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Need to Know - Thyroid disease

Dr Shahrad Taheri and Professor Stafford Lightman answer GP Dr Colin Kenny’s questions on the range of conditions affecting the thyroid gland that present in primary care

Dr Shahrad Taheri and Professor Stafford Lightman answer GP Dr Colin Kenny's questions on the range of conditions affecting the thyroid gland that present in primary care

Take-home points

• There is little evidence of long-term benefit for treatment of subclinical hypothyroidism,but it would be reasonable to treat patients with TSH levels of 5-10mIU/ml who have goitre or positive anti-thyroid antibodies.

• It may take 3-6 months and longer for patients to feel better after thyroxine.

• A TSH concentration below 0.1mIU/l WOT ml ABOVE is associated with a 30% 10-year risk of atrial fibrillation in patients over 60 and a doubling of cardiovascular mortality over 10 years.

• Postpartum thyroiditis is common and has a prevalence of 16.7%. It classically has three phases: thyrotoxic (1-3 months after delivery and lasting a few months), hypothyroid (3-6 months after delivery), and recovery (normal thyroid function within 1 year)

• Block and replace is usually achieved with 40mg/day of carbimazole and 100µg of levothyroxine. In the highly symptomatic patient, it is best to treat initially with high-dose carbimazole and add thyroxine.

• Thyroiditis may be viral, with a transient thyrotoxicosis. Later an elevated TSH and FT4 occur. Treatment is NSAIDs: it may take up to 5 weeks for pain to subside.

• The best initial imaging option is ultrasound.

• A levothyroxine dose of 175-200µg is required to achieve total suppression in thyroid cancer.
• Hashimoto's thyroiditis may very rarely be associated with thyroid eye disease.

1

Should I treat a raised thyroid stimulating hormone (at levels below 10mIU/L and borderline T4 when there are symptoms? Does the presence of thyroid antibodies influence the treatment decision?

A raised TSH (but below 10mIU/L) and free T4 (FT4) within the normal range define subclinical hypothyroidism. This is relatively common (prevalence 1 to 10%), affecting women more, with rates of progression to overt hypothyroidism raging from 3 to 20%. Those at highest risk of eventually becoming hypothyroid are those with goitre and/or elevated antithyroid antibodies. A similar biochemical picture is also seen in the sick euthyroid syndrome, and thyroid function tests need to be repeated six to eight weeks after recovery from an acute illness.

An important cause of an elevated TSH that should also be considered is untreated adrenal insufficiency (Addison's disease) since treatment with thyroxine can potentially trigger an Addisonian crisis. Usually, subclinical hypothyroidism is picked up incidentally in asymptomatic patients. In symptomatic patients, symptoms related to hypothyroidism tend to be non-specific and this makes it difficult to treat patients based on a diagnosis that relies on symptoms alone. It is important to exclude other conditions that may be contributing to the patient's symptoms, for example, obstructive sleep apnoea.

Treating subclinical hypothyroidism is controversial because there is limited evidence of long-term benefit. The arguments for treatment focus on the risks of progression to overt hypothyroidism, cardiovascular dysfunction, abnormal lipid profiles and neuropsychiatric problems. It is reasonable to treat patients with TSH levels of 5-10mIU/L who have goitre or positive anti-thyroid antibodies as these patients have the highest risk of progression to hypothyroidism. The smallest dose of levothyroxine (initially 25-50µg) is used to keep TSH at the lower end of normal. Once TSH is stable, it can be checked annually. Other patients who require treatment are pregnant women or women contemplating pregnancy, and patients with Graves's disease who have previously had radioiodine treatment. Hypothyroidism results in recurrent miscarriage and several complications in continuing pregnancies. Also, hypothyroidism in pregnancy may result in poor cognitive function in the offspring.

In highly symptomatic patients with subclinical hypothyroidism who do not fit the above criteria, it may be reasonable to give a trial of thyroxine treatment, with the thyroxine withdrawn if there is no improvement. Non-symptomatic patients who do not fit the above groups can be followed up with annual TSH measurements.

2

How frequently should treated hypothyroidism be monitored? How long does it take a newly diagnosed and treated case to feel better?

