Thyroid Disease

Question 1

Thyroid Gland

Answer 1

The thyroid gland is highly vascularized and is located just inferior to the larynx. It regulates the secretion and actions of thyroid hormones.

Question 2

Thyroid function tests

Answer 2

There are several thyroid function tests (TFTs), the most commonly reported being thyroid releasing hormone (TRH), thyroid stimulating hormone (TSH), T3 (free) and T4 (free). Thyroid receptor antibodies can also be measured. Reference ranges may show variation between labs. Interpretation can be difficult in those with acute or chronic illness, during pregnancy, those taking the oral contraceptive pill and some other medications e.g. amiodarone

Question 3

Control and feedback of thyroid hormones

Answer 3

1. Low blood levels of T3 and T4 or low metabolic rate stimulate release of TRH
2. TRH carried by hypophyseal portal veins to anterior pituitary, stimulates release of TSH by thyrotrophs
3. TSH released into blood stimulates tyroid follicular cells
4. T3 and T4 released into blood by follicular cells
5. Elevated T3 inhibits release of TRH and TSH (negative feedback)

Question 4

Actions of thyroid hormones

Answer 4

• Increase basal metabolic rate
• Stimulate synthesis of Na+/K+ ATPase
• Increase body temp
• Stimulate protein synthesis
• Increase the use of glucose and fatty acids for ATP production
• Stimulate lipolysis
• Enhance some actions of catecholamines
• Regulate development and growth of nervous tissue and bones

Question 5

What is an essential requirement for thyroid hormone synthesis

Answer 5

Iodine

Question 6

There are many causes of thyroid disease including:

Answer 6

 Thyroid neoplasia
 Hypothalamic-pituitary disease
 Thyroid disease in children - congenital
 Iodine deficiency
 Peripheral resistance to thyroid hormone

Question 7

Goitre

Answer 7

A goitre can be a feature of thyroid disease and is a swelling of the neck as a result of the thyroid gland being enlarged and not functioning properly. Goitre can be present in both hypothyroidism and hyperthyroidism.

Question 8

Effect of medications on the thyroid function

Answer 8

Some medications can alter the thyroid function and are either contra-indicated or should be used with caution e.g. lithium, amiodarone, interferons.

Question 9

Hypothyroidism

Answer 9

In hypothyroidism there is a decreased production of thyroid hormones or tissue resistance to thyroid hormones. Hypothyroidism can be primary but may be secondary to other medical conditions. The diagnosis of primary hypothyroidism is confirmed by symptoms and
TFTs - serum TSH and free T4.

Question 10

Causes of primary hypothyroidism include:

Answer 10

 Congenital
 Infective
 Autoimmune e.g. Hashimoto’s thyroiditis, postpartum thyroiditis,
 Defects of hormone synthesis e.g. iodine deficiency
 Post-surgery
 Post-irradiation
 Infiltration e.g. tumour

Question 11

Secondary hypothyroidism may be due to

Answer 11

Secondary hypothyroidism may be due to, for example, hypothalamic-pituitary disease.
Secondary hypothyroidism requires other tests and investigations and specialist referral.

Question 12

Signs and Symptoms - Hypothyroidism

Answer 12

Hypothyroid symptoms are very common, both in many other conditions and in states of normal health. These can include:
 Mental slowness, poor memory, poverty of movement, depression
 Peaches and cream complexion, loss of eyebrows, dry brittle unmanageable hair, dry skin, coarse thickened skin, puffy eyes, deep voice
 Hypertension, heart failure, bradycardia
 Cold peripheries, oedema, tiredness
 Weight gain, anorexia
 Goitre
 Arthralgia, myalgia, muscle weakness / stiffness
 Constipation, menorrhagia or oligomenorrhoea in women
 Hearing impairment, hyponatraemia, hypercholesterolaemia, myxoedema coma, slow-relaxing tendon reflexes, cold intolerance
 Anaemia

Question 13

Primary hypothyroidism may be classed as

Answer 13

subclinical hypothyroidism or overt hypothyroidism

Question 14

Subclinical hypothyroidism

Answer 14

In subclinical hypothyroidism there is a raised serum TSH level but the free T4 is normal. The decision to treat is based on criteria which includes the patient’s age and symptoms.

