DESCRIPTION of CASE
A 35-year-old woman became aware of a swelling in her neck about ten
weeks before referral. She had been trying to conceive for ten months. She
had had a missed abortion five months earlier. Because of the neck
swelling, her family doctor arranged thyroid function tests, which were in
the thyrotoxic range on two occasions five weeks apart: serum free
thyroxine, 26 and 28 pmol/l (normal range, 11–23); serum free tri-iodothyronine,
10.9 and 11 pmol/l (normal range, 3.5–6.5); serum thyroid-stimulating
hormone (TSH), <0.05 mU/l (normal range, 0.3–4.1).
Her previous medical history included a partial thyroidectomy for
thyrotoxicosis at the age of 24. Other than a goitre, she had no symptoms
except increased appetite and a slight tremor, which she had been aware of
for about eight weeks. Following the missed abortion, she had two normal
menstrual periods. Her only medication was folic acid supplements. She
worked part-time and had a two-and-a-half-year-old child.
On examination she was of average weight. Her hands were warm and
moist. There was a fine tremor. A previous thyroidectomy scar was noted.
The right lobe of the thyroid was palpable and felt smooth. There was a
bruit over the right thyroid lobe on auscultation. She had lid retraction
and lid lag but no other signs suggestive of thyroid-associated
ophthalmopathy (TAO) (Figure 1).
Her pulse rate was 100 beats per minute and regular. Her blood pressure
was 150/70 mm Hg. The rest of the examination was normal.
Figure 1. The Patient's Appearance at the Time of Presentation with
Note that there are no signs of TAO, but the patient has minimal
upper lid retraction (the upper lid should normally be halfway between
the limbus and the pupil).
What Is the Cause of Her Thyrotoxicosis?
Thyrotoxicosis is no more than a descriptor for a pattern of
biochemical abnormalities. Before considering treatment, it is the
clinician's task to define the underlying cause, as an accurate diagnosis
is an essential guide to the most appropriate treatment (Box
The most likely causes in this case were Graves disease, thyroiditis,
toxic multinodular goitre (TMNG), and toxic adenoma. The hallmark of TMNG
or toxic adenoma is the presence of one or more palpable thyroid nodules.
In this case the patient had previously undergone a partial thyroidectomy
and a vascular thyroid remnant was palpable on the right thyroid lobe.
Post-partum thyroiditis occurs within 12 months of childbirth; a variant
of this condition occurs after miscarriage. In this patient's case
post-partum thyroiditis was unlikely because her previous pregnancy was
2.5 years earlier; however, the miscarriage five months earlier may have
been relevant. Viral thyroiditis is usually preceded by an upper
respiratory tract infection and the thyroid gland is tender to touch; the
absence of these features makes viral thyroiditis unlikely. “Silent”
thyroiditis may present in this way and was a possibility here.
Laboratory tests that may help differentiate between the different
causes of thyrotoxicosis include a radiolabelled technetium or iodide
thyroid scan (Figure 2), and
measurement of anti–thyroid peroxidase (TPO) antibodies, TSH receptor
antibodies, and inflammatory markers (Table
1). The thyrotoxic phase of thyroiditis is usually followed by
spontaneous euthyroidism and in some cases hypothyroidism. Repeating
thyroid function tests within a few weeks of the first set may identify
cases of thyroiditis.
Figure 2. Technetium 99 Thyroid Uptake Scans
(B) Graves disease: diffuse increased uptake in both thyroid lobes.
(C) TMNG: “hot” and “cold” areas of uneven uptake.
(D) Toxic adenoma: increased uptake in a single nodule with
suppression of the surrounding thyroid.
(E) Thyroiditis: decreased or absent uptake.
(Image: Giovanni Maki)
Click to enlarge.
