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Methods disease
I searched Medline for English language papers with Thyrotoxicosis can have many causes;
the topics “thyrotoxicosis”, “Graves’ disease”, and “goi- determining the cause is essential to formulate a
tre”, searched the Cochrane Database of Systematic treatment plan
Reviews by using the keyword “thyroid”, and used a
personal archive of references. A radioactive iodine uptake and scan should be
performed when the cause of a patient’s
thyrotoxicosis cannot be definitively determined
How do patients with thyrotoxicosis by history and physical examination
present?
Treatment options for forms of overt
Symptoms of overt thyrotoxicosis include heat intoler-
hyperthyroidism with normal to elevated
ance, palpitations, anxiety, fatigue, weight loss, muscle
radioactive iodine uptake include antithyroid
weakness, and, in women, irregular menses. Clinical
drugs, radioactive iodine therapy, and
findings may include tremor, tachycardia, lid lag, and
thyroidectomy
warm moist skin.1 Symptoms and signs of subclinical
hyperthyroidism, if present, are usually vague and non- Treatment options for thyroiditis (low radioactive
specific. iodine uptake) induced thyrotoxicosis include
blockers to relieve symptoms and glucocorticoids
to relieve anterior neck pain, if present
What causes thyrotoxicosis?
To treat thyrotoxicosis appropriately, determining the Whether or not to treat subclinical thyrotoxicosis
cause is essential. The most common causes of remains controversial
thyrotoxicosis are discussed below; other causes are
listed in the table.
Toxic nodular goitre
Graves’ disease Toxic adenomas are benign monoclonal thyroid
Graves’ disease is an autoimmune disorder in which tumours that secrete excess thyroid hormone autono-
thyroid stimulating immunoglobulin (TSI) binds to mously. Thyrotoxicosis may develop in patients with a
and stimulates the thyroid stimulating hormone (TSH) single autonomous thyroid nodule or in those with
receptor on the thyroid cell membrane, resulting in multiple autonomous nodules (toxic multinodular
excessive synthesis and secretion of thyroid hormone.2 goitre, also known as Plummer’s disease). Nodular
Patients with Graves’ disease usually have diffuse, non- autonomy typically progresses gradually, leading first
tender, symmetrical enlargement of the thyroid gland. to subclinical, and then to overt, hyperthyroidism.w4
Ophthalmopathy, consisting of protrusion of the eyes Remission is rare. Physical examination shows a single
with periorbital soft tissue swelling and inflammation, thyroid nodule, usually at least 2.5 cm in size,w5 or a
and inflammatory changes in the extraocular muscles
resulting in diplopia and muscle imbalance, is clinically References w1-w13 are on bmj.com
evident in 30% of patients with Graves’ disease.1
Causes of thyrotoxicosis
Underlying aetiology Diagnostic features
Common causes
Graves’ disease Thyroid stimulating immunoglobulin (TSI) Increased thyroid radioactive iodine uptake with diffuse uptake on scan, positive
binds to and stimulates the thyroid thyroperoxidase antibodies; raised serum thyroid stimulating immunoglobulin;
diffuse goitre; ophthalmopathy may be present
Toxic adenoma Monoclonal autonomously secreting benign Normal to increased thyroid radioactive iodine uptake with all uptake in the nodule
thyroid tumour on scan; thyroperoxidase antibodies absent
Toxic multinodular goitre Multiple monoclonal autonomously secreting Normal to increased thyroid radioactive iodine uptake with focal areas of increased
benign thyroid tumours and reduced uptake on scan; thyroperoxidase antibodies absent
Exogenous thyroid hormone Excess exogenous thyroid hormone Low to undetectable thyroid radioactive iodine uptake; low serum thyroperoxidase
(thyrotoxicosis factitia) values
Painless postpartum Autoimmune lymphocytic infiltration of Low to undetectable thyroid radioactive iodine uptake; thyroperoxidase antibodies
lymphocytic thyroiditis thyroid with release of stored thyroid present; occurs within six months after pregnancy
hormone
Less common causes
Painless sporadic thyroiditis Autoimmune lymphocytic infiltration of Low to undetectable thyroid radioactive iodine uptake; thyroperoxidase antibodies
