By Kohler, Sibylle Wass, John A H

CLINICAL REVIEW Section 1 Epidemiology and aetiology


* Graves’ disease.

* Multinodular goitre.

* Toxic solitary nodule.

* Postpartum thyroiditis.

* Drug-induced thyroiditis (for example, amiodarone).

* Overtreatment with thyroid hormone.

* Thyrotoxicosis factitia (surreptitious ingestion of thyroid hormone in supraphysiological doses).

* Struma ovarii (teratoma containing functional thyroid tissue).

* Pituitary thyrotroph adenoma (TSHoma).

Thyrotoxicosis refers to the clinical syndrome that results when tissues are exposed to excess levels of thyroid hormones. It is 10 times more common in women than in men in the UK and affects approximately 2 per cent of the female population. The annual incidence is 3 per 1,000 women.

The most common cause is Graves’ disease, which mostly affects young women, but may affect all ages and both sexes.

Multinodular goitre affects the elderly most commonly and 30 per cent of patients are mildly thyrotoxic.

A single toxic adenoma is the third common cause and affects all ages. Rarer causes of thyrotoxicosis are shown in the box.

Risk factors include a family history, high iodine intake, smoking, and certain drugs, for example amiodarone. Amiodarone can cause thyrotoxicosis in two ways: it can increase thyroid hormone synthesis (type I) and have a direct toxic effect on the thyroid (type H).


The diagnosis of thyrotoxicosis maybe delayed if the symptoms are not classical. Obviously a goitre and eye changes point to a clear diagnosis. Unexplained weight loss, muscle weakness, oligomenorrhoea, palpitations, breathlessness, diarrhoea, loss of libido and pruritus can all be caused by thyrotoxicosis.



* Weight loss despite an increased appetite.

* Increased or decreased appetite.

* Irritability.

* Weakness and fatigue.

* Diarrhoea +- steatorrhoea.

* Sweating.

* Tremor.

* Mental illness: may range from anxiety to psychosis.

* Heat intolerance.

* Loss of libido.

* Oligomenorrhoea or amenorrhoea.


* Palmar erythema.

* Sweaty and warm palms.

* Fine tremor.

* Tachycardia-AF (common in elderly).

* Hair thinning or diffuse alopecia.

* Urticaria, pruritus.

* Brisk reflexes.

* Goitre.

* Proximal myopathy (muscle weakness +- wasting).

* Gynaecomastia.

* Lid lag (may be present in any cause of hypertnyroidism).

Section 2 Diagnosis

If symptoms and signs suggest thyrotoxicosis, thyroid function tests are indicated.

The single most useful test in confirming thyrotoxicosis is TSH which is undetectable in most cases of thyrotoxicosis (TSH

There are two exceptions to this rule, pituitary thyrotroph adenoma (TSHoma) and pituitary thyroid hormone resistance syndrome. In these cases, TSH is inappropriately normal or elevated despite high circulating levels of free hormones.

T3 thyrotoxicosis accounts for 5 per cent of all thyrotoxicoses, and is characterised by an undetectable TSH, elevated fT3 but normal fT4. Its management does not differ from that of typical thyrotoxicosis.

Subclinical thyrotoxicosis is characterised by suppressed TSH but normal concentrations of free hormones.

Once the diagnosis of thyrotoxicosis has been made, the cause has to be established. Clinical examination of the neck, thyroid antibodies and thyroid uptake scans are helpful.

Neck examination

A goitre is usually painless; if palpation of the neck is painful, thyroiditis de Quervain is likely. A diffuse goitre may be present in Graves’ disease and early stages of Hashimoto thyroiditis.

It is also important to search for palpable nodules or lymph nodes. If either is found, the patient should be referred to exclude thyroid cancer. Several palpable nodules may indicate a multinodular goitre.

Thyroid antibodies

Anti-TPO and anti-thyroglobuHn antibodies are present in 70-80 per cent and 30-50 per cent of patients with Graves’ disease respectively and in cases of Hashimoto thyroiditis. However, antibodies are non-specific and insufficient for a diagnosis.

Thyroid uptake scan

In Graves’ disease, uptake is typically homogenously increased, but a solitary area of high uptake is typical of a toxic nodule.In Hashimoto, de Quervain and postpartum thyroiditis, uptake is decreased, as thyroid tissue has been destroyed.

An uptake scan can be done two to three months after treatment for thyrotoxicosis has commenced.

Although the intensity of uptake will decrease, distribution will remain visible, and this is the important feature in discerning thyroid diseases.

Further investigations

In all cases, if symptoms have lasted for more than a year, a bone mineral density scan should be done to check for osteopenia/ osteoporosis and the patient examined for AF.

Ophthalmopathy develops in up to 30-40 per cent of patients with Graves’ disease and leads to swelling of the extraocular muscles, proliferation of orbital tissue as well as late fibrosis. All patients with thyroid eye disease shouldbe referred to anophthalmologist

Graves’ disease may be associated with other autoimmune conditions and screening is recommended.

A goitre is usually painless; if palpation of the neck is painful, thyroiditis de Quervain is likely

All patients with thyroid eye disease should see an ophthalmologist

Section 3 Management

Graves’ disease

Standard treatment for Graves’ disease is an 18-month course of antithyroid drugs (ATD). Carbimazole is the first choice in the UK. During pregnancy and lactation, propylthiouracil (PTU) is first choice because of its lower concentration in breast milk and the possible association of carbimazole with aplasia cutis.

Side-effects ofboth drugs are rash and urticaria, which are usually mild. A rare (0.5 per cent of patients) but serious sideeffect is agranulocytosis. Patients should be advised to discontinue ATD and contact a doctorimmediatelyshouldfeverand evidence of infection develop.