After the start of treatment, thyroid function is checked every six to eight weeks until stable, and then annually. It is difficult to predict how quickly patients recover, but it depends on previous symptoms (if any), duration of hypothyroidism, co-morbidities, dosing pace, and the patient's age and personality. Unless there is a specific contraindication, starting at the full replacement dose is likely to mean more rapid symptom improvement. It may take anything from three to six months and sometimes longer for patients to feel better. It is important to consider factors that may affect patients getting the full benefit of prescribed levothyroxine such as malabsorption syndromes. Other medications affect levothyroxine absorption, such as ferrous sulphate, cholestyramine, and some antacids. Some drugs increase levothyroxine metabolism, such as anticonvulsants, rifampicin and sertraline.

3

What should I do with the patient who only feels ‘well' on higher doses of thyroxine – with a totally suppressed TSH and raised T4? What are the risks to them?

The full replacement dose in an athyreotic patient is 1.6µg/kg/day (mean dose of 112µg/day; median dose of 125µg/day). It is important not to exceed the physiological dosage to render the patient thyrotoxic. A patient's symptoms may be related to other conditions accompanying hypothyroidism such as depression or an unrelated problem. In some patients, over-replacement paradoxically results in weight gain, which the patient may interpret as under-replacement. Patients require education on the risks and benefits of both under- and over-treatment. A TSH concentration below 0.1mIU/L is associated with a 30% 10-year risk of atrial fibrillation in patients over 60 and a two-fold increase in mortality from cardiovascular disease over 10 years. Atrial fibrillation, in turn, may result in stroke. Left ventricular hypertrophy may also occur. Additionally (in particular in post-menopausal women) over-treatment may result in osteoporosis.

4

I have read that postpartum thyroid disorders are relatively common. Who should I suspect has it (because tiredness, weight gain and other symptoms of thyroid disorders are common in the postpartum period)?

Post-partum thyroiditis (PPT) is an autoimmune disorder that occurs in the first year after delivery and is characterised by lymphocytic infiltration of the thyroid, resulting in a painless goitre. It is generally associated with positive antithyroid peroxidase antibodies. The ESR is normal.

PPT is relatively common in the UK with a prevalence of 16.7%. It is three times more common in women with type 1 diabetes. Screening for thyroid abnormalities in this patient population is therefore essential. Previous PPT also increases the risk of PPT after another pregnancy (70% recurrence). These women should also be screened for recurrence. Female smokers may also be at risk. There is currently no effective preventive strategy for PPT.

Classically, PPT has three sequential phases: thyrotoxic (one to three months after delivery and lasing a few months), hypothyroid (three to six months after delivery), and recovery (normal thyroid function within one year). This picture is seen in less than a third of patients. Other patients may either have thyrotoxicosis or hypothyroidism. About a third may become permanently hypothyroid.

Permanent hypothyroidism seems to occur more commonly in women with the highest levels of anti-thyroid antibodies in the hypothyroid phase, and thyroid hypoechogenicity of the thyroid on ultrasound. The rate of progression to hypothyroidism in women with PPT is the same as women in the general population with positive antithyroid antibodies (3.6% per year).

Clinical features of thyroid dysfunction are usually rare but PPT may be picked up when investigating post-partum depression. If there are clinical features of thyrotoxicosis, it is important to exclude Graves' disease which is associated with thyroid bruit, eye disease and positive anti-TSH receptor antibodies (measurement of these antibodies may not be readily available).

Treatment of PPT depends on symptoms and thyroid function. In symptomatic transient thyrotoxicosis, ß-blockers can be used until thyroid function normalises; anti-thyroid drugs are contraindicated. With transient hypothyroidism, levothyroxine replacement is given for 12 to 18 months at which point it is stopped with TSH measured six weeks later. If TSH is elevated at this stage, then permanent hypothyroidism has occurred and levothyroxine is restarted. Permanent hypothyroidism requires indefinite treatment with levothyroxine.

5

What is the most appropriate treatment for hyperthyroidism? What dose should I start on – when should block and replace regimes be used? Our local unit gives ‘urgent' appointments for new cases two to three months hence, so we have to do the initial management. How should I monitor and alter the regime?

There is no perfect treatment for thyrotoxicosis. What is important is to have local protocols for everyone to follow to prevent confusion in treating patients. The treatment approach depends on the patient's age, co-morbidities and choice, and also the cause and severity of hyperthyroidism. Your personal experience with a particular approach also makes a difference. Initially, it is important not to forget to treat symptomatic patients with a ß-blocker (propranolol or atenolol) if there are no contraindications.

