endemic regions (33). Most patients with AFTN are
clinically and biochemically euthyroid (22,24), and a dominant
nodule is often the sole finding (21,24). Tachycardia, anxiety
and weight loss suggest the possibility of hyperthyroidism, and
the absence of a bilateral goiter and eye signs point to the
correct diagnosis.
DIAGNOSTIC STUDIES
Investigations should detect hyperthyroidism, verify autonomous function, and delineate the location, size and nature
of the nodules. Relying on a single biochemical test will fail to
diagnose hyperthyroidism in some cases. Screening tests
should include a serum RIA T4, T3 uptake and FTI. Accompanying the gradual decrease in radioiodine uptake (RAIU) in
the general population, the 24 hours RAIU in TMNG has
declined simultaneously, from about 35% to 26% in one longterm study (19). The low sensitivity of RAIU in diagnosing
hyperthyroidism is apparent given the finding that 22 of 35
patients with large toxic goiters had a RAIU of less than 30%
168

(34). The RAIU is of value in estimating the radioiodine dose

given for therapeutic ablation.
Autonomy of function is supported by the finding of a
nonsuppressible RAIU in conjunction with a positive TSH
suppression scan (after T3) (8). A TRH test is a sensitive
indicator of hyperthyroidism even in the preclinical stage. A
blunted TSH response with less than a 3 mU/L rise 30 minutes
after 200 micrograms of intravenous TRH (or 3 hours after 40
mg TRH by mouth)is indicative of biochemical hyperthyroidism
(11). More recently, supersensitive TSH that reliably measures
circulating TSH below 1 mU/L offers a convenient alternative
to the TRH test. It is suppressed below 0.3 mU/L in 97% of
hyperthyroid patients (35). Aserumfree T3 should be measured
in all patients suspected to have an AFTN because of a higher
incidence (21,22) of T3 toxicosis with normal free T4 and FTI
levels (23,36), particularly in endemic goiter areas (33). TSH
stimulation can lead to preferential secretion of T3 overT4 (36)
but the serum T3 parallels the T4 level in most toxic patients
(24). These more refined tests (high sensitivity TSH or TRH
test and free T3 levels) should be employed in patients who
have longstanding goiters and clinical hyperthyroidism.
Radionuclide imaging is helpful in diagnosing a solitary
AFTN when there is relative suppression of the extranodular
parenchyma. After TSH stimulation (10IU), autonomy may be
evidenced by a redistribution of isotope to previously suppressed areas (8) or by an increased RAIU. A repeat scan after
TSH suppression produces no diminution of uptake by an
autonomously functioning hot nodule. Nonetheless, a scan
does not reliably distinguish between an AFTN and a hyperfunctioning autonomous nodule within a TMNG. Cold areas
on a radionuclide scan may harbour hyperactive follicles that
can only be visualised by autoradiography. This is partly due
to the limited sensitivity of radiographic photoemulsion films,
and partly because a functioning area will still appear cold on
scans if there is less than 9% relative uptake compared with
adjacent hot areas (37). Hunter and Oakley (38) reported that
among 22 patients with clinically solitary hot nodules, only nine
had solitary adenomas and ten had TMNG. Moreover, three
of six seemingly solitary autonomous nodules proved to be
hyperfunctioning nodules within a TMNG. Scans can help to
differentiate between TMNG and Graves' disease superimposed
on a simple goiter because nodules in the latter fail to show
isotope uptake (39).
Thoracic inlet x-rays that disclose retrosternal tracheal
compression can alert the anaesthetist to a potentially difficult
intubation. Ultrasonography provides supplementary information regarding the nature of an AFTN. A partially cystic
mass, seen in as many as one-half of AFTNs, is more likely to
undergo degeneration (24,28). Large, solid nodules should
undergo fine needle aspiration biopsy to exclude a neoplasm
that requires surgical excision. However, false-positive errors
may occur because of bizarre pleomorphic changes associated
with AFTN (32).
INDICATIONS FOR DEFINITIVE TREATMENT
Frank hyperthyroidism necessitating definitive treatment
develops in only a minority of patients with sporadic AFTN or
TMNG. On the other hand, because euthyroid patients with
endemic TMNG have a great risk of developing toxicity,
surgeons in endemic areas are more liberal in advocating
surgery. In two large studies, 56.7% and 74% of German and
Swiss patients, respectively, underwent resection for only
preclinical hyperthyroidism (11,18). This policy stems from
their young age of onset of disease, and the subsequently
longer followup period with greater likelihood of developing