Question 15

Treatment of primary hypothyroidism

Answer 15

If a patient is taking medication prior to the initiation of thyroid hormone treatment, consideration should be given regarding the need to adjust doses of this medication, as a patient responds to treatment for hypothyroidism. Levothyroxine sodium is the treatment of choice for maintenance therapy.

Titration of levothyroxine sodium dose – adults
It is valuable to take a baseline ECG before initiation of levothyroxine because changes induced by hypothyroidism can be confused with ischaemia. If a patient’s metabolism increases too rapidly, the initial dosage of levothyroxine should be reduced or withhold levothyroxine for one to two days before restarting at a lower dose.

Liothyronine sodium
Liothyronine sodium has a similar action to levothyroxine but is more rapidly metabolised and has a more rapid effect than levothyroxine. Its effects develop after a few hours and disappear within 24 – 48 hours of discontinuing treatment. Liothyronine sodium 20 - 25 micrograms is equivalent to 100 micrograms of levothyroxine. It may be used in severe hypothyroid states when a rapid response is desired. Liothyronine sodium is not normally initiated in primary care and is included in the NHS England document: Items that should not be routinely prescribed in primary care.

Question 16

Drug interactions with thyroid hormones

Answer 16

There are clinically significant interactions that can occur when a patient is taking thyroid hormones e.g. thyroid hormones enhance the anticoagulant effect of coumarins. There are also drug interactions that can increase or decrease the absorption of thyroid hormones e.g. absorption of levothyroxine is reduced by oral iron, calcium salts. A patient commencing thyroid hormones will require counselling regarding the timing of administration of these medicines and any others that affect the absorption of thyroid hormones.

Question 17

Counselling of adult patients who are newly prescribed levothyroxine

Answer 17

Explain:
 Treatment is likely to be lifelong
 Take tablets regularly each day
 Avoid taking levothyroxine at the same time of day as medications that can affect its absorption
 Take on an empty stomach to maximise absorption, preferably at least 30 minutes before breakfast, caffeine-containing liquids (e.g. coffee, tea), or other medication
(but consider other drug interactions where there should be more than a 30 minute time interval between administration)
 It will take several weeks for them to see a symptomatic improvement.
 It can take at least 6 - 8 weeks treatment at full dose for TSH to return to normal or may take longer.
 Will need blood tests as appropriate for the measurement of TSH and free T4 levels
 These patients are eligible for a medical exemption certificate for prescription charges
 If a patient is taking other medications, doses of some of these medications may need reviewing as the thyroid hormones take effect.

Question 18

If TSH levels remain persistently abnormal despite the apparent adequate dose of levothyroxine being prescribed, the cause may be

Answer 18

malabsorption, coeliac disease, autoimmune gastritis, other medications being taken, laboratory assay interference or nonadherence to thyroid hormone medication. Further investigation is needed in these patients to rule out any of the above co-morbidities or reasons

Question 19

Hypothyroid / myxoedema coma

Answer 19

In some cases a patient’s hypothyroidism can be so severe that hypothyroid coma can result.

Question 20

Examples of signs and symptoms of hypothyroid coma

Answer 20

 Severe cardiac failure
 Pericardial effusions
 Hypoventilation
 Hypoglycaemia
 Hyponatraemia
 Hypothermia
 Confusion

Question 21

Treatment of hypothyroid coma

Answer 21

Liothyronine sodium by slow IV injection is the treatment of choice in hypothyroid coma.
Other adjunctive treatment may be necessary and includes: intravenous fluids, hydrocortisone, treatment of infection if present and assisted ventilation.

