Thyroid Function Tests

Thyroid disease is common (approximately 1% population), presents with many non-specific symptoms so needs to be considered in many differentials and, once diagnosed, needs to be regularly monitored to optimise therapy. As a consequence, TFTs are the most commonly used endocrine test - 10 million thyroid function tests (TFTs) are ordered annually in the UK, at a cost of over £30 million.¹ Indeed, the nGMS contract currently includes thyroid disease as a clinical domain requiring primary care to keep practice registers of hypothyroid patients and to ensure they receive regular TFTs.²
Dissenters point out the low yield of thyroid disease when TFTs are used in patients with low clinical suspicion (0.45%) but when used in combination with clinical acumen, they have a much higher yield (3 signs or symptoms 30%, 5 signs or symptoms 80%).³

As well as use for diagnosis in individual patients with signs or symptoms of possible thyroid disease, indications for TFTs include:

Screening

Currently screening in the healthy adult population for thyroid disease is not warranted⁴ but more limited screening should be performed in:

• Neonates with the heelprick test for congenital hypothyroidism
• Patients with suspected goitre or thyroid nodules
• Women with type 1 diabetes

Surveillance

Surveillance of certain groups is advocated:

• Women with a history of post-partum thyroiditis - annual TFTs
• Patients with type 1 diabetes mellitus - annual TFTs
• Down's⁵ and Turner's syndrome - annual TFTs
• Patients receiving amiodarone or lithium
• Post neck irradiation - annual TFTs
• Post destructive treatment (radio-iodine or surgical) for thyrotoxicosis - check TFTs 4-8 weeks after treatment, 3 monthly for first year and then annually

Monitoring

• For antithyroid drug treatment, check 1-3 monthly until stable and then annually if used longterm.
• For thyroxine replacement therapy, check TFTs at least annually once stable.

When using TFTs to investigate a possible thyroid disorder, regardless of whether the patient is thought to be hypo- or hyperthyroid, the initial investigation should always be a sensitive serum TSH assay.

• The TSH level will be raised in patients with hypothyroidism and reduced in patients with hyperthyroidism.
• The advent of the sensitive TSH assay allows for the diagnosis of subclinical disease in asymptomatic patients.
• The results of the TSH assay will determine which further investigations will need to be performed.

Hyperthyroidism

Hyperthyroidism occurs as a consequence of excessive thyroid hormone activity. Common causes in the UK include thyroiditis, Grave's disease and toxic nodular goitre

Diagnosis

• The initial lab investigation with a possible diagnosis of hyperthyroidism should be a sensitive serum TSH assay which will show reduced circulating levels of TSH. The exception to this rule are rare TSH-dependent causes of hyperthyroidism eg TSH-producing pituitary tumours, syndromes of thyroid hormone resistance.
• Note that, low serum TSH (especially if below reference range but above 0.10 mU/L) is not specific for hyperthyroidism - it may also occur with "non-thyroidal illness" or with the use of some commonly prescribed drugs.
• Patient's who have a low TSH may then go on to have further investigations such as:-
  • Free T4 and T3 assays - a subnormal TSH, should trigger the measurement of FT4. If this is not elevated, FT3 should be measured to identify cases of T3-thyrotoxicosis.
  • Thyroid autoantibodies eg thyroid peroxidase antibodies (TPOAb), TSH receptor antibodies (TRAb) or thyroid stimulating immunoglobulins (TSI) - these are not routine tests but may be of use in selected cases.
  • Radioactive iodine uptake- thyroid scanning with either ¹²³I (most frequent) or ^99mTc helps to determine cause of hyperthyroidism eg diffuse pattern of uptake in Graves' disease compared to one or more 'hot' nodules in toxic nodular hyperthyroidism.

Guiding treatment

Following a diagnosis of hyperthyroidism, many patients are started on thionamides (carbimazole or propylthiouracil), usually followed by definitive treatment with radioiodine or surgery.

