Thyroid problems

Abstract

Thyroid disorders are the most-common endocrine conditions managed within primary care. Such disorders can present insidiously, but are associated with significant morbidity, and therefore, a high index of clinical suspicion is required for diagnosis. GPs need to be able to interpret the results of thyroid function tests, manage thyroid dysfunction and refer appropriately to secondary care. This article aims to provide an overview of disorders of thyroid hormone production including hyperthyroidism, hypothyroidism and thyroid emergencies, and to consider problems of thyroid anatomy including goitres and nodules.

The GP curriculum and thyroid problems

Clinical module 3.17: Care of people with metabolic problems highlights that GPs should be able to:

Understand how common metabolic disorders such as thyroid disease present

Recognise that patients with metabolic problems often have non-specific symptoms and that diagnosis is made by screening or recognising symptom complexes and arranging appropriate investigations

Recognise the central role GPs play in managing hypothyroidism

Know the indications for referral to secondary care

Understand the use and limitations of tests commonly used in primary care to investigate and monitor metabolic conditions e.g. thyroid function tests

Recognise and manage metabolic emergencies

Know that exemptions from prescription charges exist for patients with metabolic conditions

Pathophysiology

The thyroid gland is the largest pure endocrine gland in the body. Its role in thyroid hormone production is regulated by the hypothalamic–pituitary axis. The hypothalamic thyrotropin-releasing hormone (TRH) stimulates the anterior pituitary gland to release thyroid-stimulating hormone (TSH). TSH controls the thyroid gland to produce triiodothyronine (T3) and thyroxine (T4). T4 is converted in to T3 intracellularly, and in its unbound state, T3 is the metabolically active hormone which acts within cells. Dysfunctions of thyroid hormone production can be classified as either primary thyroid disease, in which there is a problem with hormone production (T3 and T4) within the thyroid gland itself or secondary thyroid disease, which refers to a problem with the hormone stimulus from the hypothalamic–pituitary axis. Figure 1 outlines the negative feedback mechanism of T3 and T4 on production of TRH and TSH.

Figure 1.

Schematic representation of thyroid hormone production and feedback mechanism.

Thyroid function tests

An estimated 10 000 000 thyroid function tests (TFTs) are requested in the UK each year, and most of these results are normal (Beckett & Toft, 2003). However, consideration of thyroid disease is recommended in patients presenting with new atrial fibrillation, osteoporosis, dyslipidaemia, infertility, auto-immune conditions (diabetes and Addison’s disease) and Down’s syndrome (British Thyroid Association, Association for Clinical Biochemistry, & British Thyroid Foundation, 2006).

When TFTs are requested TSH levels are routinely performed. TSH is normally 0.5–5 mU/L and if this is found to be abnormal then T4 levels are measured (normal level 9–25 pmol/L). However, caution is required, as normal TSH levels may not mean that a patient is euthyroid. In secondary hypothyroidism, TSH can be normal despite a low T4 level, and therefore, if hypothyroid symptoms are persistent it is important to request additional T4 testing. Further examples of common results are shown in Table 1 (British Thyroid Association, Association for Clinical Biochemistry, & British Thyroid Foundation, 2006).

Table 1.

TFT results.

TSH	T4	Diagnosis
High	Low	Primary hypothyroidism
High	Normal	Sub-clinical hypothyroidism, poor compliance with levothyroxine (L-T4)
Low/normal	Low	Sick euthyroid (general illness) Secondary hypothyroidism
High	High	Poor compliance with LT4 or secondary hyperthyroidism
Low	High	Primary hyperthyroidism Excess levothyroxine Pregnancy (human chorionic gonadotropin mimics TSH)
Low	Normal	Sub-clinical hyperthyroidism Medications (steroids)

Thyroid function tests should always be interpreted within the clinical context, as illness, medications and pregnancy can affect the results. Moreover, in pregnancy it is recommended that trimester-specific TSH and T4 reference ranges are used. Further investigations to identify the underlying cause of thyroid dysfunction may be indicated, including thyroid auto-antibodies, ultrasonography or isotope scanning, but these are normally initiated within secondary care.