Question 22

Hyperthyroidism / Thyrotoxicosis

Answer 22

 In hyperthyroidism there is an excessive production of thyroid hormones by the thyroid gland.
 Thyrotoxicosis is a clinical syndrome associated with prolonged exposure to elevated levels of thyroid hormone.

• Thyrotoxicosis is not always caused by excessive production of thyroid hormones (e.g. it can be caused by excessive ingestion of thyroid hormones). As with hypothyroidism, hyperthyroidism can be primary or secondary and can be overt or subclinical.

Question 23

Thyrotoxicosis – causes

Answer 23

Graves’ disease is the most common cause of hyperthyroidism and is due to an autoimmune process. Other causes include:
 Solitary toxic adenoma / nodule
 Toxic multinodular goitre
 de Quervain’s thyroiditis
 Postpartum thyroiditis
 Amiodarone-induced

Question 24

Thyrotoxicosis - signs and symptoms

Answer 24

 weight loss, increased appetite
 heat intolerance and sweating
 fatigue and weakness
 hyperactivity, irritability, dysphoria, insomnia, tremor, hyper-reflexia
 tachycardia, atrial fibrillation
 warm moist skin, hair loss, onycholysis

Some signs and symptoms are specific to Graves’ disease e.g. ophthalmopathy.

Question 25

Diagnosis of primary hyperthyroidism / thyrotoxicosis

Answer 25

This is confirmed by TFTs: TSH, free T4, free T3 and as appropriate TPO and thyroglobulin antibodies, TSH receptor antibodies and by radioactive iodine uptake and scan.

Question 26

Treatment of hyperthyroidism/thyrotoxicosis

Answer 26

The type of treatment is dependent on e.g. type of disease, age, gender, pregnancy, severity of symptoms, presence of associated illness and patient preference.

Question 27

Medical treatment – adults

Answer 27

Anti-thyroid drugs can be used to prepare patients for thyroidectomy or for long term management of hyperthyroidism. Carbimazole is the most commonly used anti-thyroid treatment in the UK. Propylthiouracil should be reserved for patients who are intolerant of carbimazole, for those who suffer sensitivity reactions to carbimazole and for whom other treatments are inappropriate e.g. during pregnancy

Question 28

Carbimazole

Answer 28

The dose of carbimazole is 15 to 40 mg daily; higher doses should be prescribed under specialist supervision only. The dose is continued until the patient becomes euthyroid, usually after 4 – 8 weeks. The dose is then gradually reduced to a maintenance dose of 5 to 15 mg. Therapy is usually given for 12 – 18 months.

Question 29

Propylthiouracil

Answer 29

Propylthiouracil is given in a dose of 200 to 400 mg daily in divided doses until the patient becomes euthyroid, then the dose may be gradually reduced to a maintenance dose of 50 to 150 mg daily in divided doses.

Question 30

Blocking-replacement regimen

Answer 30

A combination of carbimazole 40 to 60 mg daily with levothyroxine 50 to 150 microgram daily may be used in a blocking-replacement regimen which is usually given for 18 months.
Carbimazole is commenced initially and then levothyroxine therapy is added, usually after several weeks. This regimen is not suitable for use during pregnancy.

Question 31

Side effects - anti-thyroid drugs

Answer 31

Patients taking anti-thyroid medication need specific counselling regarding these medications. There is a CSM warning regarding neutropenia and agranulocytosis so patients should be counselled to report symptoms and signs suggestive of infection, especially a sore throat. A white blood cell count should be performed if there is any clinical evidence of infection. Treatment should be stopped promptly if there is clinical or laboratory evidence of neutropenia.

Other side effects include rash. Severe hepatic reactions have been reported in patients taking propylthiouracil. A patient needs to be counselled on how to recognise the signs of liver disorder and to seek prompt medical attention if these symptoms develop:
Patients should be given written and verbal information regarding their medication and side effects. The information given should be recorded in the medical notes.

