Matthew (Thyroid disorders)

Question 1

Thyroid anatomy

Answer 1

Located at base of neck below Adams apple and above clavicle.
The thyroid gland is made up of the pyramidal lobe, right lobe, isthmus, left lobe. It has 2 parathyroid glands; superior and inferior.

Question 2

Functions of the thyroid

Answer 2

Synthesis of thyroid hormones (T3 and T4) which have direct effects on body systems:
1) Cardiovascular- thyroid hormone increases heart rate and cardiac contractibility and therefore increases cardiac output
2) Metabolic- thyroid hormone increases mitochondrial activity in the cells and increases energy uptake. Uses energy from fats to patients may lose weight
3) Developmental- can influence growth rate which is why they are so important in foetal development and pregnancy
4) Other- affects levels of sleep, libido, mood, increased speed of though but less focused

Question 3

Functions of parathyroid

Answer 3

Maintenance of serum calcium and phosphate levels through secretion of parathyroid hormone (PTH).
PTH increases blood calcium levels by directly stimulating bone cells to break down and release the calcium stored in them.
Also increases gastrointestinal calcium absorption by activating the vitamin D and promoted calcium conservation by
promoting calcium reabsorption in the kidneys.
Regulates serum phosphate in the kidneys by inhibiting proximal tubular reabsorption of phosphorus through activation of vitamin D.

Question 4

Thyroid hormone synthesis

Answer 4

T3 and T4 are synthesised when diatary iodide ions are transported from the bloodstream into the follicle cell plasma and become oxidised in the cell.
Iodide turned to iodine which can cross into the colloid which is a space in the thyroid follicle cell that is the chief site of throyoid production. 1 or 2 iodine molecules
bind to thyroglobulin (monoiodithyronine (MIT) or diiodothyronine (DIT)).
These complexes dissociate back and covaneltly bond to each other to produce T3
or T4 e.g. a MIT and a DIT bond together to form a T3.
T3 and T4 are stored in the colloid until stimulated for release.

Question 5

Thyroid hormones

Answer 5

• TSH comes from anterior pituitary gland and stimulates the release of T3 and T4.
• TSH is stimulated by release of TRH (thyrotropin releasing hormone) which is released from the hypothalamus.
• These hormones are released in response to a demand for increased metabolic rate e.g. going for a run. Does this through a positive/negative feedback loop. If thyroid hormone is used up there will be
  lower circulating levels in the blood stream which is detected by the anterior pituitary and also in the hypothalamus which will produce TRH to produce TSH which causes more thyroid hormone to be released.
• Ratio of T4 to T3 is 10:1. (90% is inactive T4, 9% is active T3, and 1% is rT3).
• Both T3 and T4 are highly protein bound. T3 is 99.8% protein bound and T4 is 99.9% bound. Binds to either thyroid binding globulin or transthyretin or albumin within the plasma.

rT3 is reverse T3.

Question 6

Thyroid disorders introduction

Answer 6

Hypothyroidism (not enough)
- Primary hypothyroidism
- Overt
- Subclinical
- Secondary hypothyroidism
- Pituitary-hypothalamic dysfunction
- Peripheral hypothyroidism

Hyperthyroidism (too much)
- Thyroidal origin
- Pituitary disease
- Extrathyroidal origin

Question 7

Hypothyroidism

Answer 7

• Most prevalent in countries where iodine deficiency is common- due to poor diet. e.g. lower socioeconomic economic countries.
• Only affects 1-2% of the UK population as we fortify our foods (add minerals/vitamins).
• 10x more common in women than men and more so in older women. Most common age is between 30-60 (mainly in latter end).

Question 8

Primary hypothyroidism

Answer 8

• Accounts for 95% of cases.
• Can be subcategorised into overt or sub-clinical.
• Most commonly a result of autoimmune diseases, e.g. celiac, and the body attacks the thyroid destroying the thyroid follicle cells reducing its ability to make the thyroid hormone.
• Can also be due to iron deficiency or as a side effect of treatment (amiodarone or lithium) or surgery

Question 9

Secondary hypothyroidism

Answer 9

• Arises from reduced thyroid stimulation due to dysfunction outside of the thyroid most commonly from the anterior pituitary or hypothalamus. May be problems with receptors on those glands.
• Can be caused by a variety of diseases- cancer is a common cause (pituitary adenomas causing dysfunction within that gland), infiltrative disorders e.g. amyloidosis,
  can be medication induced.

