Buku Medicine

Requesting TFTs

Thyroid disorders are very common, and may have a subtle presentation, so thyroid function tests are performed increasingly frequently to diagnose and then to monitor thyroid disease.

Making the request

When ‘thyroid function test’ is requested, some laboratories will check a TSH (thyroid stimulating hormone) level alone as a screening test. If TSH is abnormally high or low, the lab may then add on a free T4 (fT4) +/- free T3 (fT3) level.

For most patients this is suitable (as normal TSH generally excludes primary thyroid disease), but for some it is important to also check thyroid hormone (free T4 +/- free T3):

Patients with pituitary disease (who may have secondary hypothyroidism i.e. T4 may be low despite normal TSH)
Patients who have recently started treatment for hyper-or hypo-thyroidism (TSH can take months to normalise but T4 and T3 change quickly)
Pregnancy
Rare diseases e.g. thyroid hormone resistance

Indications for TFTs

Symptoms consistent with hypo or hyperthyroidism
Condition that could be related to occult thyroid disturbance e.g. atrial fibrillation, hyperlipidaemia, osteoporosis, infertility/menstrual irregularity
Evaluation of thyroid lump
Evaluation of pituitary lesion
Follow up of known thyroid/pituitary disease
Screening (usually annual)
- At birth
- Down’s syndrome
- Turner syndrome
- Type 1 diabetes (inc pre-conception)
- Coeliac disease
- After thyroiditis (inc at 6-8wk check post delivery if previous post-partum thyroiditis)
- Medications – amiodarone, lithium
- After neck irradiation
- After radio-iodine

Other thyroid blood tests:

Anti-thyroid antibodies – generally anti-TPO is the test of choice as a general marker of thyroid immunity. It can be positive in autoimmune thyroid disease (inc. subacute and post-partum thyroiditis) but can also be positive in normal individuals. It is considered a positive/negative test – unlike TRAb test (below) i.e. there is no indication for monitoring a level. Anti-thyroglobulin can also be tested but (outside of thyroid cancer follow up) is not usually necessary.

Thyroglobulin – can be a marker of thyroid cancer recurrence in patients who have had complete thyroid removal.

TSH-receptor antibodies (TRAb)– aka TBII (TSH binding inhibiting immunoglobulin) - first line test in patients with hyperthyroidism – highly sensitive and specific for diagnosis of Graves’ disease. Level of titre can give indication of disease severity and may help predict treatment response.

Reverse T3 (rT3) – not available on the NHS as does not help inform treatment. Patients may sometimes undergo this privately if concerned they are not converting T4 to T3 adequately but rT3 is affected by many conditions and the assay is not felt to be accurate.

Genetic testing – genetic testing is available for some rare thyroid conditions such as thyroid hormone resistance. Testing for polymorphisms (common variations) in de-iodinase enzymes is not available beyond the research setting although patients sometimes ask for this.

References:

UK Guidelines for Use of Thyroid Function Tests. https://www.british-thyroid-association.org/sandbox/bta2016/uk_guidelines_for_the_use_of_thyroid_function_tests.pdf
NICE guideline 145 https://www.nice.org.uk/guidance/ng145

Interpreting TFTs

Note that exact reference ranges will not be quoted here as they do vary between regions and between laboratories (e.g. depending on local iodine availability and on what type of assay is used). You should use the reference range for the lab that has performed the test.

NB – there is a different ref range for the trimesters of pregnancy – in early pregnancy TSH should be lower than outside pregnancy

Borderline or unexpected test results should be repeated before acting on them.

NB – TFTs are measured by immunoassay, and this can be significantly affected in patients taking biotin vitamin supplements – they must pause these for at least 2 days before having thyroid function tests.

TSH is usually the first test for interpreting TFTs. A small change in T4 leads to a relatively large change in TSH (due to log-linear relationship).

If TSH is low this usually indicates (primary) hyperthyroidism, if TSH is high this indicates (primary) hypothyroidism. Adding free T4 (+/- T3) to this gives further info:

TSH normal

Usually indicates euthyroidism unless special circumstance as above
fT4/fT3 low - this could indicate central hypothyroidism
fT4/fT3 high - multiple causes inc assay interference, thyroid hormone resistance, TSH-oma (rare!) – see section on ‘funny TFTs’ (coming soon...)