Question 32

Surgery

Answer 32

Patients may require a thyroidectomy which can be total or subtotal/partial.
Iodine has been used for 10 - 14 days prior to partial thyroidectomy, as an adjunct to antithyroid drugs. However, there is little evidence of a beneficial effect.

Question 33

Radioactive sodium iodide (131I) solution

Answer 33

• Radioactive sodium iodide (131I) solution is used increasingly for the treatment of thyrotoxicosis at all ages, particularly where medical therapy or compliance is a problem, in patients with cardiac disease, and in patients who relapse after thyroidectomy.
• Anti-thyroid drugs should be withdrawn before sodium iodide (131I) solution is given. After administration it initially concentrates in the thyroid gland. Sodium iodide (131I) solution is contra-indicated in pregnancy and breast feeding and some other situations. Females should avoid pregnancy within six months of treatment and males should avoid fathering a child for at least four months after treatment. Precautions should be taken to ensure close contacts, family, children and the public are not put at risk from the effect of radiation after a patient has been treated with sodium iodide (131I) solution.

Question 34

Thyrotoxicosis – other therapy

Answer 34

• Unless it is contra-indicated, propranolol can be given for the rapid relief of the symptoms of thyrotoxicosis.
• It can be used in conjunction with anti-thyroid drugs or as an adjunct to radioactive iodine.
• As symptoms improve the dose can be reduced and eventually stopped.
• Propranolol can also be used in conjunction with iodine to prepare mildly thyrotoxic patients for surgery but it is preferable to make the patient euthyroid with carbimazole.
• Most experience in treating thyrotoxicosis has been gained with propranolol hydrochloride but nadolol is also used.
• Beta- blockers should be not be used if they are contra-indicated e.g. patients who have asthma.

Question 35

Thyrotoxic crisis / thyroid storm

Answer 35

This is a rare condition which is defined as a rapid deterioration of hyperthyroidism.

Question 36

Signs and symptoms include:

Answer 36

 Hyperpyrexia
 Severe tachycardia
 Extreme restlessness
 Cardiac failure
 Liver dysfunction

Question 37

Emergency treatment

Answer 37

 IV fluids
 Propranolol (if not contra-indicated)
 Hydrocortisone (as sodium succinate)
 Oral iodine
 Carbimazole or propylthiouracil – may need administering by nasogastric tube
 Other supportive measures and treatment

Question 38

Thyroid eye disease

Answer 38

Thyroid eye disease is a relatively rare condition. It is an autoimmune disorder and most patients present with concurrent thyrotoxicosis due to Graves’ disease. Smoking increases the risk of developing thyroid eye disease. Clinical features include visible swelling and redness of the eyelids and conjunctiva.

Question 39

Management and Treatment

Answer 39

Sight threatening complications need to be excluded. If the patient is a smoker, they should be counselled on smoking cessation. Thyroid dysfunction should be corrected. Suitable patients should be referred to specialist centres. The following treatments can be used as appropriate:
 Steroids
 Orbital irradiation with/without steroids
 Lubricants – artificial tears
 Prisms
 Selenium
 Surgery
 Other measures

Question 40

normal reference range for FT4

Answer 40

9–25pmol/L

Question 41

normal reference range for FT3

Answer 41

3.5–7.8pmol/L

Question 42

normal reference range for TSH

Answer 42

0.4–4.5mU/L

Question 43

Periodic thyroid function tests are recommended for patients who:

Answer 43

● Take amiodarone or lithium
● Are diabetic
● Have atrial fibrillation
● Have hyperlipidaemia
● Have Down’s syndrome, Turner’s syndrome or Addison’s disease

Question 44

Dopamine (high-dose); corticosteroids; octreotide effects on thyroid hormones

Answer 44

Decrease in TSH secretion

Question 45

Lithium; iodine; amiodarone; carbimazole; propylthiouracil effects on thyroid hormones