Question 10

Peripheral hypothyroidism

Answer 10

• Very rare. Where circulating levels of T3 and T4 and TSH are all fine but there is resistance in peripheral tissues. The tissue that the active T3 wants to act on doesn’t get the same response when it binds to the receptor. Sometimes patients aren’t able to convert T3 to T4 as well. Some neonates are born with their thyroid gland completely absent (called thyroid agenesis). Known as congenital hyperthyroidism.

Question 11

Hypothyroidism signs and symptoms

Answer 11

• Brain fog- can affect memory and ability to think clearly
• Thinning hair-can cause you to lose hair on scalp, face and body
• Mental health issues- contribute to depression and sadness
• Peripheral neuropathy- can interfere with how the nerves send signals to and from your brain, spinal cord, and body
• Jaundice
• High blood pressure
• Goiter- abnormally enlarged thyroid gland
• Heart attack risk- may increase cholesterol levels and narrow arteries
• Slow metabolism- can lead to weight gain as glucose isn’t being used as readily so will be stored as fat
• Gallstones- hard pieces made up of cholesterol or bile that form in gallbladder
• Constipation- slowed movement of food through intestines
• Stomach bloating- slows movement of food through digestive tract
• Heartburn- slowed digestion can lead to heartburn
• Menstrual changes- irregular periods and heavier flow, can affect fertility making it harder to become pregnant
• Dry skin- can also cause thickening and scaling
• Weakness- can leave muscles weak, achy or stiff

Patients with secondary will have mainly the same symptoms as primary but may present with additional symptoms e.g. severe recurrent headaches, visual disturbances, or specific to anterior pituitary- erectile dysfunction and amenorrhoea and Cushings syndrome.

Congenital hypothyroidism is hard to diagnose as babies cannot communicate how they feel. Also symptoms such as not feeding or sleeping well are common anyway in newborns so can’t be taken as a symptom of hypothyroidism. They are screened by taking bloods for a variety of diseases including hypothyroidism (test for thyroid hormone).

Question 12

Causes of hypothyroidism

Answer 12

• Autoimmune thyroiditis- main cause, autoimmune attack on thyroid
• Iodine deficiency- not common in UK but depends on diet
• Post thyroidectomy or radioactive iodine treatment- aim of this treatment is to damage thyroid and sometimes too much is damaged leading to hypothyroidism
• Drug induces
• Peripheral resistance to thyroid hormone
• congenital diseases e.g. thyroid agenesis

Question 13

Diagnosis of hypothyroidism

Answer 13

1) Symptoms- diagnosis based on clinical presentation
2) Biochemical testing- Thyroid function tests (TSH and free T4 tested (‘free’ is tested as it is usually highly protein bound)). NICE guidelines say to test TSH first. If TSH is found to be in range then you can rule out hypothyroidism. If it is out of range then you need to do the additional free T4 test. In practise you just do both tests together. Ideally all the tests should be taken from the same sample.

Question 14

Interpreting thyroid function tests

Answer 14

If the TSH level is raised and the FT4 result is low this suggests overt primary hypothyroidism. (High stimulation but still not producing enough hormone).

If the TSH level is slightly raised but the FT4 level is still within the normal reference range this is subclinical primary hypothyroidism.

If the TSH level is low and the FT4 result is low this is suggestive of secondary hypothyroidism arising from hypothalamic or pituitary dysfunction. (Problem with stimulation).

If the TSH, FT4, and FT3 levels are all within reference range then rarely we will test rT3 levels to ascertain peripheral T4 to T3 conversion. If rT3 result is low this is suggestive of peripheral hypothyroidism. (when rT3 is low the patient is not getting adequate conversion of T4 to T3)

Question 15

Additional investigations

Answer 15

Thyroid antibodies testing (can be used to give a definitive answer to the cause but not needed):
- Thyroid Peroxidase Antibodies (TPOAb)
- Thyroglobulin Antibodies (TgAb)
- Thyroid stimulating hormone receptor antibodies (TSHRAb aka TRAb)

Glucorticoid deficiency (always have to test for this when doing additional investigational tests):
- Short synacthen test

Question 16

Treatment of hypothyroidism

Answer 16

1st line= levothyroxine (T4) replacement
- Usual starting dose 1.6 micrograms per kg rounded to nearest 25 microgram dose
- Reduced starting dose of 25-50 microgram OD in patients >65 years or pre-existing CVD due to risks of over treatment.
- Congenital hypothyroidism- start at 10-15 microgram per kg for first 3 months of life (they need more as they are growing so much).
- Those with glucorticoid deficiency should be given replacement before starting thyroxine

Question 17

Monitoring

Answer 17

Initially TFTs every 3 months until stable then annually.
Can take up to 6 months for TSH to normalise. Most adult patients will be stabilised on doses between 100 and 200 micrograms daily. (If patient go above this it is usually due to poor compliance)
Dose is titrated in steps of 25 micrograms until therapeutic effect achieved.
If TSH within normal limits and symptoms still present test FT4 to investigate for secondary hypothyroidism.
When monitoring secondary hypothyroidism only adjust dose dependant on FT4.
Poor adherence regimens or for those who can’t safely self medicate (i.e. those with learning difficulties) can have once weekly administrations e.g. 700 micrograms once a week.