TSH high

fT4 normal – indicates subclinical hypothyroidism
fT4 low – indicates overt hypothyroidism
fT4 high – if on levothyroxine can indicate irregular use. Else multiple causes as above – see ‘funny TFTs’ section (coming soon...)

TSH low

fT4 high – primary hyperthyroidism
fT4 normal –> check fT3 – if high – ‘T3 toxicosis’; if fT3 also normal – subclinical hyperthyroidism
fT4 low – central hypothyroidism or sick euthyroid syndrome (aka non-thyroidal illness)

For more info, see the relevant sections on

Hypothyroidism
Hyperthyroidism
Funny TFTs (coming soon...)
Amiodarone and TFTs (coming soon...)
Non-thyroidal illness/sick euthyroid syndrome (coming soon...)

References:

UK Guidelines for Use of Thyroid Function Tests. https://www.british-thyroid-association.org/sandbox/bta2016/uk_guidelines_for_the_use_of_thyroid_function_tests.pdf
NICE guideline 145 https://www.nice.org.uk/guidance/ng145

Hypothyroidism

Quick tip; Consider interfering foods/medications if TSH levels erratic – a switch to bedtime dosing may improve reliability of absorption

Hypothyroidism is reduced production of thyroid hormone. This may be due to a problem with the thyroid gland itself (primary hypothyroidism) or of central control of the thyroid by pituitary/hypothalamus (central hypothyroidism). It is rarely caused by resistance to thyroid hormone.

Overt hypothyroidism = T4 low

Subclinical hypothyroidism = T4 normal but TSH raised

Symptoms and signs are multi-system and commonly include:

Fatigue
Weight gain
Cold intolerance
Constipation
Reduced cardiac output
Dry yellow skin, hair, nails
Periorbital oedema (peripheral in more advanced cases)
Menorrhagia
Slowing of cognition
Stiff, achey muscles
Slow-relaxing reflexes
Elevated LDL
Carpal tunnel syndrome

Causes and investigation

90% of hypothyroidism (in iodine-replete countries) is autoimmune – Hashimoto’s thyroiditis or atrophic thyroiditis
- Some rare patients may have antibodies that cause them to alternate between hypo and hyperthyroidism - refer to specialist if suspected
The remainder largely have iatrogenic hypothyroidism (post surgery or radio-iodine)

It is not usually necessary to undertake detailed investigation of the cause of hypothyroidism.

Most patients can be managed in primary care unless concerns about young age, difficult control, severe disease etc.

Treatment

Key questions to ask when starting treatment

Is treatment required?

Is hypothyroidism likely to be reversible or not?

Could this patient have adrenal insufficiency?

What dose should this patient start with?

1. Is treatment required?

Most patients with overt hypothyroidism (high TSH/low T4) should start treatment. Those with hypothyroidism due to overtreatment with anti-thyroid drugs and those in the recovery phase of thyroiditis may not require thyroid hormone
Patients with subclinical hypothyroidism do not always need treatment
- Elderly patients have a different normal range – TSH is typically higher
- Mild subclinical hypothyroidism (TSH<10) may resolve – repeat TFTs before treatment
- If TSH >10 (x2 measurements) – likely to progress to overt hypothyroidism – would usually treat
- If highly symptomatic but TSH only mildly raised a) consider other causes b) give a trial of thyroxine for 6 months – consider stopping if not beneficial
- If pregnant or planning pregnancy – treat whether subclinical or overt

2. Reversible v irreversible hypothyroidism

Hypothyroidism caused by chronic immune destruction (i.e. the commonest form) is rarely reversible – treatment lifelong
Hypothyroidism caused by subacute/postpartum thyroiditis is often reversible – may warrant trial off treatment after 6-12 months of treatment. Thyroiditis is usually distinguished by period of hyperthyroidism and often neck pain, followed by hypothyroidism. Thyroid uptake scan may help with diagnosis.
Around 50% of patients with subclinical hypothyroidism will become euthyroid without treatment

3. Could this patient have adrenal insufficiency?

Fatigue is an overlapping symptom, but weight loss, postural hypotension, hyponatraemia, pigmentation and salt craving are all suggestive of adrenal insufficiency rather than hypothyroidism. Replacing thyroxine without cortisol in that scenario can precipitate adrenal crisis (due to enhanced metabolism of cortisol). Thyroid function can sometimes normalise with cortisol replacement.