Table 1. Diagnostic Tests for Identifying the Cause of Thyrotoxicosis
In this case the prolonged time course of thyrotoxicosis, the presence
of a vascular thyroid remnant, the persistently thyrotoxic thyroid
function tests, and the elevated serum levels of TSH receptor antibodies
(62 U/l; reference range, 0–10) were in favour of a diagnosis of recurrent
What Are the Effects of Thyrotoxicosis on Fertility and Risk of
Menstrual irregularities occur in about 20% of thyrotoxic women .
Infertility is common in women with thyrotoxicosis even when they maintain
ovulatory cycles .
Thyrotoxicosis also increases the risk of miscarriage to 26% .
How Should This Patient Be Treated?
There are three treatment options for thyrotoxicosis due to Graves
disease: radioiodine (131I) therapy, thyroidectomy, and
anti-thyroid drugs . 131I
therapy is safe and effective, but pregnancy should be deferred for 4–6
months after treatment as there are theoretical risks of fetal
abnormalities. Most national regulatory authorities recommend avoidance of
close contact with adults for a few days and with children and pregnant
women for 2–3 weeks. 131I therapy was not appropriate for this
patient because she wished to proceed with pregnancy as soon as possible
and she had a two-and-a-half-year-old child, who would be difficult to
care for after 131I therapy.
A second thyroidectomy is worthy of consideration, but involves general
anaesthesia and a period of recuperation of a few weeks and therefore
disruption of family and professional life. The risks of damage to the
recurrent laryngeal nerves and parathyroid glands after a second
thyroidectomy are considerably greater than after a first operation and
are of the order of 5%–10%. Because of these considerations, thyroidectomy
was not felt to be a suitable option.
Anti-thyroid drugs (carbimazole, methimazole, and propylthiouracil)
restore euthyroidism within a few weeks of initiation of treatment .
Minor side effects (such as skin rashes) occur in about 5% of cases.
Agranulocytosis is rare (0.4%),
but the consequences are life threatening and all patients on anti-thyroid
drugs must be made aware of this complication (Box 2).
All anti-thyroid drugs have been used and are acceptable in pregnancy.
Congenital anomalies have been reported in association with
anti-thyroid drugs, but the increase in risk above background is very
marginal. The risks of aplasia cutis and choanal and oesophageal atresia
may be slightly lower with propylthiouracil than with other anti-thyroid
drugs (choanal and oesophageal atresia, scalp defects, minor facial
anomalies, and psychomotor delay compose an embryopathy implicated with
methimazole use). But because the evidence is inconclusive and the
additional risk minimal, all three drugs are widely used in pregnancy. The
lowest dose of anti-thyroid drug that maintains euthyroidism should be
used in women who wish to become or are already pregnant, in order to
avoid fetal hypothyroidism and fetal goitre formation.
In this case propylthiouracil was used initially, at a dose of 50 mg
four times per day. The patient was advised to take contraceptive measures
until euthyroidism. Four weeks later her thyroid function tests had
improved: serum free thyroxine, 13 pmol/l; serum total tri-iodothyronine,
2.5 nmol/l (normal range, 1.34–2.73); serum TSH, <0.05 mU/l. The dose of
propylthiouracil was reduced to 25 mg four times per day, and the patient
was advised that she could start trying to conceive.
What Are the Risks of TAO?
TAO is a complication that many patients fear. It can be disfiguring
and difficult to treat . If
there are no clinical features of TAO at presentation, the risk of
developing it in future is approximately 15%. Smoking is an important
predisposing factor. As this patient was a non-smoker the probability of
developing TAO is less than 10%.
What Monitoring Is Required during Pregnancy?
The dose of anti-thyroid drug usually needs to be decreased during
pregnancy, and often Graves disease remits completely and the medication
can be withdrawn. This is probably due to the overall immunosuppressive
effect of pregnancy.