Question 18

Levothyroxine counselling

Answer 18

• Importance of compliance and effects of taking ‘treatment holidays’.
• Long life need regardless of ‘feeling well’
• How to take - 30-60 minutes before food or other medication so usually easiest taken in the morning on waking - allows it to go through GI system and start to be absorbed before anything else is there
• Interactions
  
  • Food (e.g. milk/calcium)
  • Drugs (e.g. calcium supplements, oral iron, or PPIs, growth hormone can increase thyroid metabolism requiring higher doses of T4)
  • Disease (e.g. IBD, coeliac- might not absorb it as well)
• Monitoring requirements- blood tests, free prescriptions
• Pregnancy and breastfeeding advice if applicable- safe to breastfeed but in pregnancy thyroid disorder can be dangerous due to the need for correct hormone levels for foetal growth
• Side effects- flushing, restlessness, palpitations, insomnia, angina, thyroid crisis

Question 19

Liothyronine

Answer 19

• Synthetic form of T3 .
• Similar pharmacological action to Levothyroxine but is 5x more potent- rapid onset of action because it is freely ready to act rather than levothyroxine which still needs to be converted in the body.
• Not recommended due to lack of clinical evidence
• Specialist services underwent work to actively switch all on liothyronine to levothyroxine- patient don’t like to switch as it made them feel unwell
• Only now rarely used in treatment of myxoedema coma, a severe complication of hypothyroidism, due to more rapid onset of action

Question 20

Pregnancy

Answer 20

• Uncontrolled hypothyroidism can impair fertility.
• Insufficient thyroid hormone can have teratogenic effects as essential fro growth and even lead to miscarriage.
• Patients with confirmed thyroid disease planning. pregnancy will need to consult with their GP/specialist and have frequent TSH level monitoring.
• Once pregnant they should increase their levothyroxine dose by 25-50 micrograms immediately and have their TSH checked.
• TSH monitored every 4-6 weeks during the pregnancy. Target TSH level of <2.5mU/L in 1st trimester and <3.0mU/L in 3rd trimester.
• 2-4 weeks post birth TSH level should be rechecked and most patients can return to their previously stable dose.
  Levothyroxine is safe in breastfeeding and patients should be supported with this should they wish

Question 21

Myxoedema crisis

Answer 21

Extreme manifestation of hypothyroid.
Rare but potentially fatal.
Requires IV treatment
Symptoms are that of hypothyroidism but more exaggerated:
- Hypothermia
- Macroglossia (swollen tongue)
- Ptosis (upper eyelid droop)
- Periorbital swelling
- Puffy face

Precipitated by
- Stress
- Infection
- Trauma
- Drugs e.g. beta blockers

Question 22

Hyperthyroidism

Answer 22

When disproportionally high quantities of thyroid hormone are produced.
Lead to infestations of hypermetabolic diseases.
10x more prevalant in women than males. Occurs in ages of 30-50.
0.5-2% of women in UK are affected where as only 0.2% of men are.
Incidence does not increase with advancing age.

Question 23

Hyperthyroidism signs and symptoms

Answer 23

• Reduced focus- erratic thoughts, can’t stay focused on a single task, too much stimulation so jump from one to ask to another
• Mental health issues- can contribute to mood swings causing anxiety, irritability and a nervous disposition
• Brittle hair and hair loss
• Eyelid retraction- gives a widened eye appearance, occurs due to muscle inflammation from autoimmune inflammation
• Bulging eyes- muscle and fatty tissue around eyes is attacked making them appear swollen
• Insomnia- due to increased metabolic rate and energy consumption patients can struggle to get good quality sleep
• Enlarged thyroid or loiter
• Irregular heart rhythm- over stimulated cardiac rate and output leading to palpitations, tachycardia and arrhythmias
• Weight loss- increased metabolic weight leads to vast energy consumption
• Diarrhoea- food goes through GI tract too quickly
• Nausea and vomiting- parasympathetic nervous system is unregulated so stomach churning when it doesn’t need to be, leads to nausea
• Decreased appetite
• Irregular menstruation- can cause amenorrhoea leading to fertility issues
• Muscle weakness- occurs as a result of muscle breakdown and ketosis for additional energy to feed the increased metabolic rate
• Sweating- increased metabolic rate leads to excessive heat production and hyperhidrosis

Question 24

Hyperthyroidism diseases

Answer 24

Graves’ disease- most common, accounts for 70-80% of hyperthyroidism cases, an autoimmune condition.

