BMJ Learning

Hyperthyroidism: diagnosis and treatment

د. حسين محمد جمعة
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2010

Key points

The most common causes of hyperthyroidism are Graves' disease (70%) and nodular goitre (20%)
In most patients with Graves' disease the hyperthyroidism follows a relapsing and remitting course over many years. A minority (less than 30%) experience a single episode, lasting a few months only
In contrast, the hyperthyroidism associated with nodular goitre is invariably permanent

There is evidence that subclinical hyperthyroidism is a risk factor for atrial fibrillation and osteoporosis. You should therefore consider treating these patients in the same way as patients with more overt disease, particularly if they have nodular goitre.
Always consider hyperthyroidism in people with unexplained atrial fibrillation.


Hyperthyroidism developing in the first year after a patient has given birth is more likely to be due to postpartum thyroiditis than to Graves' disease
The hyperthyroidism of postpartum thyroiditis is usually mild. It lasts a few weeks only and doesn't need treatment, other than with occasional use of beta blockers

The ophthalmopathy of Graves’ disease is a difficult complication to manage, and all but the mildest cases should be referred for specialist advice.

Clinical tip

Most endocrinologists recommend that all women with menopausal symptoms should have thyroid function tests. This is because heat intolerance, palpitations, and irritability are common symptoms of both the menopause and hyperthyroidism. Also, Graves' disease most commonly presents at age 45 to 55.

What is it?

Hyperthyroidism results from excessive secretion of thyroxine (T4) or tri-iodothyronine (T3), or both.
Graves' disease the thyroid follicular cells are stimulated by an antibody directed against the thyroid stimulating hormone (TSH) receptor
nodular goitre, the nodule(s) secrete thyroid hormones autonomously In most, serum T3 and T4 are elevated. Serum T3 alone may be raised (T3 thyrotoxicosis).

Subclinical hyperthyroidism

Applied to patients with few, if any, symptoms in whom serum T3 and T4 are normal (albeit in the upper part of their reference ranges), but in whom thyroid stimulating hormone is undetectable.

Thyroiditis

Disruption of thyroid follicles with release of preformed, stored hormone into the circulation.
The thyrotoxic phase is short lived (6-8 weeks) . The symptoms are mild and treatment, if any, is with a beta blocker. Antithyroid drugs are not beneficial.

The hyperthyroidism is followed by an equally short lived episode of mild hypothyroidism because the damaged follicles are unable to synthesise new hormone.
Remarkably, given the degree of damage to the thyroid, normal thyroid function is usually restored.


The thyroiditis may be:
Viral (de Quervain's) - in these patients the thyroid is painful
Autoimmune - the thyroid is not painful. Antithyroid peroxidase antibodies are invariably present in the serum. It is known as silent thyroiditis.
If it occurs after pregnancy it is known as post-partum thyroiditis (silent thyroiditis and post-partum thyroiditis are the same condition)

Caused by amiodarone therapy in patients with no pre-existing thyroid disease. In this inflammatory condition, the drug has a direct toxic effect on thyroid follicular cells.
The condition is called type 2 amiodarone-induced thyroiditis. (Type 1 amiodarone-induced thyroiditis occurs when amiodarone is given to patients who have underlying Graves' disease or nodular goitre).

Gestational thyrotoxicosis

This occurs in the first trimester of pregnancy. It is associated with hyperemesis and is more common in women of South Asian origin than in white women. It is the result of the intrinsic thyroid stimulating activity of human chorionic gonadotrophin (HCG). The hyperthyroidism is short lived, but treatment with a beta blocker may be necessary or, in more severe cases, with an antithyroid drug for six to eight weeks.

Other causes

Other causes of hyperthyroidism include:
Excessive secretion of thyroid stimulating hormone by the pituitary gland
Ovarian teratoma, containing thyroid tissue (struma ovarii).
These conditions are so rare that they are unlikely to be met outside specialist practice.

Who gets it?

The rest of this module refers to people with Graves' disease or nodular goitre.
Women older than 40 are at greatest risk
Most patients have a family history of thyroid disease
People with organ specific autoimmune disease (such as type 1 diabetes, pernicious anaemia, vitiligo, or Addison's disease) have an increased risk of developing Graves' disease


The natural history of simple (non-toxic) diffuse goitre of young adulthood is progression to euthyroid multinodular goitre and then to toxic multinodular goitre over 30 years .

Excess intake of iodine may induce hyperthyroidism in people in remission from Graves' disease or with nodular goitre. This may occur in people taking amiodarone (type 1 amiodarone-induced hyperthyroidism) or kelp (a nutritional supplement sold at health food stores)

Most patients have had symptoms for at least six months.