Case studies.

Consider the following scenarios. As a new GP you are managing the morning telephone triage:

A 72-year-old lady calls to discuss her blood results. She recently consulted with non-specific symptoms of mild weight loss and feeling slightly breathless. Her bloods are mainly normal, except for an undetectable TSH (less than 0.4 mU/L), but normal T4. How would you advise her?

Later that morning a 38-year-old lady calls up as she is feeling generally unwell, with a very sore throat. You notice that she is taking carbimazole. How would you advise her?

Before lunch you receive a call from a 28-year-old lady who has found out she is pregnant. She is taking 100 micrograms of levothyroxine and wants advice on treatment with thyroxine in pregnancy?

What are your advice and management options? Consider these cases as you read the article.

Hyperthyroidism

Hyperthyroidism is 10-times more common in women than in men, with a prevalence level in women of 0.5–2% (Vanderpump et al., 1995). The most common cause is a dysfunction of the thyroid gland itself or primary hyperthyroidism. This is most commonly caused by autoimmune Graves’ disease, where TSH receptor antibodies stimulate the thyroid gland to over-secrete T3 and T4 (Pearce, 2006). Other specific manifestations of Graves’ disease are ophthalmopathy and pretibial myxoedema. These are also mediated by the immune system.

Hyperthyroidism is also often caused by autonomously functioning thyroid cells, either within a toxic multi-nodular goitre or a solitary adenoma (Ross et al., 2016). Rarer causes include the transient thyrotoxicosis of thyroiditis (either post-partum or post-infective de Quervain’s syndrome), secondary hyperthyroidism from a pituitary-secreting tumour (excess TSH) or related to medication, notably amiodarone and lithium.

Symptoms and signs

Hyperthyroidism classically presents with features of increased metabolic and sympathetic activity, such as heat intolerance, palpitations, weight loss and diarrhoea. However, symptoms may often be subtle, particularly in the elderly, and include mood changes, fatigue, insomnia, breathlessness and confusion (Boelaert, Torlinska, Holder, & Franklyn, 2010). The most common signs are sweaty hands, fine tremor, tachycardia or atrial fibrillation and eye changes in Graves’ disease.

Diagnosis

Primary hyperthyroidism is diagnosed by an inappropriately low TSH level with a raised T4 and T3 level. It is important to remember that in general practice excess levothyroxine is the most common cause of this pattern of results, either prescribed or taken erroneously (British Thyroid Association, Association for Clinical Biochemistry, & British Thyroid Foundation, 2006). It is therefore important when reviewing results to consider the patient’s medication and clinical symptoms. If sub-acute thyroiditis is suspected as the cause the inflammatory marker, C-reactive protein, should be checked.

Sub-clinical hyperthyroidism is diagnosed when TSH levels are suppressed but T4 levels are normal. If these results occur, then TFTs should be repeated within 2–3 months and then monitored annually thereafter (National Institute for Health and Care Excellence (NICE), 2016a). These abnormalities are often transient, but around 5% patients will convert to overt hyperthyroidism each year. Persistent sub-clinical hyperthyroidism has been associated with increased rates of atrial fibrillation, osteoporosis and heart disease, and it is recommended that these patients are discussed with secondary care (Surks et al., 2004).

Treatment

All patients with hyperthyroidism should be referred to secondary care in accordance with NICE (2016a) guidelines (Box 1). While awaiting specialist assessment, symptomatic relief can be achieved by titrating beta-blockers, for example, immediate-release propranolol in divided doses. Indeed, in a minority of patients whose history (post-viral infection or post-partum) and examination (tender thyroid) are consistent with a transient thyroiditis, beta-blockers and anti-inflammatories are often the only treatment required. Furthermore, if there is a delay in being seen, it is appropriate to seek specialist advice with a view to starting carbimazole in primary care, particularly for patients unable to tolerate beta-blockers or those with drug-induced disease.