Review Articles: Toxic Nodular Goiter

hyperthyroidism. Treatment is generally advisable in healthy
patients with a solitary AFTN larger than 3 cm in size (22),
especially in older patients or those with evidence of preclinical
hyperthyroidism. Even though they may be biochemically
euthyroid, their disease is often rapidly progressive and symptoms can be quite severe.
Tracheal obstruction can occur with huge TMNGs. In one
study, ten of 13 TMNGs weighing 200 grams or more gave rise
to tracheal compression, and seven of these were clinically
symptomatic (40). Significant compression, more likely when
there is a retrosternal component, is an indication for surgical
decompression:
Malignancy arising in a hyperthyroid goiter is an uncommon but consistent finding in most surgical series. This
possibility should be considered whenever there is a hard or
enlarging dominant nodule within a longstanding goiter. The
reported incidence ranges from 2.6% (18) up to 10% (27) and
seems to be higher in endemic goiter areas. Pacini and his
colleagues (41) observed a 7.5% incidence of cancer in TMNG
and 2.5% in AFTN. Although three of 29 patients (10.3%) with
AFTN (including 24 with nontoxic disease) were found to have
coincidental thyroid cancer in another report (24), these were
merely occult papillary carcinoma. Other surgical series note
a cancer incidence of between 4% (42) and 5.7% (24) in AFTNs.
Whether thyroxine suppression can avert definitive treatment in euthyroid patients with autonomous goiters is unsettled. TSH plays a role in the early development of nodules,
and the adenylate cyclase system in hyperfunctioning nodules
responds normally toTSH (3). Theoretically, TSH suppression
might retard nodule growth or function in its early stages of
development. This is suggested by the observation that regression in nodule size occurred in 4 of 9 euthyroid patients
with AFTNs given thyroid hormone (23). Moreover, suppression of RAIU in solitary hot nodules was accompanied by
a reduction in nodule size in 35% of 46 patients given thyroxin
(9). However, because totally autonomous nodules are TSHinsensitive (6,11), it is arguable whether their continued growth
would be impeded by the withdrawal of TSH stimulus.
Thyrotoxicosis may be induced inadvertently (12), and a TRH
test or high-sensitivity TSH level is advisable before prescribing thyroxine.
SURGICAL TREATMENT
Surgery can be performed on an elective basis in nearly all
cases. Antithyroid drugs alleviate toxic symptoms satisfactorily in all but a few elderly patients who present with acute
cardiac failure. Attunes, surgery is feasible only after radioiodine
has been given because a patient is initially too ill for
thyroidectomy (19). Antithyroid drugs may be dispensed with
in cases with only minimal hyperthyroidism (23).
Preoperatively, propanolol is used besides antithyroid drugs.
Iodine should be avoided because it can precipitate a JodBasedow form of thyrotoxicosis, particularly in iodine-deficient
areas (21,37,43).
TMNGs are treated by subtotal thyroidectomy and solitary
AFTNs by unilobar thyroidectomy (32). Partial division of the
strap muscles improves the surgical exposure for largeTMNGs.
Subcapasular dissection without lateral ligation of the inferior
thyroid arteries facilitates preservation of the blood supply to
the parathyroid glands. All macroscopic nodules should be
excised. Retrosternal gland extension can be dealt with by
carefully hugging the thyroid parenchyma and visualising the
recurrent laryngeal nerves in order to deliver the lower component through the cervical incision. At times, the recurrent
laryngeal nerve may be more conveniently identified near its