Monitoring of free thyroid hormone concentrations is of paramount
importance during pregnancy and should be performed every 4–6 weeks, or
more frequently if thyroid status is changing. The biochemical target is
to achieve and maintain maternal serum free thyroxine levels at or
slightly above the upper limit of normal, using the lowest dose of
anti-thyroid drug possible. TSH receptor antibodies should be measured in
the third trimester because positivity is predictive of neonatal
When the mother (as in this case) has a functioning thyroid gland or
remnant in situ, maternal thyroid function mirrors that of the fetus. If
there are concerns about fetal thyrotoxicosis (e.g., because maternal
hyperthyroidism proves difficult to control), fetal heart rate monitoring
should be undertaken. A persistent fetal tachycardia greater than 160
beats per minute is suggestive of fetal thyrotoxicosis. In cases where
fetal thyrotoxicosis is diagnosed, monitoring of fetal growth and fetal
goitre by ultrasound is imperative. In most cases the fetus can be treated
satisfactorily by adjusting the dose of anti-thyroid drug in the mother
and by following the fetal response clinically and by ultrasound.
What Are the Risks to the Fetus in a Woman with Graves Disease?
Poor control of maternal hyperthyroidism is associated with significant
obstetric complications including miscarriage (26%), low birth weight,
prematurity, (pre-)eclampsia, and possibly congenital malformations .
After the fetal thyroid matures (from 20 weeks of gestation onwards),
maternal TSH receptor antibodies may act on the fetal thyroid to cause
fetal thyrotoxicosis and goitre. The risk of fetal thyrotoxicosis is about
1% of all pregnancies in women with Graves disease, and if untreated,
fetal mortality may be as high as 24%. Overtreatment may lead to
hypothyroidism in the fetus, which is associated with subtle
neurocognitive deficits later on in life, particularly if the
hypothyroidism occurs in the first trimester .
Fetal goitre can develop as a result of fetal thyrotoxicosis or fetal
hypothyroidism and in severe cases can obstruct labour.
What Are the Risks of Recurrence of Thyrotoxicosis after Delivery?
The risk of relapse of maternal thyrotoxicosis is high in the
post-partum period (up to 80%), and close monitoring is required.
Anti-thyroid drugs can be used safely during breastfeeding .
Prenatal Counselling of Women with Graves Disease
Pregnancy is a common concern among women of childbearing age who are
receiving treatment for Graves disease. Some women may elect to have
definitive treatment before pregnancy, which can be either a thyroidectomy
or 131I therapy. The advantage of these treatment options is
that the risk of maternal thyrotoxicosis during pregnancy is reduced, if
not eliminated. Fertility is not affected by 131I therapy for
thyrotoxicosis, but pregnancy should be deferred for 4–6 months after
131I therapy, although the basis of this recommendation is largely
empirical. The risk of fetal and neonatal thyrotoxicosis is not eliminated
by previous thyroidectomy or 131I therapy. The most important
advice to women who have a previous history of thyroid dysfunction is to
work with their practitioner to ensure that thyroid function tests are
normal at the time of conception and throughout pregnancy.
Aetiology of Graves Disease
Graves disease is an autoimmune condition and is mediated by
stimulatory autoantibodies to the TSH receptor. There is a significant
genetic component to the aetiology of Graves disease, although
environmental factors and stress also seem to confer risk .
Typically, the thyroid gland of patients with Graves disease is diffusely
enlarged and vascular.
Toxic Multinodular Goitre
TMNG may also run in families. The pathogenesis is unknown. The disease
begins with the formation of a single or few colloid nodules, and over a
period of several years these become larger and more numerous. Some
nodules are functioning and gradually acquire autonomy. With the passage
of time serum TSH declines and may become undetectable until at a later
stage serum free thyroid hormones rise. The hyperthyroidism of TMNG is
usually mild and tends to occur in middle life or later. Toxic adenomas
are benign neoplasms of the thyroid that are autonomous. In some cases
they arise because of somatic mutations that lead to constitutive
activation of the TSH receptor. As with TMNG, the hyperthyroidism tends to
Thyroiditis is due to an inflammatory process affecting the thyroid
epithelium. Unlike other causes of thyrotoxicosis, there is no increased
synthesis of thyroid hormones; instead, stored thyroid hormones in colloid
are released into the circulation because of the leaky epithelium. The
thyrotoxic phase of thyroiditis may be followed by a hypothyroid phase a
few weeks later, but as a rule the patient recovers and euthyroidism
ensues without any intervention.