• Response to thionamide therapy is judged by serial measurement of FT4 and TSH, allowing dose adjustment and avoidance of iatrogenic hypothyroidism. Note, use of TSH alone is inadequate, since TSH is frequently suppressed for many months following initiation of thionamides. Suggested intervals for TFTs are every 4-6 weeks in the first few months, once on stable maintenance dose every 3 months. Reduce dose where FT4 falls to low normal or below normal range or where TSH rises.
• 'Block and replace' regimens (where initially treat with thionamide alone, then add thyroxine once FT4 has normalized have been shown not to be superior to a dose titration regimen (as above) and may be associated with more side effects. Again monitor TSH and FT4 levels.
• Persistently elevated FT4 despite seemingly adequate prescription of thionamides is most likely to indicate poor compliance.

Following radioiodine therapy:

• FT4 and TSH should be performed every 4-6 weeks for at least 6 months. The frequency of tests may be reduced when FT4 remains within reference range.
• After an interval of euthyroidism of at least a year, the patient may have annual tests.
• A serum TSH of >20mU/L following radioiodine therapy in a patient not receiving thionamides in the previous 6 weeks should trigger thyroxine treatment.

Hypothyroidism

Primary hypothyroidism occurs as a result of undersecretion of thyroid hormone from the thyroid gland. Common causes include as Hashimoto's thyroiditis, irradiation and drugs such as lithium. Secondary hypothyroidism may occur as a result of damage or disease of the pituitary or hypothalamus.

Diagnosis

• To diagnose primary hypothyroidism, one needs to measure both TSH and FT4. Where TSH is >10mU/L and FT4 below reference range, the diagnosis is overt primary hypothyroidism and the patient needs treatment with thyroid replacement therapy.
• Secondary hypothyroidism is suggested by low, within or mildly elevated TSH combined with a low FT4. Differentiating this from non-thyroidal illness can be difficult and clinical history, FT3 and sometimes anterior pituitary hormone tests are necessary.

Additional diagnostic tests may include:

• Thyroid auto-antibodies - antithyroid peroxidase and antithyroglobulin antibodies
• Thyroid scan
• Ultrasound examination of the thyroid gland

Guiding treatment

• Thyroxine replacement therapy's goals are to make a patient feel well and to achieve a TSH within reference range. FT4 will be within or slightly above reference range.
• It takes at least 2 months to achieve a stable hormone concentration following dose adjustment of thyroxine so do not check TFTs sooner than this.
• Patients stabilised on long-term thyroxine should have annual TSH checks.

Subclinical disease

Subclinical thyroid disease is common - american prevalence of subclinical hypothyroidism is estimated as 4 - 8.5% of the general population, and up to 20% of women older than 60 years, and about 2% general population are thought to be subclinically hyperthyroid.⁶ Diagnosis is based solely on test results. When to treat subclinical disease is contentious.
Subclinical hyperthyroidism:

• Is diagnosed by low serum TSH, normal FT4 and FT3, in the absence of non-thyroidal illness or relevant drug therapy.
• May increases risk of developing AF and CVD.
• TFTs should be repeated at 3-6 months or earlier if elderly or if patient has pre-existing CVD, to determine whether full blown hyperthyroidism has developed or if the subclinical picture has persisted.
• Patients with persistent subclinical hyperthyroidism should be referred to a specialist.

Subclinical hypothyroidism:

• Occurs where TSH is above reference range with a normal FT4.
• Diagnosis should be confirmed with repeat TFTs after 3-6 months.
• Where TSH is <10 mU/L, there is no consistent evidence of association with symptoms, hyperlipidaemias or increased risk of CVD. Above this level, there is more evidence of progression to overt thyroid disease and worsening hyperlipidaemia.
• Thyroxine therapy is not recommended unless TSH>10 mU/L or, below this, if patients are pregnant, have a goitre or are trying to conceive.