insertion into the larynx after mobilisation of the upper pole,

and subsequently traced caudad towards the larger lower pole
area. Closed suction drainage is advisable because of the large
residual dead-space. Despite even marked tracheal compression, postoperative tracheal intubation is rarely needed.
Selective surgery of autonomous nodules has been practised in endemic goiter areas (11,17). Between 6 and 20 grams
of non-nodular tissue, mostly in the upper poles, are left in situ.
This policy resulted in an early reduction in the circulating
thyroid hormone level after surgery, and eventual recovery of
TRH responsiveness in 90% of patients (11,17).
As a result of the larger gland size and older patient
population, surgery for TMNG incurs a higher surgical morbidity than that for Graves'disease.Postoperative haemorrhage
is encountered in roughly 1% of cases (18,19). Recurrent
laryngeal nerve paralysis develops in between 0.9% and 3.6%
(11,18,19,44), especially in patients undergoing re-exploration
(30) where is may be found in as much as one-fifth of patients
(18). Hypoparathyroidism is permanent in about 1% of patients
(19,30,44).
Hyperthyroidism is controlled in half of TMNG patients
within six weeks, and in over three quarters of them within a
year of surgery (19). Serum T4 drops promptly after surgery
but only a minority of patients with overt or subclinical
hyperthyroidism achieve a normal TRH response within the
first postoperative week (11). Full recovery of pituitary-thyroid
feedback control takes several weeks.
Hardly any patient with sporadic TMNG ever requires a
second treatment to alleviate hyperthyroidism (19). Persistent
hyperthyroidism occurs occasionally in endemic TMNG (18).
Lobectomy for solitary AFTNs, incurring virtually no
mortality or morbidity, eliminates hyperthyroidism in almost
all patients (21,24).
RADIOIODINE TREATMENT
Because the relatively low RAIU of most TMNGs is offset
by the large size of most glands, a bigger ablative dose than that
used for Graves' disease is required. Most patients are given
150 to 200 microCi per gram of estimated tissue (21,34,45).
Other workers prefer a larger initial dose of 40 to 50 mCi for
TMNG glands with an estimated weight between 100 and 200
grams, and between 75 mCi and 100 mCi is used for very large
goiters or in markedly toxic patients (8,37). TSH may be given
to increase the RAIU in glands that have alow RAIU or are small
in size. Antithyroid drugs are withheld until radioactive iodine
has been given. Hamburger (34) reported that a single calculated dose between 20 and 50 mCi was effective even for
large goiters (200 grams or larger). In view of the variable
response to calculated doses, and the observation that palpation consistently underestimated the gland weight [by an
average of 39 grams in one study (19)], some workers have
employed a standard initial dose with considerable success. Of
31 patients who had either TMNG or AFTN, only one required
repeat treatment after an initial 15 mCi standard dose (39). A
single dose was effective in 78% of patients with large goiters
(34).
I-131 treatment has theoretical appeal in treating solitary
AFTNs because the short-range beta particles emitted are
avidly concentrated in the targeted hot nodule while sparing
the adjacent normal parenchyma. T3 or T4 is given pretreatment to minimize isotope uptake by the TSH-responsive
extranodular parenchyma (20). An effective dose of between
10 and 15 mCi (corresponding to an administered dose of
between 30 and 45 mCi) of I-131 is needed to treat most AFTNs
that exceed 4 cm in size (37). Lugol's iodine is given after
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Journal of the Hong Kong Medical Association Vol. 42, No. 3,