Answer 45

Decreased secretion or synthesis of thyroid hormones (T3, T4)

Question 46

Iodine; amiodarone; lithium (rare) effects on thyroid hormones

Answer 46

Increased secretion or synthesis of thyroid hormones (T3, T4)

Question 47

Carbimazole; propylthiouracil; lithium effects on thyroid hormones

Answer 47

Displacement of thyroid hormone from plasma proteins

Question 48

Beta-blockers; corticosteroids; amiodarone; propylthiouracil; radiocontrast dyes effects on thyroid hormones

Answer 48

Impaired conversion of T4 to T3

Question 49

Phenytoin; carbamazepine effects on thyroid hormones

Answer 49

Increased clearance of T4

Question 50

Corticosteroids effects on thyroid hormones

Answer 50

Decreased thyroid binding globulin, total T3 and total T4

Question 51

Amiodarone effects on thyroid hormones

Answer 51

Modified action of thyroid hormones

Question 52

Clinical features of hypothyroidism include:

Answer 52

● Facial swelling
● Hair loss
● Dry, pale skin
● Bradycardia
● Husky voice
● Hypothermia
● Goitre
● Constipation
● Psychosis
● Delayed deep tendon reflexes
● Fatigue
● Weight gain
● Depression
● Menorrhagia
● Hearing impairment
● Hyponatraemia

Question 53

Common signs and symptoms of hyperthyroidism include:

Answer 53

● Tremor
● Tachycardia
● Warm, moist skin
● Weight loss and muscle weakness
● Agitation
● Sweating and heat intolerance
● Goitre
● Hunger and thirst
● Exophthalmos (protrusion of the eyeballs in their sockets)
● Atrial fibrillation
● Anorexia
● Diarrhoea

Question 54

first-line treatment for hypothyroidism

Answer 54

Levothyroxine

50–100µg of levothyroxine daily

Question 55

Some medicines can reduce the absorption of

levothyroxine

Answer 55

cholestyramine, sucralfate, ferrous sulphate and calcium salts

Question 56

Some medicines can increase levothyroxine metabolism

Answer 56

Hepatic enzyme inducers, such as rifampicin and phenytoin

Question 57

can increase thyroid binding globulin (TBG) levels.

Answer 57

Oestrogen therapies (eg, oral contraceptives and hormone replacement)

Question 58

levothyroxine — taking a dose with food

Answer 58

reduces absorption by 40–80% so take 30 mins before food. intestinal absorption is highest when it is taken on an empty stomach

Question 59

Distribution interactions

Answer 59

• Protein binding affects the amount of free drug available. Levothyroxine is extensively protein-bound to thyroxinebinding globulin (TBG) and albumin.
• Circulating liothyronine is mostly bound to TBG8, while thiamazole, the active metabolite of carbimazole, is moderately bound to plasma proteins, while 80% propylthiouracil is bound to plasma proteins.
• Endogenous and exogenous oral sex hormone (oestrogens and androgens) levels affect the concentration of TBG.
• In normal thyroid function, the feedback loop and stimulation of thyroxine synthesis compensate for this, and maintain normal free thyroxine concentrations.
• In hypothyroidism, this mechanism does not compensate; therefore patients taking levothyroxine who start taking sex hormones may require dose adjustment.
• Starting an oral contraceptive or HRT increases TBG,
  reducing circulating thyroid hormone and thus requiring an increased levothyroxine dose, whereas starting androgens reduces the concentration of TBG, and patients may require dose reduction of the levothyroxine.
• The interaction should not affect the efficacy of sex hormone therapy. Thyroid function should be assessed within several months of starting or stopping sex hormone therapy and the dose adjusted accordingly

