Disorders of the Thyroid Gland

Endocrinology

What are the learning outcomes for the thyroid gland lecture? (5 points)

1. Review the anatomy, function and control of the thyroid gland, including the role of the hypothalamic-pituitary-thyroid axis 2. Discuss the functions of thyroid hormone 3. Describe the signs and symptoms of hypothyroidism and hyperthyroidism 4. Outline the underlying pathophysiology and diagnosis of hypothyroidism and hyperthyroidism 5. Detail the therapies and treatment regimens available for the management of hypothyroidism and hyperthyroidism

What is the normal anatomy and function of the thyroid gland? (7 points)

1. The thyroid gland sits over the trachea 2. It synthesises, stores and secretes two major hormones: triiodothyronine/T3 and tetraiodothyronine/T4 3. Synthesis of T3 and T4 requires iodine 4. T3 and T4 are transported in serum bound to carrier proteins 5. Carrier proteins include thyroxine-binding globulin, albumin and thyroxine-binding prealbumin 6. The smaller free/unbound fraction is the active fraction 7. The thyroid secretes T4:T3 in a ratio of approximately 10:1

How are T4 and T3 related in normal thyroid function? (4 points)

1. T4 is secreted in greater amounts than T3 2. T4 is converted into T3 in peripheral tissues 3. Conversion mainly occurs in the liver, kidneys and brain 4. T4 can be thought of as a precursor to the active T3 hormone

What do the normal thyroid anatomy/function diagrams show? (2 points)

1. The thyroid gland’s anatomical position in the neck over the trachea 2. The relationship between thyroid structure and hormone production/release

What are the actions of thyroid hormone? (7 points)

1. T3 is the active hormone 2. T3 acts by binding to thyroid hormone receptors 3. Thyroid hormones increase metabolism of carbohydrates, fats and proteins 4. They directly control enzymes involved in carbohydrate metabolism 5. They act synergistically with other hormones 6. They increase basal metabolic rate 7. The liver is the major site of metabolism, with free and conjugated metabolites secreted in bile and urine

Why is T4 cleared more slowly than T3? (1 point)

1. T4 clearance is slower because it has high affinity for thyroxine-binding globulin

What are the two broad categories of thyroid gland disorders? (2 points)

1. Hypothyroidism, which is characterised by deficiency in thyroid hormones 2. Hyperthyroidism, which is characterised by excessive thyroid hormone levels

What section is introduced after thyroid pathophysiology? (1 point)

1. Pathophysiology and treatment of hypothyroidism

What are the signs and symptoms of hypothyroidism? (8 points)

1. Fatigue/weakness 2. Intolerance to cold conditions 3. Depression 4. Weight gain 5. Joint aches 6. Dry skin/hair loss 7. Constipation 8. Menstrual irregularities

What causes primary hypothyroidism? (5 points)

1. Primary hypothyroidism accounts for around 95% of cases 2. It results from factors affecting the thyroid gland itself 3. Causes include autoimmune thyroid disease 4. Causes include post-surgery or exposure to radioactive iodine 5. Other causes include inherited disorders, iodine deficiency and drug-induced hypothyroidism from amiodarone, lithium or anti-thyroid medicines

What causes secondary, tertiary and central hypothyroidism? (4 points)

1. Secondary hypothyroidism results from factors interfering with TSH secretion from the anterior pituitary 2. Tertiary hypothyroidism occurs when there is an issue with TRH secretion from the hypothalamus 3. Secondary and tertiary hypothyroidism are collectively called central hypothyroidism 4. Central hypothyroidism can be caused by damage to the pituitary or hypothalamus

What are thyroid hormone resistance syndromes? (1 point)

1. Thyroid hormone resistance syndromes are very rare conditions where tissues are insensitive to the action of T3

How is hypothyroidism diagnosed? (7 points)

1. TSH rises early in thyroid failure, but patients may be asymptomatic if T3 and T4 remain normal 2. This early state is called subclinical hypothyroidism 3. Later, thyroid hormone levels fall and patients become symptomatic 4. This later state is called overt hypothyroidism 5. Primary hypothyroidism is diagnosed with low circulating T3/T4 and markedly raised TSH above 10 mU/L 6. Central hypothyroidism should be suspected when both free T4 and TSH are suppressed 7. TSH may be suppressed in acute illness