Box 1.

NICE referral guidelines for hyperthyroidism.

• Emergency admission if symptoms of a thyroid storm

• Urgent referral using 2-week wait cancer pathway if a person has a thyroid nodule or goitre and malignancy is suspected; such patients often have normal TFTs

• Refer all other people with overt hyperthyroidism to an endocrinologist, the urgency depending on clinical judgement

• Refer all pregnant women with overt or sub-clinical hyperthyroidism

• Routine referral of persistent sub-clinical hyperthyroidism

Source: NICE (2016a).

There are three main treatment options for hyperthyroidism: anti-thyroid drugs, radioiodine and thyroid surgery. The main anti-thyroid medication is carbimazole; it works by inhibiting thyroxine synthesis and is often given for 12–18 months, either on its own or occasionally in a titration-replacement regimen with levothyroxine (L-T4). Medical therapy is often used first line, as it is easier to administer and has a more favourable side-effect profile. However, it is associated with a high relapse rate and the possibility of agranulocytosis, a significant side effect (Pearce, 2006).

For more definitive treatment radioiodine is often used. However, there are complications associated with this treatment, including deteriorating thyroid eye disease. Multiple doses are often required, with a risk of relapse between treatments. Patients are required to follow radio-protective precautions, such as avoiding pregnancy for 4 months and prolonged contact with pregnant women or children for 3 weeks after radiation. Furthermore, it is contraindicated in pregnancy.

Surgery is often reserved for large goitres or if other treatments have been unsuccessful. This commonly involves total thyroidectomy and usually results in permanent hypothyroidism. Complications include recurrent laryngeal nerve palsy and hypoparathyroidism.

Hypothyroidism

It is estimated that the prevalence of overt hypothyroidism is around 2%, but up to 10% of the population may have sub-clinical disease (Vanderpump et al., 1995). The most common cause is the dysfunction of the thyroid gland, in primary hypothyroidism. Worldwide this is most commonly due to iodine deficiency, but in the UK this is more usually because of inflammation in the gland in an autoimmune condition (Hashimoto’s thyroiditis) or secondary to treatment for hyperthyroidism (surgery or radioiodine). Rarer causes include a congenital abnormality of the gland or secondary hypothyroidism due to hypothalamic-pituitary dysfunction.

Signs and symptoms

The symptoms are often non-specific and associated with reduced metabolic and sympathetic activity. They include fatigue, depression, weight gain, impaired fertility and cold intolerance. Signs include hair loss or thinning, bradycardia and reduced tendon reflexes.

Diagnosis

Sub-clinical hypothyroidism is detected early when there is a raised TSH concentration above the normal reference range (5 mU/L) in association with normal T3 and T4. If the TSH is found to be raised, but T4 is within reference range, then TFTs should be repeated after a 2–3 month interval along with thyroid peroxidase antibodies (TPO). The presence of TPO antibodies increases the likelihood of conversion to overt hypothyroidism. However, it is worth noting that for pregnant women, overt hypothyroidism is defined solely in terms of TSH level (greater than 10 mU/L) and irrespective of the T4 level (De Groot et al., 2012).

Primary hypothyroidism is defined by raised TSH (to above 10 mU/L) with reduced T3 and T4 levels. If primary hypothyroidism is detected, then addition tests are recommended, including full blood count (FBC), glycated haemoglobin and serum lipids as it can be associated with anaemia, diabetes and dyslipidaemia (NICE, 2016b).

