Thyroid disease: challenges in primary care

Thyroid dysfunction is common, but thyroid testing should only be requested after a detailed clinical history and targeted physical examination have suggested thyroid problems.

Thyroid disease: challenges in primary care

Key points

  • Requests for thyroid tests are increasing, although in many cases clinical need is not evident.
  • If thyroid dysfunction is suspected, measuring TSH alone is recommended as the first step. Test T4 only when TSH is abnormal.
  • Ultrasound should be considered for patients with thyroid dysfunction and a goitre (enlarged thyroid) or palpable thyroid nodules, but NOT if the only abnormality is hypothyroidism or elevated antithyroid antibodies.
  • Repeat TSH testing within 12 months is generally not recommended if TSH is normal.
  • Fatigue alone should not be the basis of thyroid testing. Instead, take a detailed clinical history and perform a targeted physical examination before requesting tests or treatment.

Thyroid function tests

A series of blood tests commonly used to investigate problems associated with underlying thyroid disease, such as goitre, as well as a range of non-specific symptoms such as tiredness, unexplained weight gain, depression and anxiety.1 These include tests for thyroid stimulating hormone (TSH), free thyroxine (T4) and free triiodothyronine (T3).

 

Thyroid problems in Australia

"Thyroid disorders are very common. As many symptoms of thyroid disease are non-specific, careful history taking and physical examination are key to avoiding unnecessary testing."
Associate Professor Shane Hamblin, Head of Endocrinology and Diabetes at Western Health, Victoria

The number of people undergoing thyroid testing in Australia is increasing at a faster rate than the population,2 and evidence indicates that at least some of these tests may be clinically unnecessary.3

Increased testing carries the risk of incidental findings which may lead to a cascade of tests and procedures, as well as uncertainty and anxiety for patients.3,4 To ensure the benefits of thyroid testing outweigh harms, adherence to testing guidelines is important.

 

Identifying thyroid disease in general practice

Thyroid disease can be broadly categorised as:

  • thyroid dysfunction (hypothyroidism, hyperthyroidism,) or
  • structural disease (goitre, nodules and cancer).

Hypothyroidism is the most common disorder of thyroid function, with a prevalence ranging from 0.5% to 5% for overt and subclinical cases, respectively.5 Hyperthyroidism (low TSH, high free T4/T3) is less common than hypothyroidism, with a prevalence of around 0.5%–1.0%.5-7

When to suspect thyroid dysfunction

Signs and symptoms of hypothyroidism may vary depending on patient characteristics and the severity of dysfunction. Classic symptoms include fatigue, weight gain, cold intolerance, arthralgia, constipation, menorrhagia, irregular menstrual cycles, and dry skin and hair.8 Physical signs include coarse skin and hair, bradycardia and goitre but these may be absent in mild hypothyroidism.8

Many of the signs and symptoms are not specific to hypothyroidism: around 20%–25% of people with normal TSH report one or two of these symptoms.9 Laboratory tests are required to establish a diagnosis of hypothyroidism.

Hypothyroidism can be classified as overt, subclinical or secondary (central).

  • Overt hypothyroidism (high TSH, low free T4) is usually symptomatic and readily diagnosed, although there are exceptions.
  • Subclinical hypothyroidism (elevated TSH, normal free T4) is more common than overt hypothyroidism, but less frequently detected clinically as many patients have vague symptoms.
  • Secondary (or central) hypothyroidism is caused by disorders of the pituitary gland or hypothalamus and is characterised by decreased TSH and a disproportionately low concentration of free T4.10 Secondary hypothyroidism is uncommon, but in situations where a central cause is suspected (eg, known pituitary tumour or head injury) it is essential that T4 is checked as well as TSH, since TSH may be in the normal range.

Classic symptoms for hyperthyroidism include weight loss, heat intolerance, palpitations, breathlessness, anxiety, diarrhoea, menstrual disturbances, tremor and proximal muscle weakness. Physical signs include tremor, tachycardia, ophthalmopathy (if due to Graves disease), goitre and difficulty rising from a squatting position.8 However some patients (especially in older age groups), may present with ‘apathetic hyperthyroidism’ and lack many of the classical features.

  • Overt hyperthyroidism is characterised by increased free T4 and free T3 and low TSH. It is most commonly caused by Graves disease, or toxic nodular goitre.
  • Subclinical hyperthyroidism is characterised by suppressed TSH and normal free T3/T4 in patients with or without symptoms of hyperthyroidism.11,12 Mild subclinical hyperthyroidism (with low but detectable TSH levels) may be caused by autonomous thyroid nodules but may also be found in healthy individuals.8 Approximately 5% of individuals progress from subclinical to overt dysfunction yearly.13 Because of the diversity of clinical presentations of hyperthyroidism, laboratory testing is appropriate on a low index of suspicion.14

Current recommendations for monitoring, testing and treating thyroid dysfunction are summarised in Table 1.

