Thyroid disease is common (approximately 1% of the population), presents with wide ranging and often nonspecific symptoms - so needs to be considered in many differentials and, once diagnosed, needs to be regularly monitored to optimise therapy. As a consequence, thyroid function tests (TFTs) are the most commonly used endocrine test - 10 million TFTs are ordered annually in the UK, at a cost of over £30 million. Dissenters point out that TFTs are widely used in patients with a low pretest probability of thyroid disease and have a low yield consequently.In General Practice, the most common use of a TFT is as part of a screen for nonspecific fatigue or illness. The value of such tests without a goitre or other clinical features has been challenged and some advocate the use of watchful waiting with the delayed use of laboratory tests (at 4 weeks post presentation) as a more appropriate strategy for investigating unexplained fatigue. Similarly the value of performing TFTs on obese patients without any other symptoms suggestive of hypothyroidism is doubtful.
British guidelines have also been developed to promote the rational use of TFTs
On this page
Indications
Using thyroid function tests
Drug effects
Special situations
References
Physiology
An understanding of normal homeostatic mechanisms helps to interpret TFTs:
The hypothalamus, pituitary gland and the thyroid all play a part in the feedback and regulatory mechanisms involved in the production of thyroxine (T4) and triiodothyronine (T3) from the thyroid gland.
Thyroid releasing hormone (TRH) is secreted by the hypothalamus and stimulates the production of the polypeptide thyroid stimulating hormone (TSH) from the anterior pituitary.
TSH then stimulates the production and release of T4 and T3 from the thyroid.
Once released, T4 and T3 then exert a negative feedback mechanism on TSH production.
T4 is the main hormone produced by the thyroid.
T3 is mainly produced by peripheral conversion of T4.
T3 and T4 are largely protein bound in the plasma, mainly to thyroxine-binding globulin (TBG). Only the unbound or 'free' portion (FT3, FT4) is active.
T3 and T4 both act via nuclear receptors to increase cell metabolism.
Indications
Diagnosis of possible thyroid disease
Consider where signs or symptoms are compatible with possible thyroid disease, as well as with:
Goitre or thyroid nodule
Atrial fibrillation (AF)
Osteoporosis
Subfertility
Dyslipidaemia
Screening
Currently, screening in the healthy adult population for thyroid disease is not warranted[5] but more limited screening should be performed in:
Neonates, with the heelprick test for congenital hypothyroidism.
All patients with diabetes (types 1 and 2) at time of diagnosis.
Women with type 1 diabetes preconception, at booking and 3 months postpartum.
Surveillance
Surveillance of certain groups is advocated:
Women with a history of postpartum thyroiditis (annual TFTs, prenatally and postnatally in future pregnancies).
Patients with type 1 diabetes mellitus (annual TFTs).
Down's syndrome and Turner's syndrome (annual TFTs).
Patients receiving amiodarone (pretreatment, then every 6 months until off treatment for a year) or lithium (pretreatment, every 6-12 months whilst on treatment).
Post neck irradiation (annual TFTs).
Post destructive treatment (radioiodine or surgical) for thyrotoxicosis (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 long-term.
For thyroxine replacement therapy, check TFTs at least annually once stable.
Using thyroid function tests
When using thyroid function tests (TFTs) to investigate a possible thyroid disorder, regardless of whether the patient is thought to be hypothyroid or hyperthyroid, the initial investigation should always be a sensitive serum thyroid stimulating hormone (TSH) assay. In unselected populations, measurement of serum TSH has a sensitivity of 89-95% and specificity of 90-96% for overt thyroid dysfunction.
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.
There are situations where TSH alone is unhelpful:
Common:
Recent treatment of thyrotoxicosis
Pituitary disease
Non-thyroidal illness
Rare:
TSH-secreting pituitary tumour
Thyroid hormone resistance The requesting doctor should provide adequate clinical information to guide the laboratory in the selection of the most appropriate TFTs.