Treatment

Most patients with hypothyroidism can be managed in primary care. Starting doses of levothyroxine are recommended at 50–100 micrograms; or at a reduced level of 25 micrograms in patients over the age of 50 years or with cardiac problems (British Medical Association and Royal Pharmaceutical Society of Great Britain, 2016). TSH levels should be monitored every 2 months after any dose change. If doses need to be adjusted this should be in increments of 25–50 micrograms based on patient’s symptoms and TSH levels (NICE, 2016b). The aim is to normalise TSH and avoid over-suppression, as this is associated with increased risk of osteoporosis and atrial fibrillation. Levothyroxine requirements are based on lean body mass, with an average daily dose of 1.6 micrograms/kg. This usually equates to a maintenance dose of levothyroxine of between 100 and 150 micrograms daily (Vaidya & Pearce, 2008).

When TSH levels have normalised to within the lower end of the normal reference range (0.4–2.5 mU/L) monitoring can occur annually. An accurate database recording all patients on levothyroxine replacement enables appropriate annual monitoring.

Hypothyroidism in pregnancy is associated with increased complications, and therefore, tighter control of TSH levels is required, aiming to keep TSH to below 2.5 mU/L. Indeed, patients undergoing treatment for infertility may be started on levothyroxine despite normal TFTs to suppress TSH levels to below 2.5 mU/L (Stagnaro-Green et al., 2011). All pregnant women should be referred to an endocrinologist, but while awaiting review thyroxine doses should be increased by 30% in the first 6 weeks (De Groot et al., 2012). Further referral criteria are outlined in Box 2.

Box 2

NICE referral guidelines hypothyroidism.

• Emergency admission if myxoedema coma

• Urgent referral to Endocrinology if secondary hypothyroidism is suspected

• Urgent referral for all pregnant women with overt or sub-clinical hypothyroidism.

• Referral or discussion with Endocrinology:

▪ Hypothyroidism due to suspected thyroiditis (fever and painful goitre)

▪ Hypothyroidism in relation to another endocrine disorder, especially Addison’s disease where glucocorticoid replacement needs to happen prior to thyroxine treatment

▪ Persistently raised TSH or symptoms despite adequate treatment (where poor compliance and drug interactions have been excluded)

Source: NICE (2016b).

Treatment considerations

If adequate or high doses of levothyroxine are required, but TFTs remain abnormal, consider issues with medication compliance, drug interactions and problems with absorption. It is recommended that levothyroxine is taken on an empty stomach as milk, coffee, iron medications and ant-acids can affect its absorption. A common result seen in general practice is raised TSH with normal T4 levels in a patient on levothyroxine. This suggests poor compliance. Such patients may only be taking their medication just prior to having TFTs (British Thyroid Association, Association for Clinical Biochemistry, & British Thyroid Foundation, 2006).

Patients on levothyroxine treatment are entitled to free prescriptions through completing the FP92A exemption certificate. There has been no benefit identified from using combined therapy (T3 and T4) compared with L-T4 preparations, and it is not recommended that T3 preparations are prescribed in primary care (Kraut & Farahani, 2015).

Sub-clinical hypothyroidism

Sub-clinical hypothyroidism is common. Over 35% of patients with sub-clinical disease will spontaneously revert to euthyroidism (Pearce et al., 2013) and most patients will not require treatment. However, overt hypothyroidism is more likely to occur in women, people with TPO auto-antibodies and patients with higher TSH levels (Cooper & Biondi, 2012). Patients with symptomatic sub-clinical disease may benefit from a trial of levothyroxine. Annual TFTs are therefore recommended in people with sub-clinical disease with TPO antibodies or a goitre. Monitoring is important, as studies have shown that patients with TSH levels greater than 10 mU/L are at an increased risk of dyslipidaemia, coronary heart disease and cardiac failure (Pearce et al., 2013). Management of these patients should be based on their age, TSH levels and symptoms as outlined in Fig. 2.

Figure 2.

Suggested management algorithm for sub-clinical hypothyroidism.