Thyroid nodular disease- second most common, specific physical problem with certain part of the thyroid, tens to get gaiters or enlargement.

Thyroiditis- inflammation of thyroid- can be autoimmune mediated, while it is inflamed thyroid hormone will leak from the follicles which causes a transient rise in thyroid hormones for a short period of time. Can turn into hypothyroidism

Pituitary disease- overstimulation, very rare

Question 25

Graves’ disease

Answer 25

Graves’ disease is the main cause of thyrotoxicosis. It is autoimmune mediated and happens where there is abnormal production of immunoglobulin G. IgG then occupies the space on the thyroid that TSH would activate and stimulates the thyroid follicle to secrete thyroid hormone. IgG is an immune receptor antibody (sits in receptor and activates it, but shouldn’t be there).

Eyelids retract, bulging eyes, redness, sore and dry eyes.

Question 26

Nodular disease

Answer 26

Can be either single or multi nodular goiter.
Most common in women over the age of 60 years old.
Actively release T3/T4.
Imaged using radioactive iodine.

Can cause problems with compression especially multi-nodular goiters can press on the windpipe causing a hoarse voice.

Most of the time when patients present with this type of disease you can see it due to the physical symptoms. It can be more difficult to see in obese patients though. If you place both hands around their neck gently from the back and get them to swallow you should feel that the thyroid is uneven.

Question 27

Thyroiditis

Answer 27

Inflammation of thyroid follicles- usually painful and tender.
Caused by infection, trauma, drug induced, or autoimmune mediated.
T3 and T4 ‘leak’ from inflamed follicle cells.
Can be transient (impermanent) and resolve leaving patient euthyroid (normal levels).
Can progress leading to irrevocable damage and hypothyroidism.
Occasionally self limiting and can resolve itself within 6 months of onset but normally it leads to hypothyroidism.

Question 28

Diagnosis of hyperthyroidism

Answer 28

1) Symptoms- diagnosed based on clinical presentation
2) Biochemical testing- Thyroid function tests, TSH, Free T4 and free T3, and TRABs

Question 29

Interpreting thyroid function tests

Answer 29

If the TSH level is low but FT4 and FT3 are raised this suggests hyperthyroidism of thyroidal origin. Likely to be Graves’ disease but could be thyroiditis (would have to confirm thyroiditis with TRABs).

Definitive diagnosis will require 2 sets of TFTs taken at leats 6 weeks apart. Thyrotoxicosis is usually safe enough to wait and observe while having further investigations.

In rare cases TSH level may be raised and FT4 and DT3 also raised which suggests hyperthyroidism of extra thyroidal origin indicating wither pituitary or hypothalamic disease.

Use imaging to see which disease is causing the change in hormone levels.T

Question 30

Aim of treatment:

Answer 30

• Acute- manage symptoms
  
  • Over-activation of sympathetic nervous system results in up-regulation of beta adrenergic receptors. Beta blockers
    can be used in the acute period to get rid of symptoms like tremor, sweating, tachycardia, and gives time for the longer time interventions to work.
• Chronic- effectively suppress thyroid hormone back to euthyroid levels

Question 31

Treatment of hyperthyroidism

Answer 31

Antithyroid drugs
Radioactive iodine
Thyroidectomy

Depending on patient state at presentation they either require urgent admission if they are in thyroid crisis or an urgent referral to specialist services. If they have a bad goiter or symptoms of compression they need urgent referral to ENT surgical team for resection. In less serious cases it can be a routine referral. Hyperthyroidism is generally managed in secondary care anyway so it should be managed by a specialist rather than a GP.

Ablative therapies- more invasive/intensive therapies. It is the removal or destruction of a body part (radiotherapy/surgery). Patient needs to be fully informed about all treatment options as they can be intensive.

Question 32

Antithyroid drugs (Thionamides)

Answer 32

Carbimazole and Propythiouracil.
6-8 weeks to show therapeutic effect.
Induce remission in around 50% of patients with Graves’ disease.
Choice of regimen:
- Titration
- Block and replace
Patients can choose whether they want to decrease drug slowly (titration) or if they want to do a block and replace which is where they stay at the high doses used in the initial period and completely eliminate all natural thyroid hormone production and supplement them with levothyroxine.
The titration method requires hospital visits every month and blood tests whereas block and replace is more straightforward as they do not need as many blood tests because we know what the levels will be as the doses are so high.

