Clinical Review: Thyrotoxicosis

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

Section 1 Epidemiology and aetiology
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 II).

Presentation
The diagnosis of thyrotoxicosis may be 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.

Causes of thyrotoxicosis

  • 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).

Presentation of thyrotoxicosis

Presentation of thyrotoxicosis
Symptoms
  • 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.
Signs
  • 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 hyperthyroidism).

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 <0.01mU/l). If TSH is undetectable, free hormone concentrations (fT4 and fT3) are requested.

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-thyroglobulin 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.

All patients with thyroid eye disease should see an ophthalmologist

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 should be referred to an ophthalmologist.

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

Hormone Concentrations in Thyroid Abnormalities
ConditionTSHFree T4Free T3
Thyrotoxicosisundetectable↑↑
T3 thyrotoxicosisundetectablenormal↑↑
Subclinical thyrotoxicosissuppressednormalnormal
TSHoma↑ or normal
Thyroid hormone resistance↑ or normal

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 of both drugs are rash and urticaria, which are usually mild. A rare (0.5 per cent of patients) but serious side- effect is agranulocytosis. Patients should be advised to discontinue ATD and contact a doctor immediately should fever and evidence of infection develop.

The starting dose of carbimazole is 40mg once daily if fT3 is >6pmol/l and 30mg if fT3 is <6pmol/l. Carbimazole 40mg is equivalent to PTU 400mg.

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.

A minority 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 (<1m) to children under the age of 11 for two weeks after treatment. ATDs are continued after radioiodine, as it needs time to show effect.

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 lifelong if a euthyroid state 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 the thyrotoxicosis 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 that complications (such as AF) in subclinical thyrotoxicosis are more common if the TSH is completely suppressed (<0.1mU/l). Therefore, if the TSH is persistently <0.1 mU/l for over six months, treatment is indicated. A thyroid uptake scan should be requested to search for a toxic nodule. If one is found, radioiodine should be used. If there is diffuse uptake, either carbimazole or PTU can be prescribed for 18 months.

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.

Follow-up
After discontinuing ATD, TFTs are repeated every 6-8 weeks for six months, then six-monthly 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.

Following radioactive 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 the last few years.

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 earlier 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 monitoring of thyroid function, probably yearly, is recommended.

Resources
1. Bartalena L, Wiersinga W, Tanda M et al. Diagnosis and management of amiodarone-induced thyrotoxicosis in Europe: results of an international survey among members of the European Thyroid Association. Clin Endo 2004; 61: 494-502.

2. Pearce E, Farwell A, Braverman L. Current concepts: Thyroiditis. N Engl J Med 2003; 348: 2,646-55.

3. Weetman A. Medical progress: Graves' disease. N Engl J Med 2000; 343: 1,236-48.

4. Toft A. Subclinical hyperthyroidism. N Engl J Med 2001; 345: 512-6.

5. Wiersinga W, Bartalena L. Epidemiology and prevention of Graves' ophthalmopathy. Thyroid 2002; 12: 85s5-60.

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.

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