When antithyroid medications are prescribed, patients should be warned about the side-effects, especially the small risk of neutropenia. There is no place for routine monitoring of the white cell count.

In the early stages of Graves's disease, mild neutropenia may occur that gets better as the disease is treated. Carbimazole is the antithyroid thionamide of choice as propylthiouracil is expensive and requires multiple daily doses. Propylthiouracil is also not used long term as it can be associated with vasculitis. Propylthiouracil is generally used in pregnancy because carbimazole carries a small risk of the scalp disorder aplasia cutis in the baby.

In the elderly patient with mild hypothyroidism, small (5-10mg) doses of carbimazole may be sufficient. In younger patients with more severe thyrotoxicosis, higher doses are required (40mg/day). On this dosage, up to 85% of patients will be euthyroid by four weeks, with the response depending on the initial FT4 level. Less severe cases may need half this dose. Carbimazole can be given once a day as it has a long half-life. Repeats of thyroid function tests at six to eight weeks' time should be carried out and the dose adjusted as necessary to achieve an TSH in the normal range. The dose is reduced (to 5-15mg/day) when the patient is euthyroid.

If hypothyroidism occurs with the original dosage, the high dose can be maintained and levothyroxine added; the average patient requires 100µg in addition to the antithyroid drug.

The advantage of block and replace is that it is easier to manage, especially in Graves's disease where the disease can be variable. Block and replace is also preferable if it is difficult to monitor the patient on a regular basis, and is usually achieved with 40mg/day of carbimazole and 100µg of levothyroxine. In the highly symptomatic patient, it is best to treat initially with carbimazole at high dose and add thyroxine later.

Block and replace is not used in pregnancy as antithyroid drugs at high doses cross the placenta more then levothyroxine, thus affecting the foetal thyroid.

6

How common is thyroiditis and how should I manage it?

Thyroiditis can be broadly classified into painful and painless forms. Painful thyroiditis is rare and includes subacute granulomatous (de Quervain's thyroiditis), suppurative, and trauma- and radiation-induced thyroiditis caused by local radiotherapy or radioactive iodine treatment.

Painless thyroiditis is more common and includes Hashimoto's disease (see WHERE), and subacute lymphocytic, post-partum, drug-induced and Riedel's thyroiditis. Each form of thyroiditis has its own time course, abnormalities in thyroid function and radioactive iodine uptake imaging findings. We will discuss the most common types from each group in more detail.

• Subacute granulomatous thyroiditis is the commonest cause of painful thyroiditis. It is more common in women and in middle age. It peaks in the summer, suggesting a viral origin. This form presents with fatigue, anorexia, weight loss, muscle pains, sore throat, low-grade temperature, and diffuse thyroid pain that may go up to the ears (sometimes unilaterally). With progression, there will be tenderness that marches through the thyroid, affecting new areas as old areas get better.

The inflammation of the thyroid results in transient (three to six weeks) thyrotoxicosis (suppressed TSH, low FT4) which may be associated with sweating and tachycardia. ESR and C-reactive protein are often elevated early in the disease. There may also be mild anaemia and slight leukocytosis.

Distinction from Graves's disease should be made as this may alter management. Levels of antithyroid antibodies will generally be normal in subacute granulomatous thyroiditis. In Graves's disease, there will be associated eye signs and a thyroid bruit. Also, while radioiodine uptake is increased in Graves's disease, it is low in subacute granulomatous thyroiditis. Later in the disease, an elevated TSH and FT4 may be noted.

Treatment involves NSAIDs; it may take up to five weeks for pain to subside. If there's no improvement after a week, prednisolone (40-60mg) may be given and tapered over four to six weeks. ß-blockers (propranolol or atenolol) are used to control symptoms of thyroid overactivity. Levothyroxine is given in the hypothyroid phase. This form of thyroiditis may recur in 2% of patients. Thionamides (carbimazole and propylthiouracil) do not work as the disorder is caused by the release of pre-synthesised hormone.

• Suppurative thyroiditis is rare but should not be missed. It can be caused by several micro-organisms and it is usually due to spread of infection from adjacent structures. It results in neck pain, erythema of the skin overlying the thyroid and an exquisitely tender thyroid. Raised ESR and neutrophilia are generally seen. Fine needle aspiration, culture and intravenous antibiotics are required.