thyroid with release of stored thyroid present
hormone
Subacute thyroiditis Thyroid inflammation with release of stored Low to undetectable thyroid radioactive iodine uptake; low titre or absent
thyroid hormone; possibly viral thyroperoxidase antibodies
Iodine induced hyperthyroidism Excess iodine Low to undetectable thyroid radioactive iodine uptake
Drug induced thyrotoxicosis Induction of thyroid autoimmunity (Graves’ Thyroid radioactive iodine uptake elevated in Graves’ disease or low to
(lithium, interferon alfa) disease) or inflammatory thyroiditis undetectable in thyroiditis
Amiodarone induced Iodine induced hyperthyroidism (type I) or Low to undetectable thyroid radioactive iodine uptake
thyrotoxicosis inflammatory thyroiditis (type II)
Rare causes
Thyroid stimulating hormone Pituitary adenoma Raised serum thyroid stimulating hormone and -subunit with raised peripheral
(TSH) secreting pituitary serum thyroid hormones
adenoma
Gestational thyrotoxicosis Stimulation of thyroid gland thyroid Thyroid radioactive iodine uptake contraindicated in pregnancy. First trimester,
stimulating hormone receptors by human often in setting of hyperemesis or multiple gestation
chorionic gonadotrophin
Molar pregnancy Stimulation of thyroid gland thyroid Molar pregnancy
stimulating hormone receptors by human
chorionic gonadotrophin
Struma ovarii Ovarian teratoma with differentiation primarily Low to undetectable thyroid radioactive iodine uptake (raised uptake of radioactive
into thyroid cells iodine in pelvis)
Widely metastatic functional Thyroid hormone production by large tumour Differentiated thyroid carcinoma with bulky metastases; tumour radioactive iodine
follicular thyroid carcinoma masses uptake visible on whole-body scan
atresia—in rare case reports.14 For this reason, PTU is Radioactive iodine therapy is relatively contraindi-
preferred over methimazole or carbimazole during cated in children and adolescents because of the lack of
pregnancy in regions where it is available.5 Although data regarding the long term risks associated with
small amounts of thionamide medications are secreted radiation. Radioactive iodine is absolutely contraindi-
in breast milk, prospective clinical studies have shown cated during pregnancy and lactation.
that the use of up to 750 mg/day of PTU or up to 20
mg/day of methimazole in lactating mothers does not
affect infants’ thyroid function.15 16
Thyroidectomy
A meta-analysis found that thyroidectomy cures
Other drugs
hyperthyroidism in more than 90% of cases.21 In addi-
In patients with severe hyperthyroidism or those with
tion, it eliminates compressive symptoms from large
thyroiditis (in whom thionamides are inappropriate),
toxic multinodular goitres. Unlike radioactive iodine
adjunctive drugs may be used to alleviate symptoms or
treatment, it is not associated with worsening of Graves’
restore euthyroidism more rapidly. None of these
ophthalmopathy. Thyroidectomy is safe in the second
therapies treat the underlying causes of thyrotoxicosis.
trimester of pregnancy. The procedure bears almost no
blockers relieve symptoms such as tachycardia,
risk of death when carried out by experienced
tremor, and anxiety in thyrotoxic patients. blockade
surgeons. However, thyroidectomy is complicated by
should be used as the primary treatment only in
recurrent laryngeal nerve injury or permanent
patients with thyrotoxicosis due to thyroiditis. High
hypoparathyroidism in 1-2% of patients.1 Transient
dose glucocorticoids may be used to inhibit conversion
hypocalcaemia, bleeding, or infection are also potential
of T4 to T3 in patients with thyroid storm (the most
complications. Surgery results in permanent hypothy-
severe form of thyrotoxicosis). Glucocorticoids may
roidism in most patients.
also be used to relieve severe anterior neck pain and to
Thionamides are used to restore euthyroidism
restore euthyroidism in patients with painful subacute
before thyroidectomy to avoid more severe thyrotoxi-
thyroiditis. Inorganic iodide (SSKI or Lugol’s solution)
cosis from leakage of thyroid hormone into the circu-
decreases the synthesis of thyroid hormone and
lation at the time of surgery and to reduce operative
release of hormone from the thyroid in the short term.