 

Optimising the use of thyroid testing and imaging

Screening for thyroid dysfunction is not recommended in asymptomatic patients unless there is a clinical suspicion of thyroid dysfunction or the patient is in a high-risk group (such as patients with autoimmune disease or type 1 diabetes).15

Measuring TSH is recommended as the first-line test for possible thyroid dysfunction.1. If TSH is in the reference range, additional tests (T3,T4 and thyroid antibodies) are generally not required except in patients with pituitary disease (in which case TSH is unreliable).8

Guidelines recommend a two-step approach to thyroid testing, in which T4 is assessed only in cases of abnormal TSH.15,16 A recent cross-sectional analysis of the population-based Busselton Health Study compared the two-step approach with the one-step approach (initially testing TSH and T4 together) and found that the two-step approach avoided T4 testing in almost 93% of people without increasing the risk of missing thyroid dysfunction.6

When should T3 also be tested?

Serum T3 should only be tested when TSH is supressed. If TSH is low but free T4 is normal, elevated T3 may indicate early Graves disease or ‘T3 toxicosis’ caused by an autonomously functioning thyroid nodule.13

Physiologic factors influencing TSH values

Several factors can alter the normal range of TSH values, and should be considered when making a clinical decision.

  • First, unexplained intra-individual variation may occur in healthy individuals, as well as those with subclinical hypothyroidism.11 These changes do not necessarily indicate a change in thyroid function or status.16
  • Second, the normal range for TSH values tend to increase with age, such that the upper limit (97.5th percentile) of normal values ranges from 3.5 mIU/L for 20–29-year-olds to 7.5 mIU/L for 80+ year-olds.17
  • Third, TSH values follow a circadian rhythm, with peak values from midnight to 4 am and a nadir from midday to 6 pm.18 This variation can account for differences of 1-2 mIU/L in healthy individuals as well as those with subclinical hypothyroidism.19,20
  • Finally, low TSH values are common in the first trimester of pregnancy, but often normalise in the second and third trimesters.21 Detailed discussion of thyroid function and pregnancy is beyond the scope of this MedicineWise News. Please consult current guidelines for the management of thyroid dysfunction during pregnancy and post-partum.21-24

Don’t test at the first sign of fatigue

Fatigue is the most common unexplained complaint in general practice,25 and is often the basis for thyroid testing.

While fatigue is present in many cases of thyroid disease,26 it is not itself a direct indicator of thyroid dysfunction. For example, a Dutch trial of unexplained fatigue in 173 patients found only a single patient with hypothyroidism,27 while a recent cross sectional study of 2035 patients who had undergone TSH testing reported no association between fatigue and abnormal TSH results.3

‘It can be tempting to jump to the pathology or imaging request slip, especially when the patient’s symptoms are vague and the waiting room is full,’ says Professor Hamblin. ‘However, the time investment to take a detailed clinical history and perform a targeted physical examination is worthwhile.’

Other causes of fatigue should be evaluated alongside thyroid dysfunction, and thyroid testing should be considered only when fatigue is present alongside other symptoms and indicators, such as autoimmune disease or a strong family history of hypothyroidism.

 

Management and medicines

"The media love villains and magic bullets: the thyroid tends to be a favourite on both counts. Patient perceptions, especially regarding the thyroid and weight, can be very difficult to change, given the amount of media misinformation." 
Shane Hamblin

The goals of treatment for hypothyroidism are normalisation of TSH levels and relief of symptoms.8 For patients with diagnosed overt hypothyroidism recommended first-line treatment is thyroid hormone replacement at an initial dose of levothyroxine 50–100 micrograms /day, or 25 micrograms/day for frail or elderly patients.28 Current recommendations are that patients should have TSH and T4 retested 6–8 weeks after initiating levothyroxine to determine if a change in dosage is required. Non-adherence to treatment is the most common explanation for persistent elevations in TSH.8

For hyperthyroidism, choice of treatment depends on the patient’s age, symptoms, comorbidities and the underlying cause of illness.8,29 Most symptomatic patients, regardless of the cause of their condition, benefit from beta blockers to manage their adrenergic symptoms.30

Graves disease can be treated with antithyroid medicines (thionamides, which inhibit thyroid peroxidase), radioactive iodine or surgery. Since many patients with Graves disease who are treated with thionamides experience remission, medicines can be trialled initially, with alternatives sought for non-responders.31

Patients who respond well to antithyroid medicines can complete an 18-month course of treatment. A reduction in dosage should be considered for patients who have a decrease in serum T3 and T4 at their 3–4-week follow-up. For longer-term maintenance therapy, it is currently recommended that thyroid function should be reviewed every 6–8 weeks, and every 3–4 months once stable.14