New cases of pituitary hypothyroidism are rare, but can present with very vague symptoms so an additional request of FT3/FT4 should be considered where there is persistent fatigue with a normal TSH, particularly with signs or symptoms of gonadal dysfunction.
Hyperthyroidism
Hyperthyroidism occurs as a consequence of excessive thyroid hormone activity.
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.
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.
Patients who have a low TSH may then go on to have further investigations such as:
FT4 and FT3 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. Antithyroid antibodies are negative in about 10% cases of Graves' disease.
Radioactive isotope uptake - thyroid scanning, usually with 123 I, helps to determine the cause of hyperthyroidism, eg diffuse pattern of uptake in Graves' disease compared with one or more 'hot' nodules in toxic nodular hyperthyroidism.
Interpreting thyroid function tests
Low TSH Raised FT3 or FT4 Common causes:
Primary hyperthyroidism - Graves' disease, multinodular goitre, toxic nodule
Relatively common causes with low radioiodine uptake:
Transient thyroiditis (postpartum, post-viral, De Quervain's)
Rare with a low radioiodine uptake:
Thyroxine ingestion
Ectopic thyroid tissue
Iodine induced
Amiodarone therapy
Rare with a positive pregnancy test:
Gestational thyrotoxicosis with hyperemesis gravidarum
Hydatiform mole
Rare:
Familial TSH receptor mutation
Low TSH Normal FT3 or FT4 Common causes:
Subclinical hyperthyroidism
Thyroxine ingestion Rare causes:
Steroid therapy
Dopamine and dobutamine infusion
Non-thyroidal illness
Low or normal TSH Low FT3 or FT4 Common causes:
Non-thyroidal illness
Recent treatment for hyperthyroidism
Rare causes:
Pituitary disease
Congenital TSH or TRH deficiencies
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 that 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 a stable maintenance dose every 3 months. Reduce the dose where FT4 falls to low normal or below normal range or where TSH rises.
'Block and replace' regimens (where treatment is initially with thionamide alone, then adding thyroxine once FT4 has normalised) 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 >20 mU/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. 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 >10 mU/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.
Interpreting thyroid function tests
Raised TSH Low FT4 or FT3 Common causes:
Chronic autoimmune thyroiditis
Post radioiodine
Post thyroidectomy
Transient thyroiditis - hypothyroid phase
Rare causes (anti-TPO negative):
Post external beam radiotherapy to the neck
Drugs - amiodarone, lithium, interferons, interleukin-2
Iodine deficiency
Amyloid goitre
Congenital causes:
Thyroid dysgenesis
Iodine transport defects
TSH receptor defects
TSH resistance
Raised TSH Normal FT4 or FT3 Common causes:
Subclinical autoimmune hypothyroidism
Rare causes:
Drugs - amiodarone, sertraline, colestyramine
Recovery phase after non-thyroidal illness
Heterophile (interfering) antibody
Congenital causes:
TSH-receptor defects
TSH resistance
Normal or raised TSH Raised FT4 or FT3 Rare causes:
Amiodarone
Interfering antibodies
Familial
TSH-secreting pituitary tumour
Acute psychiatric illness
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. 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 the risk of developing AF and cardiovascular disease (CVD).
TFTs should be repeated at 1-2 months or earlier if the patient is elderly or 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.
Where treatment is not undertaken, TFTs should be repeated ever 6-12 months to ensure overt hyperthyroidism has not developed.
Subclinical hypothyroidism
Occurs where TSH is above reference range with a normal FT4.
Diagnosis should be confirmed with repeat TFTs (TSH and FT4) after 3 months, having excluded non-thyroidal illness and drug interference. Measure TPO antibodies; if present, these increase the risk of developing hypothyroidism. Where positive, repeat TFTs on an annual basis.
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.
Drug effects
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 thyroid function tests (TFTs) may be more difficult as a consequence.
Drugs with a direct effect on thyroid function (mostly suppression) include:
Amiodarone.
Lithium.