and postoperative complications associated with
It is used to treat patients with thyroid storm or, more
anaesthesia and surgery in thyrotoxic patients. SSKI or
commonly, to reduce thyroid vascularity before
Lugol’s solution is given for seven to 10 days before
thyroidectomy. Iopanoic acid, an oral cholecysto-
surgery for Graves’ disease to decrease thyroid
graphic agent rich in iodine, decreases synthesis and
vascularity.
release of thyroid hormone and inhibits the conversion
of T4 to T3. Short term use of iopanoic acid is effective
for the treatment of thyroid storm or for rapid prepa- Should subclinical thyrotoxicosis be
ration for thyroidectomy, but it is ineffective as long treated?
term therapy.w10
If serum TSH values are low because of overzealous
Radioactive iodine treatment of hypothyroidism (in non-thyroid cancer
Treatment with 131I is effective for patients with hyper- patients), the dose of L-thyroxine should be lowered.
thyroidism due to Graves’ disease or toxic nodular The question of whether endogenous subclinical
goitre: retrospective data show that 80-90% will hyperthyroidism should be treated remains controver-
become euthyroid within 8 weeks after a single 131I sial, but current guidelines based on available evidence
dose, whereas the remainder will require one or more recommend considering treatment when serum TSH
additional doses.17 In patients with toxic multinodular values are persistently < 0.1 mU/l.22 23 Treatment of
goitre, a prospective clinical study has determined that subclinical hyperthyroidism may decrease the risk of
radioactive iodine therapy will reduce goitre size by
40%.18 131I eventually causes permanent hypothy-
roidism in almost all patients.
Possible side effects of 131I therapy include mild Box 2: Unanswered questions and ongoing
anterior neck pain caused by radiation thyroiditis or clinical trials
worsened thyrotoxicosis for several days, owing to the Unanswered research questions
leakage of preformed thyroid hormones from the What factors predict remission in Grave’s disease
damaged thyroid gland. Pretreatment with a thiona- patients?
mide may reduce the risk for worsened thyrotoxicosis What is the optimal dose and duration of anti-thyroid
after treatment with 131I. Retrospective studies have medication for Graves’ disease?
shown that the efficacy of treatment with 131I is What are the risks and benefits of treatment for sub-
decreased after PTU treatment,w11 but both prospective clinical hyperthyroidism?
and retrospective studies have shown that the efficacy Should antithyroid drugs be used before and after
of 131I is not diminished after treatment with methima- radioactive iodine treatment?
zole or carbimazole as long as the drug is discontinued Current ongoing clinical trials
three to five days before 131I is administered.w11 w12 Block replacement therapy during radioiodine therapy
Graves’ ophthalmopathy may develop or worsen (Odense University Hospital, Denmark)
after treatment with 131I, especially in smokers and in Retuximab in the treatment of Graves’ disease (Odense
patients with severe hyperthyroidism.19 Strong pro- University Hospital, Denmark)
spective evidence shows that the exacerbation of Lanreotide (somatuline autogel) in thyroid associated
Graves’ ophthalmopathy can be prevented by the ophthalmopathy treatment (Ipsen, Paris, France)
simultaneous administration of glucocorticoids.20
Conclusions
Thyrotoxicosis can be readily diagnosed on the basis of Endpiece
serum thyroid function tests in patients with typical
signs or symptoms. Several effective forms of therapy The art of medicine
for thyrotoxicosis exist, all of which have advantages The aim of the art of medicine is health, but its end
and disadvantages. The choice of treatment depends on is the possession of health. Doctors have to know
the cause and severity of the thyrotoxicosis, as well as on by which means to bring about health, when it is
patients’ preferences. Box 2 gives information on unan- absent, and by which means to preserve it, when it
swered research questions and ongoing clinical trials. is present.
Galen. On the sects for beginners. Translated
Competing interests: None declared.
by Walzer R, Frede M. Indianapolis:
Hackett Publishing, 1985.
1 Cooper DS. Hyperthyroidism. Lancet 2003;362:459-68.
2 Streetman DD, Khanderia U. Diagnosis and treatment of Graves’ disease. Submitted by E Tullo, postgraduate student, history
Ann Pharmacother 2003;37:1100-9. of medicine, University of Newcastle upon Tyne
3 Pearce EN, Farwell A, Braverman LE. Current concepts: thyroiditis. N
Engl J Med 2003;348:2646-55.