Question 33

Carbimazole: MoA, doses, tests

Answer 33

• Pro-drug which undergoes metabolism by hepatic enzymes to the active metabolite, thiamazole, known as methimazole.
• First line choice due to quick thyroid hormone correction.
• Mechanism of action: inhibition of the organification of iodide and thyroglobulin and the coupling of iodothyronine residues which in turn suppress the synthesis of thyroid hormones.
• Initial dose: 20-60mg daily in divided doses
• TFTs to be checked every 6-8 weeks
• Once thyroid hormone levels are within reference range patients choose titration or block and replace and continue for 12-18 months.
• Titration: 5-15mg OD. Regular TFT checks at hospital and dose adjusted to response
• Block and replace: remains on high starting dose to ensure endogenous T3/T4 production completely suppressed but levothyroxine is started alongside to supplement. Thyroxine is then titrated until TSH, &3 and T4 are within reference range.

Question 34

Carbimazole: Side effects, contraindications, counselling

Answer 34

Side effects:
- Macropapular rash- can be treated with a generic antihistamine
- Bone marrow suppression and some fatal cases of agranulocytosis have occurred in patients treated with carbimazole
- On initiation patients need to be counselled on the signs and symptoms of blood dycrasias- sore throat, bruising, bleeding, mouth ulcers, fevers and malaise. They need to tell us if they have any symptoms.
- Full blood count to be checked as a baseline and 6 monthly during treatment

Contraindications:
- Severe hepatic impairment (unable to be metabolised to active metabolite)
- Pre-existing blood disorders (risk of dyscrasias)
- History of pancreatitis (may exacerbate)

Counselling:
- Advise on dose to be taken during initial dosing then dependant on regimen elected for and monitoring as appropriate to that regimen.
- Need for additional medications i.e. beta blockers for symptom management
- May take 6-8 weeks to have an observable effect as do not alter existing levels of T3 and T4.
- Advised on the urgency of reporting onset of severe sore throats, bruising or bleeding, mouth ulcers, fever and malaise.
- Women of childbearing age advised for need for contraception due to teratogenic effects of carbimazole and previous cases of foetal malformation

Question 35

Propythiouracil: doses and regimens

Answer 35

• Initial dose: 200-400mg once daily (licensed for doses up to 600mg in initiation)
• When switching from carbimazole- 1mg of carbimazole is roughly equivalent to 10mg of propythiouracil
• TFTs to be checked every 6-8 weeks
• Once thyroid hormone levels are within reference range patients choose either a titration or block and replace regimen and continue for 12-18 months
  
  • Titration: 50-150mg OD. Regular TFT checks at hospital and dose adjusted to response
  • Block and replace: remains on high starting dose to ensure endogenous T3/T4 production completely suppressed but levothyroxine is started alongside to supplement. Thyroxine is then titrated until TSH, T3 and T4 are within reference range

Question 36

Propylthiouracil: Side effects, contraindications, counselling

Answer 36

Side effects:
- Macropapular rash- can be treated with generic antihistamine
- Severe hepatic reaction causing acute liver injury (some cases of which were fatal and some requiring a liver transplant)
- Bone marrow suppression, thrombocytopenia, risk of agranulocytosis
- On initiation patients need to be counselled on the signs and symptoms of blood dycrasias- sore throat, bruising, bleeding, mouth ulcers, fevers and malaise. They need to tell us if they have any symptoms.
- Full blood count to be checked as a baseline and 6 monthly during treatment

Contraindications:
- Severe hepatic impairment (unable to be metabolised to active metabolite)
- Pre-existing blood disorders (risk of dyscrasias)
- History of pancreatitis (may exacerbate)

Counselling:
- Advise on dose to be taken during initial dosing then dependant on regimen elected for and monitoring as appropriate to that regimen.
- Need for additional medications i.e. beta blockers for symptom management
- May take 6-8 weeks to have an observable effect as do not alter existing levels of T3 and T4.
- Advised on the urgency of reporting onset of severe sore throats, bruising or bleeding, mouth ulcers, fever and malaise.
- Some cases of severe hepatic reactions, both in adults and children, including fatal cases and cases requiring a liver transplant have been reported with propylthiouracil. Patients should be advised to report any jaundice, dark urine, abdomen pain, pruritus, nausea and vomiting.
- Time to onset has varied but in most cases the liver reaction occurred within 6 months
- If significant hepatic enzyme abnormalities develop stop treatment and find an alternative

Question 37

Anti-thyroid drug monitoring

Answer 37

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