The starting dose of carbimazole is 40mg once daily if fT3 is >6pmol/l and 30mg if fT3 is

Propranolol 20-80mg three times daily is added if symptoms such as tremor, anxiety and palpitations are present and continued until the ATD have been effective (4-6 weeks).

TFTs should be repeated every 6-8 weeks and the dosage of ATD adjusted if necessary: carbimazole is gradually reduced in steps of 5 to 10mg(PTU in steps of 50 to 100mg) every 6-8 weeks as soon as fT4/fT3 have dropped into the normal range and later TSH begins to rise.

Treatment should be continued for a total of 18 months to ensure a 50 per cent chance of cure.

Radioactive iodine is administered orally as a capsule or drink. A dose of 400-800MBq is sufficient to cure thyrotoxicosis in 90 per cent.

Aminority of patients require a second dose of radioiodine (15 per cent) and only very rarely is a third dose necessary.

Patients should not have close contact (

Surgery is indicated in patients with moderate-to-severe Graves’ ophthalmopathy, patients who fear or reject radioiodine or patients in whom a rapid control of symptoms is required.

ATDs (or potassium iodide in severe thyrotoxicosis) are given preoperatively to achieve euthyroidism.

Risks of surgery are infection, laryngeal nerve damage, hypothyroidism and hypoparathyroidism.

Thyroxine replacement is started postoperatively at 100 microgram once daily and adjusted by 25 microgram upwards or downwards to get the TSH in the low part of the normal range. Calcium is checked postoperatively or if symptoms develop.

Graves’ ophthalmopathy

In Graves’ ophthalmology, hypothyroidism must be avoided, because this worsens the ophthalmopathy. All patients should be encouraged to stop smoking, as this exacerbates the problem. Referral is indicated.

Toxic solitary nodule

In this cause of thyrotoxicosis, as the nodules are autonomous, thyrotoxicosis will recur after ATDs are stopped, so definitive treatment is indicated. The first choice is radioiodine treatment

Multinodular goitre

Because relapse is invariate after discontinuing ATDs in multinodular goitre with thyrotoxicosis, radioiodine treatment is recommended for definitive control. Surgery is preferred for patients with local compressive symptoms. In elderly patients (>70 years of age) without osteoporosis or AF, ATDs can be continued lifelongifaeuthyroidstate is achieved with low dosages.

De Quervain thyroiditis

This viral infection is treated with NSAIDs. Occasionally, if painful, prednisolone 20-40mg once daily is effective. ATDs are rarely indicated because in De Quervain thethyrotoxicosis settles. The TFTs have to be monitored regularly as patients may develop hypothyroidism.

Postpartum thyroiditis

Postpartum thyroiditis affects 5-10 per cent of women within one year of pregnancy and is caused by a postpartum immune response. Often, hyperthyroidism develops within the first four months of delivery, followed by hypothyroidism 3-7 months after delivery, and spontaneous recovery within one year.

Treatment is recommended if the patient is symptomatic. If hyperthyroid, PTU is the drug of choice because of its lower concentration in breast milk. If hypothyroid, thyroxine is prescribed. Treatment should be withdrawn after six months to determine if spontaneous recovery has taken place. TFTs should be monitored annually in women with previous postpartum thyroiditis, as hypothyroidism develops in 40 per cent.

Amiodarone-induced thyroiditis

These patients may be difficult to render euthyroid because the iodine in the drug induces resistance to ATDs and should therefore be referred to an endocrinologist. If possible, amiodarone should be discontinued.

Subclinical thyrotoxicosis

There is evidence thatcomplications (such as AF) in subclinical thyrotoxicosis are more common if the TSH is completely suppressed (

In pregnancy, PTO is the drug of choice because of its lower concentration in breast milk

Section 4 Prognosis

Hyperthyroidism is characterised by relapses and remittances, with the relapse rate at about 50 per cent.

There is a threefold increased risk of death from osteoporotic fracture and 1.3-fold increase risk of death from cardiovascular disease (CVD) and stroke in untreated hyperthyroidism.

Long-term follow-up studies have shown increased mortality from CVD and cerebrovascular disease in those with a past history of treatment with radioiodine for overt hyperthyroidism.


After discontinuing ATD, TFTs are repeated every 6-8 weeks for six months, then six-monthIy for two years and annually thereafter, or earlier if symptoms return.

If there is recurrence, definitive treatment (radioiodine or surgery) has to be discussed with patients, as a second course of ATDs alone almost never results in remission.

Surgical treatment and radioactive iodine can both lead to hypothyroidism, and close follow up with TFTs is therefore required.

Followingradioactive iodine, hypothyroidism develops in 50 per cent of patients after 10 years, so that TFTs need to be checked every six months and thereafter yearly or earlier if symptoms are noted.

New developments

The management of thyrotoxicosis has not changed greatly in thelastfewyears.

It seems that ophthalmic Graves’ disease is less common, partly related to a decrease in smoking.

Amiodarone-induced thyroid disease remains common and difficult to treat.

In some centres radioactive iodine therapy is given ear lier in the treatment of Graves’ disease, because of the high recurrence rate – typically in men – and a lack of long-term side-effects.

The prognosis is good with treatment, but regular monitoringof thyroid function, probably yearly, is recommended.


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6. Schwartz K, Fatourechi V, Ahmed D, Pond G. Dermopathy of Graves’ disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab 2002; 87: 438-46.

Contributed by Dr Sibylle Kohler, specialist registrar, and Professor John A H Wass, consultant endocrinologist, at Churchill Hospital, Oxford

Copyright Haymarket Business Publications Ltd. May 16, 2008

(c) 2008 GP. Provided by ProQuest Information and Learning. All rights Reserved.