Others argue that evidence for any benefit of treating subclinical disease is limited and recommend against routine treatment.⁷

Many commonly-used drugs affect the regulation of thyroid function either by altering production of the hormones along the regulatory pathway or the measured hormone levels due to changes in protein binding. Interpretation of TFTs may be more difficult as a consequence.

Amiodarone⁸

Amiodarone has multiple effects on the thyroid due to its high levels of iodine (one 100 mg tablet contains 250x the recommended daily intake) and its direct toxicity on the thyroid. It can induce hyperthyroidism (primarily in iodine deficient areas of the world) or hypothyroidism.

TFTs in pregnancy

• In pregnancy, oestrogen levels increase and TBG concentrations rise - this leads to an increase in TT4 and TT3.
  • In the first trimester, serum TSH also falls due to the effect of HCG and there may be a small fall in FT4.
  • In the second and third trimesters, FT4 and FT3 decrease, sometimes below the non-pregnant women's reference level.
• Always use trimester-related reference ranges for TSH and total and free thyroid hormones to assess pregnant patients' thyroid status.
• Changes in the immune system during and after pregnancy may alter the course of pre-existing autoimmune thyroid disease and predispose to relapse or to developing novel autoimmune thyroid disease.
• Some feel that we should be screening all pregnant women for thyroid disease¹⁰ but current British Thyroid Association recommendations are for screening, ideally pre-conceptually, in women with:
  • Type 1 diabetes
  • Previous thyroid disease
  • Current thyroid disease
  • Family history of thyroid disease
  • Goitre
  • Symptoms of hypothyroidism
• TFTs in pregnancy should comprise both TSH and FT4. TPO-Ab should also be considered as it has predictive value for post-partum thyroiditis and foetal impairment.

Hypothyroid pregnancies

• Increased foetal loss and IQ deficits in infants are associated with mothers who had undiagnosed or undertreated hypothyroidism during pregnancy. Thyroxine requirements are also likely to change during pregnancy. It is important that specialist medical-obstetric teams manage such pregnancies.
• The thyroid status of pregnant hypothyroid patients should be checked:
  • Prior to conception (where possible)
  • At diagnosis of pregnancy
  • At antenatal booking
  • At least once during the 2nd and 3rd trimesters and again post-partum
  • If newly diagnosed, every 4-6 weeks until stable

Hyperthyroid pregnancies

Similarly pregnancies in hyperthyroid women offer challenges and should be managed by specialists:

• In those receiving anti-thyroid drugs, TFTs should be checked prior to conception and drugs adjusted to a minimum dose of anti-thyroid drug only. Patients on carbimazole are sometimes switched to propylthiouracil which is felt to be preferable for breastfeeding.
• Recheck TFTs at the time of diagnosis of pregnancy and booking. Again consider modifying therapy and dose reduction, if appropriate.
• FT4 should guide therapy and be maintained at the upper end of the trimester-related reference range.
• Those on anti-thyroid drugs need frequent TFTs during pregnancy whilst women previously successfully treated and who are euthyroid at booking need checks again only in 2nd and 3rd trimesters.
• All should be retested after delivery.
• Note that women who have previously undergone thyroidectomy for Graves' disease and who are euthyroid or even hypothyroid during pregnancy, may nonetheless still have high titres of TSH-RAb and therefore their babies may be at risk of neonatal Graves' disease.

Neonatal screening for congenital hypothyroidism

Congenital hypothyroidism is a common and preventable cause of mental retardation. If thyroid replacement is not initiated soon after birth, it becomes irreversible.

• The UK has a national screening programme - all newborn babies have a bloodspot TSH measured from a heel prick sample taken on day 2-8 after birth.
• Where an elevated TSH is found (>20 mU/L), confirmation of the diagnosis is based on measurement of maternal and neonatal TSH and FT4 as well as TSH-RAb in the mother. Maternal tests ensure that there has been no placental transfer of maternal autoantibodies.
• Treatment should be started within the first 18 days of life.