radioiodine ablation to retard damage to normal recovering
thyroid follicles (8,37). A single ablative dose proved effective
in most patients with solitary AFTNs (31,39) but four of 35 toxic
AFTNs in one report (24) underwent surgery after failing to
respond to initial radioiodine. Arapid uptake into a small iodine
pool with a short turnover may lead to an insufficient exposure
of the lesion to the radioiodine (24,37).
Hyperthyroidism tends to persist longer after radioiodine
ablation than after surgery (19). Only about 60% of TMNG
patients are no longer toxic within a year of radioiodine treatment (19). Large initial doses control hyperthyroidism more
reliably and with a reduced need for a repeat dose. Nevertheless, even 50 mCi was not effective after two months in a half of
patients in one series (37). Occasional deaths [with even
thyroidstorm (51)] occurring before euthyroidism was achieved
have been reported after RAI but this is less common after
surgery (37). This is probably due to radioablation being
selected for more critically ill, often hospitalized, patients (19).
A repeat course of radioiodine, necessary in a quarter of
patients, practically ensures successful control (19,31).
To avoid large doses of radioiodine, mostlarge TMNGs are
treated by surgery rather than I-131. The average gland weighs
more than 100 grams in surgical series (11,19) but in only
between 4% and 11% of radioablated patients (40). Although
gland regression occurs in as many as one-third of TMNG
patients after radioiodine, this is usually modest, and a sizable
residual goiter is the rule (6). In one report (40), tracheal
compression was reduced in five of seven patients with large
TMNG treated by radioiodine but only one derived relief of
obstructive symptoms, and one patient required surgery later.
After radioiodine treatment, only eight of 22 patients with
AFTN in one series with long followup data had complete
resolution of their nodules, and two even developed larger
lesions (20). About half of these residual nodules were cold and
the rest were either warm or even hot on postoperative scans
(20). Most patients rendered euthyroid after radioactive iodine
had persistent preferential isotope uptake in the nodule with
suppression of the extranodular tissue (21).

RECURRENCE
The major advantage of subtotal thyroidectomy for TMNG
is that not only is hyperthyroidism alleviated but the risk of
recurrence is extremely low. Endemic AFTN or TMNG relapsed
in between 0% (24) and 4.2% of patients (18) compared with
none after surgery in sporadic goiter areas (19). Because of the
dissociation between follicular growth and function, destruction
of only hyperfunctioning tissue by selective surgery or
radioiodine treatment may not prevent recurrent goiter formation from hypofunctioning nodules (6). Six of seven goiters
that recurred after selective resection arose from macroscopically normal lobes that were not resected (11). This supports
the role of subtotal thyroidectomy in the operative management
of TMNG.
The value of thyroxine supplement to decrease the likelihood of relapse after thyroidectomy is unsettled. Thyroxine
has little to offer after resection of AFTN where the recurrence
rate is less than 1% (8). Most recurrences in TMNG probably
arise from the proliferation of residual autonomous follicles.
This is suggested by the observation that 10% of patients who
were euthyroid postoperatively had a persistently negative
TRH test (11). As such, not only would these patients not be
expected to respond to exogenous thyroxine but there is the
possibility of producing iatrogenic hyperthyroidism (11). In
endemic goiter areas, however, the iodine metabolism of the
residual TSH-dependent thyroid tissue may be impaired, and
exogenous thyroxine supplement may abolish postoperative
170