Acute thyroid emergencies

Hyperthyroid crisis (thyroid storm)

A thyroid storm is a rare condition that presents with symptoms of acute over-activity of the sympathetic system (tachycardia, fever, diarrhoea, heart failure and agitation). It tends to occur in people who have either poorly treated or undiagnosed hyperthyroidism and are exposed to excess stress (trauma, surgery or infection). This requires emergency admission and treatment with intravenous fluids, beta-blockers and anti-thyroid medication.

Hypothyroid emergency (myxoedema coma)

Myxoedema coma refers to a rare, but serious, hypothyroid emergency that tends to present with hypothermia, bradycardia, reduced conscious level and seizures. It is usually seen in older patients with undiagnosed or poorly controlled disease, and is often precipitated by another medical illness, such as sepsis. Urgent hospital admission is required, and the initiation of treatment with intravenous levothyroxine and correction of associated electrolyte abnormalities (hypoglycaemia and hyponatraemia).

Thyroid lumps

Thyroid lumps are often classified as either a goitre or nodule. A goitre represents a diffusely enlarged gland that may be either physiological, related to an auto-immune condition (Graves’ or Hashimoto’s disease) or due to inflammation of the gland (thyroiditis). Thyroid nodules are discrete areas of enlargement that occur more commonly as people get older, and are usually associated with normal thyroid function tests (Pearce, 2006). If an abnormality of the thyroid anatomy is detected, then the thyroid gland should be examined along with the evaluation of a person’s thyroid status.

Examination

Inspection: Initially from the front, both for scars and on swallowing to assess movement and size of the gland

Palpation: Palpation of the gland from behind to evaluate the size, nodularity (uni-, or multi-nodular), consistency, tenderness (in thyroiditis) and mobility (cancers may be tethered)

Percussion: Percusion of the sternum to detect for retro-sternal spread

Auscultation: To see if there is a bruit over the gland (associated with increased blood flow in Graves’ disease)

Most nodules detected in general practice will be benign, but all patients should be investigated with TFTs and referred appropriately based on NICE (2016c) guidance as outline in Box 3.

Box 3.

NICE referral guidelines for thyroid lumps.

• Admit immediately if there are symptoms of tracheal compression, such as stridor at rest.

• Urgently refer on 2 week cancer pathway in people with:

▪ An unexplained thyroid lump.

▪ Unexplained voice changes with a goitre.

▪ Cervical lymphadenopathy with a thyroid mass.

▪ A painless thyroid mass, rapidly increasing in size over a period of weeks.

• Consider a non-urgent referral for:

▪ Thyroid nodules and abnormal TFTs: Thyroid cancer is very rare in this group

Source: NICE (2016c).

Case studies: Advice and further management.

The first lady’s result suggests sub-clinical hyperthyroidism. You enquire about symptoms and she denies any and feels that her weight is now stable. She has not recently been unwell and she is not on any medication that could be causing the results. You therefore advise her that she should have repeat blood tests in 2 months and if it is persistent you would refer to endocrinology. You notice that the second patient is taking carbimazole and you remember that this can cause agranulocytosis. You arrange for this lady to come in that day for urgent review and blood tests. Luckily the blood tests will not show neutropenia and she therefore will not require admission. Finally, you advise the 28-year-old pregnant lady that she should come in for TFTs as you need to closely monitor TSH in pregnancy. You advise her that you will refer her to Endocrinology, but whilst awaiting this review you will increase her levothyroxine by 25–50 micrograms.

KEY POINTS

TFTs must be interpreted within clinical context as illness, medications and pregnancy can affect results

Repeat TFTs, either due to abnormal TSH results or post levothyroxine dose adjustments, should be carried out at 2–3 month intervals

A rare, but important, side effect of carbimazole is agranulocytosis, and it is therefore important to carry out an FBC in people presenting with sore throat

Sub-clinical hypothyroidism required annual monitoring of TSH levels and treatment depends on age, TSH levels and symptoms

Patients taking levothyroxine are entitled to free prescriptions

All patients presenting with a thyroid lump should be investigated with TFTs and referred appropriately based on NICE guidance

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