4. What dose? NICE Guidance says:

Most patients with hypothyroidism can start full thyroid replacement right away – this usually amounts to around 1.6 micrograms/kg of thyroxine.
Older patients (e.g. >65 yrs), those with ischaemic heart disease and those with longstanding very severe hypothyroidism are recommended to start at low dose e.g. 25-50 mcg of thyroxine with slow uptitration (25mcg every 6-8 weeks) to avoid any cardiac stress.

NB – hyperlipidaemia is common with untreated hypothyroidism. Treat the thyroid first and then re-evaluate (may normalise).

Target ranges

For most people, the aim should be obtaining TSH within the normal range.

Remembering that women in pregnancy have a different TSH reference range at each trimester in the early stages of pregnancy. A TSH target of < 2.5 mIU/L is usually advocated.

For patients with secondary hypothyroidism TSH is not used to guide treatment - the aim is usually fT4 level in the mid-normal range (depending on age, symptoms etc). Titration usually done in secondary care.

Pre-treatment counselling

How to take – advise with water and away from any other food/medications as can affect absorption. For some may be easier to take at night.

Miss a dose – T4 has a long half-life. Missing an occasional dose should not cause problems. Can take same day if forget to take at usual time.

Alternative forms – available in liquid if difficulties swallowing/enteral feeding etc but much more expensive than tablet

Pregnancy – aim for optimal TSH before conceiving if possible. Patients well controlled pre-pregnancy will need an increase as soon as conceive – usually advise increase by 25-50 mcg and check TFTs. Will need frequent (6-8 weekly) monitoring through pregnancy (in 1ry or 2ry care). Safe to breastfeed on thyroxine (passed in small amounts).

Monitoring

Usually 3 months, 6 months then annually when stable
NB TSH can take months to normalise if was very high – don’t necessarily need to up dose if continues to fall and fT4 is normal (so useful to check TSH and fT4 here)

Suggested references

BTA – professional guidelines and resources: https://www.british-thyroid-association.org/current-bta-guidelines-and-statements
NICE guideline 145 https://www.nice.org.uk/guidance/ng145
Endo text – comprehensive overview of hypothyroidism - Wiersinga WM. Adult Hypothyroidism. [Updated 2014 Mar 28]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK285561/

Erratic TSH levels

Dealing with erratic TSH levels and patient dis-satisfaction

Erratic levels

If struggling to achieve therapeutic range consider
- Interactions with food/meds
  - Fibrous foods and coffee reduce absorption
  - Some meds reduce absorption – bile acid sequestrants, oral iron, oral calcium, oral aluminium, possibly orlistat, PPIs (due to change in pH)
  - Some meds will require a dose increase – oestrogens, liver enzyme inducers (e.g. anti-epilepsy drugs)
- Can usually be managed with change in timing of dose, or change in dose
Malabsorption (check coeliac status)
- Will often require endo review and potentially an absorption test (challenge)
Compliance
- Will often require endo review and potentially an absorption test (challenge)
Rare resistance syndromes, antibody interference or binding protein anomalies
- Will often require endo review and potentially an absorption test (challenge)

Due to the long half-life, thyroxine can be administered as a once weekly dose in select patients where compliance is an issue.

Alternative thyroid preparations

Patients feeling unwell on thyroxine frequently ask about combination therapy with liothyronine (T3) in addition to T4, or desiccated thyroid extract (Armour ® Thyroid)
Some patients may feel better on a higher dose of T4 (such that TSH is at the lower end, although should still be measurable to avoid long term risks e.g. AF and osteoporosis)
Other causes for symptoms should always be considered e.g. vitamin deficiencies, sleep apnoea etc. It can be worth reviewing the circumstances of the initial diagnosis.
There is no clear evidence that combination treatment is superior and is difficult to administer due to cost and limited dose availability of T3. This should not be initiated in primary care. Not all endocrinologists/endocrine centres will consider prescribing T3 (and this is supported clinically within the NICE guidance) – there may be local guidelines on this.
Armour ® Thyroid is desiccated pig thyroid extract containing a mix of T4 and T3. The ratio is not the same as in humans (more T3 in pigs) and this is an unregulated, unlicensed medication which should not be prescribed in the UK. Patients can be supported to transition to levothyroxine (conversion tables available).