Corticosteroids.
Iodinated contrast media and other iodine preparations.
Interferons.
Dopamine, levodopa.
Drugs which may cause analytical interference (increased FT4 by displacement) include:
Heparin.
Non-steroidal anti-inflammatory drugs.
High-dose aspirin (>2 g/day).
Drugs which increase thyroxine replacement requirement (cytochrome P450 inducers):
Phenytoin.
Carbamazepine.
Ritonavir.
Rifampicin.
Intestinal absorbers* include:
Sucralfate, colestyramine and colestipol, antacids containing aluminium.
Ferrous sulfate.
Proton pump inhibitors. *Take thyroxine at least 4 hours apart from these medications.
Amiodarone
Amiodarone has multiple effects on the thyroid due to its high levels of iodine (one 100 mg tablet contains 250 x 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.
Changes to TFTs in euthyroid patients on amiodarone:Raised FT4 and reverse T3
Initial rise followed by a normalisation of TSH
Lowered FT3
No change in TBG levels
Amiodarone-associated hyperthyroidism is difficult to diagnose and should be based on high FT4 associated with high or high/normal FT3 and undetectable TSH since, even in euthyroid individuals, amiodarone therapy causes moderate elevation of FT4 with reduced FT3 because of its effect on the peripheral deiodination of T4 to T3. If this condition is suspected, refer for specialist assistance, since further investigations may be required and management is frequently complicated.
Special situations
Thyroid function tests in pregnancy
In pregnancy, oestrogen levels increase and thyroxine-binding globulin (TBG) concentrations rise - this leads to an increase in total T4 and T3.
In the first trimester, serum thyroid stimulating hormone (TSH) also falls due to the effect of human chorionic gonadotropin (hCG) and there may be a small fall in FT4.
In the second and third trimesters, FT4 and FT3 decrease, sometimes below the nonpregnant 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 disease 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
Thyroid function tests (TFTs) in pregnancy should comprise both TSH and FT4. TPOAb should also be considered, as it has predictive value for postpartum thyroiditis and fetal 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 postpartum.
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 antithyroid drugs, TFTs should be checked prior to conception and drugs adjusted to a minimum dose of antithyroid drug only. Patients on carbimazole are sometimes switched to propylthiouracil which is felt to be preferable for breast-feeding.
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 antithyroid drugs need frequent TFTs during pregnancy, whilst women previously successfully treated and who are euthyroid at booking need checks again only in the 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 level 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.
On this page
Indications
Using thyroid function tests
Drug effects
Special situations
References
Physiology
An understanding of normal homeostatic mechanisms helps to interpret TFTs:
The hypothalamus, pituitary gland and the thyroid all play a part in the feedback and regulatory mechanisms involved in the production of thyroxine (T4) and triiodothyronine (T3) from the thyroid gland.
Thyroid releasing hormone (TRH) is secreted by the hypothalamus and stimulates the production of the polypeptide thyroid stimulating hormone (TSH) from the anterior pituitary.
TSH then stimulates the production and release of T4 and T3 from the thyroid.
Once released, T4 and T3 then exert a negative feedback mechanism on TSH production.
T4 is the main hormone produced by the thyroid.
T3 is mainly produced by peripheral conversion of T4.
T3 and T4 are largely protein bound in the plasma, mainly to thyroxine-binding globulin (TBG). Only the unbound or 'free' portion (FT3, FT4) is active.
T3 and T4 both act via nuclear receptors to increase cell metabolism.
Indications
Diagnosis of possible thyroid disease
Consider where signs or symptoms are compatible with possible thyroid disease, as well as with:
Goitre or thyroid nodule
Atrial fibrillation (AF)
Osteoporosis
Subfertility
Dyslipidaemia
Screening
Currently, screening in the healthy adult population for thyroid disease is not warranted[5] but more limited screening should be performed in:
Neonates, with the heelprick test for congenital hypothyroidism.
All patients with diabetes (types 1 and 2) at time of diagnosis.