Question 60

Metabolic interactions

Answer 60

Enzyme induction by rifampicin, carbamazepine, phenytoin or barbiturates enhances thyroid hormone metabolism, and can result in reduced serum concentrations. This interaction is of little significance for patients who have had the dose of levothyroxine titrated according to a clinical response and thyroid function
test. However, clinical hypothyroidism can occur in patients taking levothyroxine if started on an enzyme-inducing drug, and the levothyroxine dose should be increased appropriately following a thyroid function test. Conversely, if the enzymeinducing therapy is stopped, hyperthyroidism could occur.
Case reports indicate that use of chloroquine with proguanil for malaria prophylaxis may cause induction of liver enzymes, with a subsequent increased metabolism of levothyroxine. Monitoring of the thyroid function should be considered if an interaction is suspected.

Question 61

Thyroid function interactions

Answer 61

Medicines used for the management of unrelated conditions may have a direct effect on thyroid function. The most commonly implicated drugs are amiodarone and lithium, and thyroid function should be monitored closely.
Amiodarone is known to have complex effects on thyroid function owing to its high iodine content. It has been implicated in causing both hyperthyroidism and hypothyroidism. Amiodarone may inhibit the peripheral de-iodination of T4 to T3 resulting in a decreased concentration of active hormone, which can cause more overt symptoms in patients with existing hypothyroidism Amiodarone is therefore contraindicated in patients with
current or previous thyroid dysfunction.
Lithium may lead to clinical hypothyroidism due to a direct action on the thyroid gland, inhibiting the release of thyroid hormones.

Question 62

Antidiabetic medicines

Answer 62

can be affected as correction of the hypothyroidism may
increase insulin or oral hypoglycemic requirements. Therefore blood glucose monitoring should be performed and reviewed frequently in patients with diabetes starting
treatment for hypothyroidism, for patients already monitoring their blood glucose, they may continue with the usual schedule, for patients that do not manage their own testing, they should ensure they have blood glucose checked every two to three months during the period of adjustment. As levothyroxine takes weeks to achieve therapeutic levels these changes may be prolonged

Question 63

Propanolol

Answer 63

plasma concentrations are reduced in hyperthyroidism, probably owing to increased clearance. Propanolol may
also inhibit the de-iodination of T4 to T3.

Question 64

Digoxin

Answer 64

serum concentrations appear to be lower in patients with hyperthyroidism and higher in those with hypothyroidism. Patients with hyperthyroidism have a degree of insensitivity to digoxin therapy, and therefore may require higher digoxin doses than normal, which then need to be reduced as treatment with antithyroid drugs is started. Conversely, patients with hypothyroidism may need digoxin doses increased as hypothyroidism is corrected.
Proposed mechanisms for these effects include altered response of the heart due to changes in thyroid hormone levels, and altered glomerular filtration rates affecting digoxin clearance

Question 65

Oral anticoagulants (e.g. warfarin)

Answer 65

can be affected by thyroid dysfunction, and patients will require increased monitoring of international normalised ratio (INR) when thyroid therapy is started, adjusted or stopped. The suggested mechanism is that changes to metabolic rates governed by the thyroid hormones affect the metabolism of clotting factors.
Hypothyroidism decreases the metabolism of clotting factors. Therefore, patients taking an anticoagulant may have been taking a higher dose than normally required to achieve their target INR. If such a patient starts treatment for hypothyroidism his or her dose of anticoagulant may need to be reduced. Conversely, patients with hyperthyroidism treated with anti-thyroid drugs may require an increase in the anticoagulant dose.
Starting other medicines that can alter thyroid function as an adverse effect (e.g. amiodarone) may also require the patient’s anticoagulant doses to be adjusted

Question 66

Theophylline

Answer 66

levels may be modestly altered in thyroid dysfunction. In hyperthyroidism, theophylline metabolism is increased, and therefore the dose may need to be reduced as thyroid levels are corrected. Conversely, patients with hypothyroidism may need the dose of theophylline increased as treatment with levothyroxine or liothyronine continues.