In older people appetite is often diminished, raising the suspicion of gastric carcinoma. Proximal myopathy may impair mobility and the patient appears apathetic rather than fidgety and excitable. Atrial fibrillation and cardiac failure may predominate.

Pruritus and diarrhoea are rare but, if troublesome, may result in inappropriate referral to dermatology and gastrointestinal clinics.
Gritty eyes, periorbital puffiness, conjunctival injection, and excessive lacrimation - all features of Graves' ophthalmopathy - are often diagnosed initially as allergy to cosmetics.

Clinical features

Typically patients are thin, anxious, and have a tremor when they stretch out their fingers. Their hands are warm and moist. They have a sinus tachycardia with an increased pulse pressure and bounding pulse. Their hair thins and is lifeless.
Other clinical features are:
Not all patients with Graves' disease have goitre or ophthalmopathy.
Pretibial myxoedema is rare (1-2%)

Graves' ophthalmopathy may be unilateral and may present before the onset of hyperthyroidism or for the first time many years after successful treatment.
It is more common in smokers.
Palmar erythema is common, especially in older people with multinodular goitre
Nodular goitre is usually obvious but, particularly in older people, it may be impalpable and apparent only after isotope imaging.


Investigations
Ideally you should measure serum T3, T4, and TSH. TSH is suppressed or undetectable (<0.05 mU/l). as a result of negative feedback from inappropriately raised concentrations of T3 or T4, or both.

The combination of raised T4 and undetectable thyroid stimulating hormone, although consistent with a diagnosis of hyperthyroidism, is also found in patients with non-thyroidal illness (for example, in patients with acute exacerbation of chronic obstructive pulmonary disease, rheumatoid arthritis, and heart failure).
But serum T3 is always elevated in hyperthyroidism, whereas it is normal or slightly low in people without thyroid disease.

In non-thyroidal illness there is reduced conversion of T4 to T3 with a subsequent rise in serum T4 and fall in serum T3, often to the low-normal range.

Unless biochemical hyperthyroidism is associated with obvious features of Graves' disease, patients usually need to be investigated further in specialist centres to determine the cause. Specialist centres may carry out isotope imaging and measure antibodies to the thyroid stimulating hormone receptor.

How should I treat it?

There are three types of treatment for hyperthyroidism:
antithyroid drugs, iodine-131, and surgery.
Non-drug measures
Patients with moderate to severe hyperthyroidism (free T4 >45 pmol/l; normal 10-25) often have difficulty coping with stress, are easily irritated, concentrate poorly, and find physical activity demanding. It is good practice to consider advising sick leave until appropriate antithyroid therapy is established.

In my experience, patients who visit herbalists or other alternative therapists for advice are often given an iodine containing compound in the mistaken belief that all thyroid diseases are related to iodine deficiency. This is likely to exacerbate the hyperthyroidism, if taken for more than a few weeks.

Drug measures

Non-selective beta blockers
Beta blockers have little or no effect on thyroid hormone concentrations. Their role is to provide temporary symptomatic relief while patients are waiting to see a specialist or during the latent period before antithyroid drugs or iodine-131 take effect (two to three weeks and six to eight weeks, respectively).


The most widely used beta blocker is propranolol. This alleviates, but does not abolish, many symptoms of hyperthyroidism, such as tremor and palpitations.
Dose
The usual dose of propranolol is 80-160 mg daily, as Inderal-LA. An alternative is nadolol in the same dose.

Antithyroid drugs

Antithyroid drugs are usually the treatment of choice for young people with Graves' disease. They act by inhibiting the synthesis of thyroid hormones. They have no influence on the natural history of the hyperthyroidism of Graves' disease.
The most commonly used antithyroid drug in the UK is carbimazole (its metabolite, methimazole, is used in Europe and North America).

Carbimazole is given for an arbitrary period of 18-24 months to identify people destined to have a single episode of hyperthyroidism, and who will remain in remission after the drug is stopped. Most patients feel better after 10-14 days and will be euthyroid at four to six weeks.
Smokers take longer to come under control.

Side effects

The most common side effect is an urticarial rash (2-4% of people). The most serious side effect is agranulocytosis (1 in 300-500 people).
Other side effects include arthralgia, headache, and alopecia. If these effects are going to develop they will do so in the first four to six weeks of treatment.
Intolerance to carbimazole is an indication for using propylthiouracil, but there is a small degree of cross sensitivity.

Rarely, propylthiouracil has been associated with liver failure, most often in children, and it would seem sensible to check liver function tests at first clinical review.
All patients should be instructed to stop the medication if they develop a fever or sore throat. Agranulocytosis is a medical emergency and help should be sought at an emergency department out of hours rather than waiting until the next working day.