Women with type 1 diabetes preconception, at booking and 3 months postpartum.
Surveillance
Surveillance of certain groups is advocated:
Women with a history of postpartum thyroiditis (annual TFTs, prenatally and postnatally in future pregnancies).
Patients with type 1 diabetes mellitus (annual TFTs).
Down's syndrome and Turner's syndrome (annual TFTs).
Patients receiving amiodarone (pretreatment, then every 6 months until off treatment for a year) or lithium (pretreatment, every 6-12 months whilst on treatment).
Post neck irradiation (annual TFTs).
Post destructive treatment (radioiodine or surgical) for thyrotoxicosis (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 long-term.
For thyroxine replacement therapy, check TFTs at least annually once stable.
Using thyroid function tests
When using thyroid function tests (TFTs) to investigate a possible thyroid disorder, regardless of whether the patient is thought to be hypothyroid or hyperthyroid, the initial investigation should always be a sensitive serum thyroid stimulating hormone (TSH) assay. In unselected populations, measurement of serum TSH has a sensitivity of 89-95% and specificity of 90-96% for overt thyroid dysfunction.
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.
There are situations where TSH alone is unhelpful:
Common:
Recent treatment of thyrotoxicosis
Pituitary disease
Non-thyroidal illness
Rare:
TSH-secreting pituitary tumour
Thyroid hormone resistance The requesting doctor should provide adequate clinical information to guide the laboratory in the selection of the most appropriate TFTs.
New cases of pituitary hypothyroidism are rare, but can present with very vague symptoms so an additional request of FT3/FT4 should be considered where there is persistent fatigue with a normal TSH, particularly with signs or symptoms of gonadal dysfunction.
Hyperthyroidism
Hyperthyroidism occurs as a consequence of excessive thyroid hormone activity.
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.
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.
Patients who have a low TSH may then go on to have further investigations such as:
FT4 and FT3 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. Antithyroid antibodies are negative in about 10% cases of Graves' disease.
Radioactive isotope uptake - thyroid scanning, usually with 123 I, helps to determine the cause of hyperthyroidism, eg diffuse pattern of uptake in Graves' disease compared with one or more 'hot' nodules in toxic nodular hyperthyroidism.
Interpreting thyroid function tests
Low TSH Raised FT3 or FT4 Common causes:
Primary hyperthyroidism - Graves' disease, multinodular goitre, toxic nodule
Relatively common causes with low radioiodine uptake:
Transient thyroiditis (postpartum, post-viral, De Quervain's)
Rare with a low radioiodine uptake:
Thyroxine ingestion
Ectopic thyroid tissue
Iodine induced
Amiodarone therapy
Rare with a positive pregnancy test:
Gestational thyrotoxicosis with hyperemesis gravidarum
Hydatiform mole
Rare:
Familial TSH receptor mutation
Low TSH Normal FT3 or FT4 Common causes:
Subclinical hyperthyroidism
Thyroxine ingestion Rare causes:
Steroid therapy
Dopamine and dobutamine infusion
Non-thyroidal illness
Low or normal TSH Low FT3 or FT4 Common causes:
Non-thyroidal illness
Recent treatment for hyperthyroidism
Rare causes:
Pituitary disease
Congenital TSH or TRH deficiencies
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 that 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 a stable maintenance dose every 3 months. Reduce the dose where FT4 falls to low normal or below normal range or where TSH rises.
'Block and replace' regimens (where treatment is initially with thionamide alone, then adding thyroxine once FT4 has normalised) 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 >20 mU/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. 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 >10 mU/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.