• Post-partum thyroiditis is discussed elsewhere.

• Subacute lymphocytic thyroiditis is similar to post-partum thyroiditis except that it is not associated with pregnancy. Drugs that commonly result in thyroiditis include amiodarone, interleukin (for malignancy), interferon-a (for viral hepatitis) and lithium carbonate.

• Amiodarone can result in both hypo- and hyperthyroidism. Amiodarone contains excessive iodine, which can exacerbate underlying thyroid disorders such as multinodular goitre or Graves's disease. This is called Type 1 amiodarone-induced thyrotoxicosis (AIT). As with thyrotoxicosis, treatment is with ß-blockers to control symptoms and antithyroid drugs.

Type 2 AIT is due to a destructive thyroiditis and does not respond to antithyroid drugs. Prednisolone (40-60mg for three months) is used to treat this form, which is usually self-limiting but may over time develop into hypothyroidism.

Distinguishing between Type 1 and Type 2 AIT may be difficult despite reported decreased doppler colour flow in Type 2 AIT. Because of this, some endocrinologists initiate treatment with both antithyroid drugs and prednisolone. Managing AIT can be tricky and needs specialist care, especially in patients who have complex cardiac disease.

• Reidel's thyroiditis is rare and is associated with fibrosis in the thyroid (rock-hard fixed thyroid) and adjacent structures resulting in oesophageal and tracheal compression and associated symptoms.

• Scarring of the thyroid results in about a third of patients becoming hypothyroid. About two thirds of patients have positive antithyroid antibodies. Treatment requires specialist surgical and endocrine care. The flow chart WHERE shows the general approach in diagnosing thyroiditis.

7

When should radioactive iodine be considered? What should patients know about it that we might forget to tell them?

Graves's disease, multinodular goitre, and solitary overactive nodule (toxic adenoma) are the main cause of thyroid overactivity. The choice of treatment (medication, radioiodine I131 or surgery) depends on factors including the underlying thyroid disorder, the patient's age, co-morbidities, preferences, and the endocrinologist and local protocols.

All treatments for thyrotoxicosis are effective but imperfect. Radioiodine is safe without any adverse effects on fertility or increased incidence of cancer in patients or their children.

In the UK, we tend to treat Graves's disease with anti-thyroid drugs for 18 months and then withdraw treatment. About half the patients remain in remission at this stage. Patients in remission for a year or more after stopping treatment have the best chance of long-term remission.

Relapse after remission is treated with radioiodine. A patient may prefer radioiodine from the outset and can be treated this way. Patients with mild thyrotoxicosis can be treated with ß-blockers alone before radioiodine. Other patients are first stabilised on antithyroid drugs, which are stopped a few days before radioiodine treatment.

It may take up to six months for the full effect of radioiodine to be observed so patients generally go back on treatment after radioiodine with frequent testing of thyroid function off medication.

In Graves's disease, transient hypothyroidism (thyroid stunning) then relapse may occur.

Radioiodine is contraindicated in pregnancy, with breastfeeding and in young children. In women contemplating pregnancy, contraception is required up to six months after radioiodine.

Radioiodine may make Graves's ophthalmopathy worse and patients may need steroid therapy. About 10% of patients require a repeat dose. Most patients receiving radioiodine become hypothyroid over time and need to be monitored. Radioiodine may also be considered in patients with overactive goitre since it results in goitre shrinkage. Since multinodular goitre and toxic adenoma are not cured by anti-thyroid dugs, radioiodine is used in these cases. In the case of a solitary toxic adenoma, the adenoma can be selectively ablated by radioiodine, since it will have the highest uptake.

It is important to be familiar with local protocols for the treatment of patients with radioiodine ensuring safe and effective treatment. Radioiodine is usually administered at a typical dose of 400Mbq as a capsule or drink. Higher doses are required for large multinodular goitre and when rapid response is needed. Women with young children may find it difficult to adhere to the radiation precautions.

8

What are the best imaging options for a thyroid swelling?

The best initial imaging option is ultrasound to detect important thyroid and local pathology; fine needle aspiration can be carried out at the same time. If there is a nodule in conjunction with thyrotoxicosis (low or undetectable TSH), then an uptake scan may reveal a hot nodule that can be effectively treated with radioiodine. Only 5% of thyroid nodules are hot.