Dose

Carbimazole
The starting dose of carbimazole is 40 mg daily orally, taken as a single dose (20 mg for mild hyperthyroidism).
After three to four weeks the dose can be reduced to 20-30 mg daily. After six to eight weeks it can be reduced to 20 mg daily. The maintenance dose is 5-15 mg daily, depending on clinical and biochemical assessment.


Patients with fluctuating thyroid function might benefit from a combination of carbimazole 30-40 mg daily and thyroxine 100-125 µg daily.

Propylthiouracil

The dose of propylthiouracil is 400 mg daily, usually given as 200 mg twice a day.
It is best to give propylthiouracil rather than carbimazole during breastfeeding because propylthiouracil is excreted in the milk to a lesser extent.

Even after an 18 month course of antithyroid drugs, more than 50% of patients will relapse. Most of these will relapse in the first one or two years.

Iodine-131

Iodine-131 is the first choice of treatment for patients older than 40. But it is increasingly prescribed for younger patients in some centres.

Thyroid follicular cells concentrate iodine more avidly than any other. They can't distinguish between stable dietary iodine and its radioactive isotopes, and are "fooled" into taking up what is effectively a magic bullet. The cells are killed or rendered unable to divide.

Euthyroidism is restored in

80-90% of patients after three months of a standard dose of 400 MBq (approximately 11 mCi) iodine-131.

Side effects

Hypothyroidism should be viewed as inevitable rather than as a side effect in patients with Graves' disease. Up to 90% of patients develop thyroid failure at one year. But hypothyroidism is much less common after iodine-131 therapy for toxic nodular goitre.

After more than 50 years of use there is no evidence of a significant risk of leukaemia or cancer of the bladder or gastrointestinal tract.
Iodine-131 therapy is contraindicated in pregnancy because of the risk of fetal hypothyroidism.


There is some evidence that of all the treatments for Graves' disease, iodine-131 therapy is most likely to be associated with deterioration of ophthalmopathy.
This risk can be diminished by giving prednisolone 30-40 mg daily for six weeks following iodine-131 therapy. These patients need to be reviewed closely by a specialist.

Surgery

Subtotal thyroidectomy is the treatment
of choice for:
• Young patients with Graves' disease with large vascular goitres and moderate to severe hyperthyroidism
• People who have relapsed after a course of antithyroid drugs
• People who are poorly compliant .
• toxic nodular goitre if this is causing mediastinal compression.

One year after surgery for Graves' disease:

80% of patients are euthyroid
15% hypothyroid
5% remain thyrotoxic.
Thereafter, 2-4% of patients develop thyroid failure, reflecting the natural history of the hyperthyroidism of Graves' disease. Late relapse even 20 to 40 years after seemingly successful surgery is well recognised.

There is a fashion among surgeons to advocate near total thyroidectomy for Graves’ disease with the intention of causing hypothyroidism. This makes no sense as, if hypothyroidism is the desired outcome, iodine-131 would achieve the same result without the additional risks of surgery.

Complications

The complications of surgery are:
• Recurrent laryngeal nerve palsy (1-2%)
• Hypoparathyroidism (1-2%)
• Keloid scar formation.
• Subtle voice change is common, but is of no consequence unless the patient depends on their voice for a living.


Treating hyperthyroidism during pregnancy
The specialist will see the patient each month during their pregnancy.
Radio-iodine is absolutely contraindicated in pregnancy because it is concentrated by the fetal thyroid, causing hypothyroidism.
The mainstay of treatment is drug therapy using the minimum dose that maintains normal thyroid function.

Propylthiouracil is the drug of choice, because it is believed to be less teratogenic than carbimazole.
Untreated hyperthyroidism is associated with:
• Miscarriage
• Premature labour
• Low birth weight
• Eclampsia.

There is an increasing list of drugs which interfere with the absorption of thyroxine (oral iron preparations, calcium carbonate, proton pump inhibitors) or increase its metabolic breakdown (antidepressants). It is sensible, therefore, in this case to advise that the thyroxine is taken last thing at night and that the final dose of ferrous sulphate is taken around teatime.

The ophthalmopathy of Graves' disease rarely resolves completely and may continue to be troublesome many years after the hyperthyroidism has been successfully treated. Orbital decompression, radiotherapy, extra-ocular muscle surgery, and eyelid surgery may be necessary to protect visual acuity, correct diplopia, or improve cosmetic appearance.

Previously, patients with subclinical hyperthyroidism were just reviewed annually until they developed overt hyperthyroidism. But we now know that subclinical hyperthyroidism may be a risk factor for osteoporosis and atrial fibrillation. These patients should therefore probably be treated in the same way as those with more overt disease.