Interpreting thyroid function tests
Raised TSH Low FT4 or FT3 Common causes:
Chronic autoimmune thyroiditis
Post radioiodine
Post thyroidectomy
Transient thyroiditis - hypothyroid phase
Rare causes (anti-TPO negative):
Post external beam radiotherapy to the neck
Drugs - amiodarone, lithium, interferons, interleukin-2
Iodine deficiency
Amyloid goitre
Congenital causes:
Thyroid dysgenesis
Iodine transport defects
TSH receptor defects
TSH resistance
Raised TSH Normal FT4 or FT3 Common causes:
Subclinical autoimmune hypothyroidism
Rare causes:
Drugs - amiodarone, sertraline, colestyramine
Recovery phase after non-thyroidal illness
Heterophile (interfering) antibody
Congenital causes:
TSH-receptor defects
TSH resistance
Normal or raised TSH Raised FT4 or FT3 Rare causes:
Amiodarone
Interfering antibodies
Familial
TSH-secreting pituitary tumour
Acute psychiatric illness
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. 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 the risk of developing AF and cardiovascular disease (CVD).
TFTs should be repeated at 1-2 months or earlier if the patient is elderly or 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.
Where treatment is not undertaken, TFTs should be repeated ever 6-12 months to ensure overt hyperthyroidism has not developed.
Subclinical hypothyroidism
Occurs where TSH is above reference range with a normal FT4.
Diagnosis should be confirmed with repeat TFTs (TSH and FT4) after 3 months, having excluded non-thyroidal illness and drug interference. Measure TPO antibodies; if present, these increase the risk of developing hypothyroidism. Where positive, repeat TFTs on an annual basis.
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.
Drug effects
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 thyroid function tests (TFTs) may be more difficult as a consequence.
Drugs with a direct effect on thyroid function (mostly suppression) include:
Amiodarone.
Lithium.
Corticosteroids.
Iodinated contrast media and other iodine preparations.
Interferons.
Dopamine, levodopa.
Drugs which may cause analytical interference (increased FT4 by displacement) include:
Heparin.
Non-steroidal anti-inflammatory drugs.
High-dose aspirin (>2 g/day).
Drugs which increase thyroxine replacement requirement (cytochrome P450 inducers):
Phenytoin.
Carbamazepine.
Ritonavir.
Rifampicin.
Intestinal absorbers* include:
Sucralfate, colestyramine and colestipol, antacids containing aluminium.
Ferrous sulfate.
Proton pump inhibitors. *Take thyroxine at least 4 hours apart from these medications.
Amiodarone
Amiodarone has multiple effects on the thyroid due to its high levels of iodine (one 100 mg tablet contains 250 x 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.
Changes to TFTs in euthyroid patients on amiodarone:Raised FT4 and reverse T3
Initial rise followed by a normalisation of TSH
Lowered FT3
No change in TBG levels
Amiodarone-associated hyperthyroidism is difficult to diagnose and should be based on high FT4 associated with high or high/normal FT3 and undetectable TSH since, even in euthyroid individuals, amiodarone therapy causes moderate elevation of FT4 with reduced FT3 because of its effect on the peripheral deiodination of T4 to T3. If this condition is suspected, refer for specialist assistance, since further investigations may be required and management is frequently complicated.
Special situations
Thyroid function tests in pregnancy
In pregnancy, oestrogen levels increase and thyroxine-binding globulin (TBG) concentrations rise - this leads to an increase in total T4 and T3.
In the first trimester, serum thyroid stimulating hormone (TSH) also falls due to the effect of human chorionic gonadotropin (hCG) and there may be a small fall in FT4.
In the second and third trimesters, FT4 and FT3 decrease, sometimes below the nonpregnant 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 disease 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
Thyroid function tests (TFTs) in pregnancy should comprise both TSH and FT4. TPOAb should also be considered, as it has predictive value for postpartum thyroiditis and fetal 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 postpartum.
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 antithyroid drugs, TFTs should be checked prior to conception and drugs adjusted to a minimum dose of antithyroid drug only. Patients on carbimazole are sometimes switched to propylthiouracil which is felt to be preferable for breast-feeding.
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 antithyroid drugs need frequent TFTs during pregnancy, whilst women previously successfully treated and who are euthyroid at booking need checks again only in the 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 level 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.
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