Thyroiditis may occur after a viral infection (referred to as subacute
or De Quervain thyroiditis), in which case the patient typically has a
viral sore throat, the thyroid is tender, and inflammatory markers
(erythrocyte sedimentation rate and C-reactive protein) are raised.
“Silent” thyroiditis is autoimmune and characterised by positive anti-TPO
Investigating the Cause of Thyrotoxicosis
In many cases of thyrotoxicosis the aetiology will be apparent from
information that can be obtained from the history and clinical
examination. In cases where there is doubt, additional investigations are
indicated. Direct measurement of TSH receptor antibody levels is not
widely available, but can be very valuable as modern assays are highly
sensitive and specific. TSH receptor antibodies can occasionally be
positive in post-partum thyroiditis (this seems to be particularly rare in
Europe, though reported in North America and Japan), and in cases of doubt
a thyroid scan showing no uptake of radioisotope is diagnostic of
thyroiditis . TSH receptor
antibody measurement is indicated in pregnancy to assess the risks of
fetal and neonatal thyrotoxicosis. Anti-TPO antibodies occur in a
significant proportion of the normal population, and this limits the use
of this test. High concentrations of anti-TPO antibodies are present in
silent and post-partum thyroiditis. Radioisotope scans are useful in
identifying the cause of thyrotoxicosis (Figure
2), but should be avoided in pregnancy.
Treatment of Thyrotoxicosis
The treatment of thyrotoxicosis depends on the underlying cause.
Anti-thyroid drugs are effective in Graves disease, TMNG, and toxic
adenoma (Table 2), but not in
thyroiditis because the latter is not associated with increased de novo
synthesis of thyroid hormones.
Click to enlarge.
Table 2. Response of Common Causes of Thyrotoxicosis to 131I
Therapy and Anti-Thyroid Drugs
After a course of anti-thyroid drug treatment, remission may be
expected in Graves disease as a result of the immunosuppressive effect of
anti-thyroid drugs on synthesis of TSH receptor antibodies, but relapse is
the rule in cases of TMNG or toxic adenoma.
131I therapy is effective for Graves disease, TMNG, and
toxic adenoma. 131I therapy is ineffective in thyroiditis
because iodine uptake is reduced or absent in this condition (Figure
2). Most patients with Graves disease develop permanent hypothyroidism
after 131I therapy, whereas most patients with TMNG and toxic
adenoma do not. 131I therapy is associated with a small risk of
exacerbation of new development of TAO, particularly in smokers.
Thyroiditis may require symptomatic treatment with beta blockers during
the thyrotoxic phase.
The type of thyroidectomy (subtotal versus total) for Graves disease as
primary treatment has been the subject of controversy for some years. The
argument in favour of total thyroidectomy is that the risk of recurrence
of the thyrotoxicosis is eliminated, and that if performed by skilled
thyroid surgeons the probability of hypoparathyroidism and vocal cord
palsy is no greater than for a subtotal thyroidectomy .
A subtotal thyroidectomy, on the other hand, provides the best chance of
any treatment for Graves disease for long-term euthyroidism without the
need for thyroxine or other treatments for thyrotoxicosis.
The choice of treatment for Graves disease should be tailored to the
needs of the individual patient, but also depends on local facilities,
surgical expertise, and patient choice.
Box 1. Causes of Thyrotoxicosis
Common causes of thyrotoxicosis in a young female
- Graves disease
- Toxic multinodular goitre
- Toxic adenoma
- Iodine excess
Other rare causes of thyrotoxicosis
- Hyperemesis gravidarum
- TSH-producing pituitary adenoma
- Iatrogenic thyrotoxicosis
- Factitious thyrotoxicosis
- Struma ovarii
- Metastatic follicular thyroid cancer
- Thyroid hormone resistance syndrome