9

When should cancer of the thyroid be considered? What is the prognosis? I have noticed these patients are given very high doses of thyroxine – how should that be monitored and why is that done? Does it cause side-effects?

Thyroid nodules are common, but mostly benign. Thyroid cancer, however, is the commonest endocrine malignancy with about 900 new cases and 250 deaths in the UK every year. The most common form is papillary, which has the best prognosis with a 98% 10-year survival rate.

Malignancy should be suspected in patients previously exposed to radiation (especially in childhood), and in young and/or male patients. Rapidly growing nodules, nodules that are hard and irregular, compressive nodules, local lymph node enlargement and compressive symptoms are suspicious. Family history of thyroid carcinoma and familial polyposis are also important. A rapidly growing nodule in a Hashimoto's goitre is suspicious for thyroid lymphoma (see ?WHERE). After surgery and ablative treatment, levothyroxine is administered to suppress TSH to inhibit tumour growth and prevent recurrence. TSH levels should be kept as low as possible, preferably less than 0.1 mIU/ml WOT. A levothyroxine dose of 175-200µg is required to achieve this. Guidance for follow-up should be available from a specialist in the multi-disciplinary team managing the patient. In carefully treated patients, long-term problems such as osteoporosis are rare.

ONLINE EXTRA

10

What is Hashimoto's thyroiditis and how can it be recognised clinically and biochemically?

Hashimoto's thyroiditis is the most common autoimmune disorder of the thyroid. It is eight to nine times more common in women and has a peak incidence between the ages of 40 and 60. About 90% of patients have a diffusely enlarged painless symmetrical goitre (pebbly or bumpy surface on palpation) while 10% have thyroid atrophy. On histology, the thyroid is diffusely infiltrated by lymphocytes with some follicle cells developing an oxyphilic appearance (Hurthle cells). Patients may have normal thyroid function, frank hypothyroidism (high TSH, low FT4), or subclinical hypothyroidism (elevated TSH, normal FT4). Some 90% of patients have antithyroid antibodies. Hyperglobulinaemia, positive antinuclear antibodies and a raised ESR may also be observed with Hashimoto's thyroiditis. Solitary nodules in a Hashimoto's goitre should be examined by ultrasound and fine needle aspiration. A rapidly growing nodule in a Hashimoto's goitre may be a thyroid lymphoma (60 to 80 times more common in Hashimoto's), or less commonly, papillary carcinoma. As it is an autoimmune disorder, Hashimoto's thyroiditis may occur in conjunction with other autoimmune conditions such as Addison's disease, Type 1 diabetes mellitus, pernicious anaemia, premature gray hair, vitiligo, premature ovarian failure, rheumatoid arthritis, and connective tissue diseases. Monitoring for these conditions is therefore necessary. Hashimoto's thyroiditis may rarely be associated with thyroid eye disease.

Dr Shahrad Taheri is senior lecturer in endocrinology at the University of Birmingham and consultant endocrinologist at Birmingham Heartlands Hospital

Professor Stafford Lightman is professor of medicine at the University of Bristol and consultant endocrinologist at Bristol Royal Infirmary

• I will tell patients to expect to wait three to six months before they feel the benefit from thyroid replacement therapy in hypothyroidism.

• I will actively screen for atrial fibrillation in those patients over 60 who have hypothyroidism.

• I will coWhat I will do now : Dr Kenny reponds to the answers to his questions

• I will tell patients to expect to wait three to six months before they feel the benefit from thyroid replacement therapy in hypothyroidism.
• I will actively screen for atrial fibrillation in those patients over 60 who have hypothyroidism.
• I will consider doing thyroid antibodies in patients with subclinical hypothyroidism.
• I will consider hypothyroidism in Type 1 patients booking for confinement.
• I will counsel hypothyroidism patients carefully about situations where levothyroxine might not be absorbed.
• I will carefully watch maximal doses of levothyroxine as this may cause weight gain without more symptom control.
• I will tell hyperthyroid patients that they can be rendered euthyroid in four weeks with judicial use of carbimazole.
• If they are stable after being rendered euthyroid I would consider referral for radioiodine if they relapse a second time.
• If there is a concern about the appearance or feel of the thyroid I will arrange an ultrasound scan as an initial investigation.

Dr Colin Kenny is a GP in Dromore, Co Down, Northern Ireland

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