Radioactive iodine or thyroidectomy are the primary treatment options for toxic nodular goitre.8

Patients with milder subclinical hyperthyroidism often stabilise without treatment, so careful monitoring and repeat testing every 6 months may be all that is required.8 Treatment should also be considered for symptomatic elderly patients, patients with underlying cardiovascular disease, and those with symptoms suggestive of hyperthyroidism or associated comorbidities.13

Accelerated bone loss is also related to hyperthyroidism. When TSH is less than 0.1 mIU/L, a bone density scan should be considered to assess for osteoporosis as this may influence the decision to treat the thyroid.32

Less common causes of hyperthyroidism, such as subacute thyroiditis and amiodarone thyroiditis, are best managed by a specialist.

‘The decision to refer a patient with hyperthyroidism will depend on the experience of the GP managing this condition and the severity of the hyperthyroidism,’ says Professor Hamblin. ‘In contrast to hypothyroidism, most patients with hyperthyroidism are appropriately referred to an endocrinologist or consultant physician.’

 

What about subclinical hypothyroidism?

The importance of treating subclinical hypothyroidism – particularly the need to medicate – remains less clear. Since spontaneous normalisation is common, monitoring – rather than immediate treatment – should be the first step in management (see Table 1).

Most guidelines recommend treatment in subclinical cases (< 10 mIU/L) only for patients who are younger than 65, symptomatic or have other clear indications, such as cardiovascular disease.33

A recent systematic review and clinical practice guide advised against thyroid hormones in most adults with subclinical hypothyroidism.33 This review evaluated 21 trials with 2,192 patients, and consistently found that hormone replacement therapy did not produce clinically relevant benefits.

Subclinical to overt hypothyroidism: which patients are at greatest risk?

The risk of progression from subclinical to overt hypothyroidism is between 2% and 5% per year.34 ‘Clinicians should focus periodic thyroid function testing on those most at risk of disease progression,’ says Professor Hamblin. These include patients with the following characteristics:34-36

  • Female sex
  • Older age
  • Presence of thyroid peroxidase antibodies
  • Serum TSH values > 10.0 mIU/L
  • A history of radioiodine ablation for Graves disease
  • A history of external radiation therapy for non-thyroidal malignancies
  • A history of long-term lithium treatment
  • A history of consuming a large amount of iodine (eg, iodine contrast agents, kelp extract, amiodarone)

A recent study indicated that older adults with subclinical thyroid dysfunction are unlikely to progress to overt thyroid dysfunction over the following 5 years. Clinical assessment in this group should therefore be based on thyroid symptoms and risk factors, such as the risk of progressive hypothyroidism (see box above) rather than thyroid function tests alone.30

‘Subclinical hypothyroidism is a biochemical diagnosis, which in some cases may be a misnomer,’ says Professor Hamblin. ‘It is termed subclinical even when the patient may indeed have a variety of symptoms potentially related to hypothyroidism.’

 

Thyroid scans and imaging

Thyroid ultrasounds may be used to assess clinically detected, visible or palpable thyroid nodules or goitre.8,37 They are not indicated in the absence of goitre or palpable nodules and should not be used as part of the routine evaluation of abnormal thyroid function tests.14

Thyroid nuclear scans are functional tests that assess the activity of the thyroid.37 These differ from ultrasound, which provides information on gross morphology.

Thyroid nuclear scans are primarily useful in differentiating the causes of hyperthyroidism and assessing the function of thyroid nodules, but may also be used to differentiate probable causes of hyperthyroidism even when nodules are not present.37 Functioning nodules suggest that treatment is the likely next step, while non-functioning nodules warrant further investigation, such as by ultrasound. The pattern of uptake can provide insight into the appropriate diagnosis.37

Judicious use of ultrasounds is essential to avoiding overdiagnosis

The incidence of thyroid cancers is increasing in Australia,38,39 and ultrasound scans may play a role by detecting small papillary nodules that would otherwise not become clinically apparent.40

Autopsy studies reveal that small thyroid nodules are present in up to 5% of people,41 but the lifetime risk of clinically diagnosed thyroid cancer is less than 1%.8

 

Autoimmune thyroid disease and antibody testing

Autoimmune thyroid disease affects 10%–15% of the population and is the most common cause of thyroid dysfunction in Australia.8 Patients with subclinical hypothyroidism are at particular risk: one study found that approximately 80% of subclinical hypothyroidism patients had increased levels of antithyroid antibodies, indicative of autoimmune disease.42

The two major autoimmune thyroid diseases are Hashimoto disease (which causes hypothyroidism) and Graves disease (which causes hyperthyroidism), both of which are characterised biochemically by the presence of circulating thyroid-specific auto-reactive antibodies.43

If a person has elevated TSH, antithyroid antibody tests should be ordered to help determine the diagnosis.44 If TSH is completely suppressed and T4 and/or T3 are elevated, TSH receptor antibodies should be checked to determine if Graves disease is present. Testing should not be repeated as it does not alter the course of management.