References

UK position statements on T3 here (BTA ad RCP) but local CCGs usually have a formulary policy
- https://www.british-thyroid-association.org/sandbox/bta2016/bta_statement_on_the_management_of_primary_hypothyroidism.pdf
- https://static1.squarespace.com/static/53b1670ee4b0be242b013ed7/t/543ee743e4b05588d7c67389/1413408579862/RCP+Diagnosis+and+management+of+primary+hypothyroidism+2011.pdf

Hyperthyroidism

Quick tip; Make sure patient is not taking biotin supplements when checking TFTs as can cause an interference mimicking hyperthyroidism including positive TRAb antibody!

Hyperthyroidism is an excess of circulating thyroid hormone. It almost always represents excess production of hormone from the thyroid due to Graves’ disease or an autonomous (aka toxic) nodule (s), or due to release of stored hormone in thyroiditis.

Rarely there is an extrathyroidal source, or TSH is produced in excess by a pituitary lesion (TSH-oma).

Hyperthyroidism (regardless of cause) will generally have secondary care management.

Symptoms and signs

Unexplained weight loss
Palpitations
Sweating
Psychological symptoms – anxiety, insomnia, reduced concentration
Tremors
Diarrhoea
Amenorrhoea

Some clues as to the cause

Neck pain (+/- goitre) – severe pain over the thyroid is characteristic of subacute thyroiditis
Thyroid eye disease (TED) – periorbital puffiness, redness, watering, proptosis, diplopia – all signs of TED which indicated Graves’ disease
Goitre – smooth symmetrical in Graves’, may be irregular in toxic-multinodular goitre
Drugs – amiodarone, interferons, some new immunotherapies (e.g. alemtuzumab for multiple sclerosis) can cause
Weeks-months post-partum – lymphocytic thyroiditis

Subclinical hyperthyroidism

Some dubiety about which patients will require treatment
May have long term risk of atrial fibrillation and osteoporosis
Patients with TSH just below ref range (not fully suppressed) may have sick euthyroid/ non-thyroidal illness syndrome
If persistent on repeat testing consider referral for work up/consideration of treatment

Investigations

TFT patterns:

NB – make sure patient not taking biotin supplements as can cause an interference mimicking hyperthyroidism inc positive TRAb!

TSH low, T4 high – overt hyperthyroidism
TSH low, T4 normal, T3 normal – subclinical hyperthyroidism – repeat before acting
TSH low, T4 normal, T3 high- ‘T3 toxicosis’ – usually an early stage of hyperthyroidism
TSH normal/high, T4 high – see ‘funny TFTs’ section for interpretation

Diagnostic tests

TRAb (aka TBII) – stands for TSH receptor antibody – antibodies which stimulate the TSH receptor are the cause of Graves’ disease. Current assays have sensitivity and specificity approaching 100% so are an excellent test. The TRAb level (unlike TPO) can be measured over time – it predicts response to treatment and risk of thyroid eye disease.

If TRAb negative – thyroid uptake scan (usually now technetium rather than iodine based) – can distinguish antibody negative Graves’ disease (global high uptake of tracer in the thyroid), thyroiditis (low uptake) and toxic nodule(s) (focal uptake). Usually organised in secondary care. Contraindicated in pregnancy.

Thyroid US is not usually performed unless there is a palpable lump to be characterised, or sometimes in patients taking amiodarone where uptake scans may be unhelpful. TPO test is often positive in Graves’ disease but in itself is not diagnostic – TRAb is required.