goiter stimulation by a supranormal TSH level (11). Hence,

thyroxine prophylaxis against postoperative recurrence may
be appropriate for goiters not giving rise to hyperthyroidism,
particularly in endemic areas (11).
Apart from the one-quarter of patients who require a second
dose of radioiodine to alleviate hyperthyroidism, a small proportion relapse after initial control. Among 21 patients with
TMNG, a cumulative 13% of patients relapsed within one to five
years after 20 mCi of radioiodine (31). An unexpectedly high
proportion of patients (17%) relapsed two or more years after
receiving 10 mCi for AFTN (31). The authors postulated that
these cases might have been TMNG that were misdiagnosed
as AFTN. Alternatively, these might have represented recurrence in persistently functioning areas after radioiodine ablation (21).
IATE HYPGTHYROIDISM
After subtotal thyroidectomy for sporadic TMNG, about
16% of patients become hypothyroid one year postoperatively
(19). Although Simms and Talbot (29) reported a l2% incidence
of hypothyroidism after a mean followup of 5.8 years, other
groups note a much higher incidence of 50% (30) and even up
to 70% (19) within five years of surgery. Hypothyroidism
should be expected in patients who undergo repeat treatment
by either surgery or radioiodine (19). A higher dietary iodine
content (19) or more aggressive resection may account for the
rising incidence of hypothyroidism seen recently. Others
believe that the risk of late hypothyroidism is related to differences in the underlying pathology. Hypothyroidism developed in 31% of patients with TMNG and diffuse hyperplasia
(perhaps representing Graves' disease in a nodular goiter) but
only 3% of those with TMNG and nodular hyperplasia (46).
Hypothyroidism develops in between 16% (19) and 24% (31)
of patients after radioiodine ablation of TMNG. Earlier series
recorded a lowerrate (47) but more recent reports (48) suggest
a rising incidence that may be due to larger doses of radioiodine
given or longer followup.
Permanent hypothyroidism develops in less than 10% of
patients after lobectomy for solitary AFTN (21,30). A higher
reported incidence can be ascribed to destruction of normal
extranodular parenchyma by either prior radioiodine therapy
(24) or subtotal thyroidectomy (49), or to an atrophic residual
lobe (24). The normal lobe may take several months before
recovering function so hypothyroidism should be considered
permanent only if it persists beyond the first few months after
surgery.
Reports of few or even no instance (21,45,50,51) of clinical
hypothyroidism among patients receiving about 10 mCi I-131
for solitary AFTNs supported the notion that radioiodine could
selectively destroy the toxic lesion. However, Goldstein and
Hart (20) recorded a 36% incidence of hypothyroidism among
22 patients followed an average of 8.5 years after receiving a
mean dose of 23 mCi. Danaci and co-workers (31) also
reported a 40% cumulative rate of hypothyroidism within five
years of receiving an average dose of 12 mCi. Perhaps a lower
initial dose might be equally effective without producing such
a high incidence of late hypothyroidism.
RECOMMENDED MANAGEMENT
Both radioiodine ablation and surgery offer effective definitive treatment of toxic nodular goiter. The choice between
the two methods should be individualised according to the
general health and age of the patient, the severity of toxicity, the
goiter size and presence of obstruction, the possible risk of
malignancy, and prior treatment.
Extreme safety and ease of administration makes radioiodine

Review Articles: Toxic Nodular Goiter

ablation appealing in medically unfit or very elderly individuals,
especially if there is only mild toxicity or a small gland. A fixed
initial dose seems as suitable as a calculated dose based upon
the estimated weight and RAIU. A repeat dose should be given
if hyperthyroidism is not alleviated within six months. Because
of the higher morbidity attending reoperations, recurrences
after surgery are best treated by radioiodine.
Besides eradicating hyperthyroidism, surgery also removes
what is usually a sizable gland with only a minimal risk of goiter
recurrence. Hence, operative management is optimal in otherwise healthy patients, especially if they are young or live in an
endemic goiter area. Even elderly patients with marked toxicity can be rapidly and predictably improved by surgery so
long as their cardiac problems can be controlled before
thyroidectomy. Patients with obstructing lesions or a suspicious
nodule should be regarded in the same manner as those with
nontoxic goiters and undergo operation.
Solitary toxic AFTNs are also best treated by a lobectomy.
It is extremely safe, spares the normal thyroid parenchyma
thereby achieving a high rate of euthyroidism, and avoids a
large dose of radioiodine that is attended by a high incidence
of late hypothyroidism.
Thyroxine need not be given routinely after definitive
therapy, especially after lobectomy for AFTN. It may be
necessary after subtotal thyroidectomy for TMNG if serum
TSH levels are raised. Lifelong followup is essential even after
initially successful treatment. Periodic thyroid function tests
are needed to detect late-onset hypothyroidism and to adjust
thyroxine replacement doses.

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