Positive antibody tests indicate the following conditions:8,44

  • TSH receptor antibodies (TRAb): Graves disease
  • Thyroid peroxidase antibodies (TPOAb): Hashimoto disease
  • Thyroglobulin antibody (TgAb): Hashimoto disease. This test may also be part of thyroid cancer follow-up when interpreting the results of thyroglobulin levels.

Antibody testing is not recommended when TSH is in the normal reference range.8

"Most GPs are very comfortable requesting thyroid antibodies when investigating hypothyroidism. However, few request TRAb when investigating hyperthyroidism. TRAbs will be elevated in most cases of active Graves disease and can be very useful when deciding on duration of antithyroid therapy." 
Shane Hamblin

When to seek specialist input

Consider referral for patients with Graves disease, toxic nodular goitre or an unclear diagnosis. Although overt hyperthyroidism is uncommon during pregnancy, it increases the risk of pregnancy loss and other harms, so pregnant women with suspected hyperthyroidism should be referred urgently.8

 

How often should tests be repeated?

Repeat TSH tests are frequently requested earlier than necessary. Recent MBS data indicate that 38% of patients have repeat TSH tests within 12 months of their initial test, and that these are requested by GPs in 90% of cases.45

However, guidelines advise against repeat testing within 12 months of a normal TSH test, unless there has been a change in the patient’s underlying thyroid condition or their thyroid hormone replacement treatment.45

A recent study of 2,936 adults aged 65 or older demonstrated that changes in thyroid function are uncommon in repeat tests conducted 5 years after a normal or subclinical result.30 Thyroid function worsened in only 2%–4% of participants, and 61% of participants had a repeat TSH value within 0.5 mIU/L of their original result.

The use of repeat tests should be based on patient symptoms and other indicators, such as comorbidities, regular medicines, age, sex and TSH levels.

Table 1: Summary of clinical features and current recommendations for monitoring, testing and treatment for thyroid dysfunction1,8,30,46

A detailed algorithm will be available from NPS MedicineWise in late 2019.


ConditionTSH, T4, T3 Monitoring and testing
Euthyroid (normal), asymptomatic or suspected cases

Typical reference ranges in healthy individuals:

  • TSH: 0.4–4.0 mIU/L
  • T4: 10–25 pmol/L T3:2.6–6.0 pmol/L
(actual ranges will vary depending on the assay platform used)

  • Asymptomatic patients: no testing is required, except in the circumstances described above; TSH should not be used for screening.
  • Suspected thyroid condition: TSH alone as the first step.

Overt hypothyroidism High TSH, low T4
  • Hypothyroidism is treated by hormone replacement therapy with levothyroxine.
  • Imaging is not indicated.
  • Measure TSH/T4 at 6–8 weeks after starting medication to determine need for dose adjustment.
  • If levels are stable, test TSH annually.
  • If levels are not stable, explore adherence with patient, including if they are taking levothyroxine on an empty stomach. Measure TSH/T4 after a further 6–8 weeks.
Subclinical hypothyroidism Elevated TSH, normal T4 and T3
  • Some cases of subclinical hypothyroidism may benefit from hormone replacement therapy with levothyroxine.
  • Imaging is not indicated.
  • If TSH ≤ 10 mIU/L: measure TSH/T4 at 6 months. If stable, monitor TSH/T4 annually.
  • If TSH > 10 mIU/L: Measure TSH/T4 at 6–8 weeks for dose adjustment. If stable, test TSH annually.
Overt hyperthyroidism Suppressed TSH, elevated T4 and/or T3
  • Cause of disease should be established before treatment, unless patient is very symptomatic.
  • Treatment typically consists of antithyroid medicines (thionamides) and beta blockers for adrenergic symptoms.
  • Milder cases may in selected situations be treated with radioactive iodine, without pre-treatment with thionamides.
  • Test TSH/T4/T3 every 4–6 weeks. Monitor situation closely and adjust antithyroid treatment as required.
Subclinical hyperthyroidism Low TSH, normal T4, normal T3
  • If TSH ≤ 0.1 mIU/L on two occasions: refer to specialist.
  • If TSH ≥ 0.1 mIU/L: measure TSH/T4 at 4–8 weeks. 
  •  If TSH is low and T4/T3 are normal, repeat testing every 6–12 months.

 

Expert reviewers

Associate Professor Shane Hamblin

Head of Endocrinology and Diabetes at Western Health, Melbourne and consultant endocrinologist at The Alfred, Melbourne.

Dr Jill Thistlethwaite

GP and Medical Adviser, NPS MedicineWise.

 

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