Treatment options

Symptomatic management

Beta blockers (usually propranolol) are helpful for symptoms in hyperthyroidism of any cause and can be started in primary care. If intolerant (e.g. asthma) then rate-limiting calcium channel blockers can be helpful.
Patients with thyroiditis may not require any other specific therapy

Targeted management

Choice of treatment depends on a number of factors (e.g. age, severity, likelihood of remission, pregnancy…)
Most patients will require at least a period on antithyroid drugs (carbimazole/propylthiouracil) to gain control
~50% of patients with Graves’ disease will remit with ATD treatment alone – less likely if high TRAb level, large goitre, severe hyperthyroidism with very high T3/T4, recurrent disease…. Such patients usually require radio-iodine or thyroidectomy (both of which expected to cause long term hypothyroidism)
Toxic nodules do not typically remit and will require long term treatment – usually radio-iodine or low dose long term ATD

References

NICE guideline 145 https://www.nice.org.uk/guidance/ng145

Hyperthyroidism specifics

Specifics of management of hyperthyroidism

Antithyroid drugs and side effects

Carbimazole (once or twice daily) and propylthiouracil (PTU) (three time daily) are used in UK. Generally safe and well tolerated.
Can take weeks to reduce thyroid hormone levels
Patients must be counselled about side effects and pregnancy before beginning
Caused by both - rash, joint pains, hair loss and agranulocytosis (see below)
Carbimazole linked to teratogenicity – aplasia cutis – if given 1st trimester so women should be counselled re avoiding pregnancy. Also newly linked to acute pancreatitis
PTU linked to acute severe hepatitis – avoided in children and in later pregnancy for this
Given as ‘block and replace’ (high dose ATD then levothyroxine added) or dose titrated down against effect

Agranulocytosis

Drop in granulocyte (inc neutrophil) count usually defined as neutrophils <0.5 x10^9/L
Usually occurs within first 3 months of starting but rare (<0.5%)
Patients must have verbal and written warning before starting ATDs (see link to leaflets below) – if develop fever, sore throat, other signs of infection then stop drug, same day full blood count
If neutropenia confirmed will require admission for high dose antimicrobials and possible G-CSF
- NB if mild, asymptomatic neutropenia, esp if not new, d/w endocrinologist as may be normal for patient. Some patients with Graves’ disease have a mild neutropenia due to hyperthyroidism which improves as thyroid hormones settle – FBC results before treatment can help distinguish
Will not be able to resume either ATD (risk of recurrence with either drug) after agranulocytosis

Radio-iodine

Contraindicated in pregnancy/breastfeeding and those with active thyroid eye disease
Likely to cause hypothyroidism long term – may need progressive increase in levothyroxine over years
Restrictions on personal contacts after administration to avoid radiation exposure to others – may not be suitable for those with caring responsibilities etc
Require regular TFT follow up with endocrine nurses post-Rx to institute levothyroxine swiftly
May require more than one dose
2019 raised concerns about long term risk of cancer after RAI however this has not been replicated in other studies and has been disputed – see position statement

References

Position statement radio-iodine - https://www.british-thyroid-association.org/sandbox/bta2016/bta_radioactive_iodine_statement_2020.pdf
Patient information leaflets available from British Thyroid Foundation inc agranulocytosis warning - https://www.btf-thyroid.org/pages/category/patient-leaflets

Thyroid eye disease

Thyroid eye disease (TED) occurs with both Graves’ disease and Hashimoto’s thyroiditis – patients may be hyper/hypo/euthyroid at presentation.

More likely to occur in patients with very high TRAbs
More likely in SMOKERS – smoking cessation is key aspect in Graves’ management to both prevent and help manage TED

Common signs and symptoms – patients with Graves’ disease should be counselled to alert HCPs if these develop ASAP - inform patient’s endocrinologist

Grittiness, periorbital swelling, lid or conjunctival redness, watery eyes, retroorbital pain/pain on moving eyes, double vision
NB not usually itchy or sticky unlike allergy/infection

As well as concerns over appearance, TED carries a threat to sight in severe cases

Mild TED is managed with lubricating eye drops, optimisation of thyroid function and selenium supplements (can get OTC) with endocrinology support.
Mod-severe TED should be managed in a specialist MDT thyroid eye clinic (ophthalmology and endocrinology). May require imaging, high dose steroids, surgery or other advanced therapies.
Indications for urgent (e.g. same day) referral include severe pain, blurry vision, loss of colour vision, corneal opacification, inability to close eyes.

References

TEAMEd advice on thyroid eye disease - https://www.endocrinology.org/endocrinologist/125-autumn17/features/teamed-5-improving-outcomes-in-thyoid-eye-disease/