What other conditions or abnormalities can be associated with hypothyroidism? (5 points)

1. Adrenal insufficiency can be associated with raised TSH that resolves with glucocorticosteroid treatment 2. Anaemia 3. Hyponatraemia 4. Hypercholesterolaemia 5. Elevated creatine kinase

How is hypothyroidism treated with levothyroxine? (8 points)

1. Hypothyroidism requires lifelong replacement therapy 2. Levothyroxine, synthetic T4, is preferred 3. It is preferred because of efficacy, clinical experience, side effect profile, ease of administration, absorption, long half-life and low cost 4. Typical adult starting dose is 50–100 micrograms daily 5. Dose is adjusted in steps of 25–50 micrograms every 3–4 weeks 6. Usual maintenance dose is 100–200 micrograms daily 7. In elderly patients or those with cardiac disorders, start at 25 micrograms daily 8. In elderly/cardiac patients, adjust by 25 micrograms every 4 weeks

How is levothyroxine adjusted in pregnancy and different types of hypothyroidism? (4 points)

1. Dose increases of 25–50% may be required during pregnancy 2. In primary hypothyroidism, therapy is titrated to achieve normal TSH 3. In central hypothyroidism, trough free T3 and T4 guide response and dose titration 4. Levothyroxine should be taken 30 minutes before breakfast, caffeine-containing products or other medicines to improve absorption

Why might subclinical hypothyroidism still matter? (4 points)

1. It may progress to overt hypothyroidism 2. It may have cardiovascular effects 3. It may contribute to hyperlipidaemia 4. It may have psychiatric effects

Why is combined T3 and T4 treatment controversial? (6 points)

1. Some people advocate combined T3 and T4 replacement 2. Some studies suggest it improves well-being and cognitive function compared with T4 alone 3. It may be trialled in patients who remain symptomatic despite optimal levothyroxine 4. Desiccated thyroid extracts such as Armour Thyroid are not recommended 5. Desiccated thyroid extracts have non-standardised T3 and T4 concentrations and may cause unnaturally high T3 levels 6. Raised T3 may be dangerous in cardiac disease and may be linked to osteoporosis

Why is levothyroxine alone usually preferred? (2 points)

1. Levothyroxine therapy alone is associated with lower T3 and higher T4 levels 2. This pattern is more comparable to healthy individuals

What is myxoedema coma? (5 points)

1. Myxoedema coma is a rare but life-threatening complication of severe untreated hypothyroidism 2. It is characterised by altered mental state 3. It is characterised by defective thermoregulation 4. Defective thermoregulation may present as hypothermia or absence of appropriate fever 5. It is usually precipitated by a specific event

What can precipitate myxoedema coma? (6 points)

1. Loss in circulating volume 2. Electrolyte abnormalities 3. Infection 4. Exposure to cold weather 5. Stroke or heart failure 6. Use of central nervous system depressants

How is myxoedema coma managed? (7 points)

1. Identify and treat the precipitating factor 2. Warm the patient slowly, aiming for slow rise in core temperature 3. Correct electrolyte abnormalities 4. In hypothyroid coma, give liothyronine 5–20 micrograms IV every 12 hours, increasing to every 4 hours if required 5. Alternative liothyronine regimen is 50 micrograms initially, followed by 25 micrograms every 8 hours, then reduced to 25 micrograms twice daily 6. Oral levothyroxine 50–100 micrograms daily can be given in less severe cases 7. If cortisol deficiency is present, give hydrocortisone 50–100 mg three to four times daily

What section is introduced after hypothyroidism? (1 point)

1. Pathophysiology and treatment of hyperthyroidism

What are the signs and symptoms of hyperthyroidism? (10 points)

1. Palpitations 2. Nervousness, shakiness or insomnia 3. Difficulty concentrating or irritability 4. Emotional lability 5. Increased appetite 6. Heat intolerance 7. Fatigue, weakness or exertional dyspnoea 8. Hyperdefecation 9. Brittle hair 10. Increased menses

What are hyperthyroidism and thyrotoxicosis? (2 points)

1. Hyperthyroidism occurs when excess thyroid hormone is produced 2. Thyrotoxicosis occurs when excess thyroid hormone causes exaggerated biochemical effects at tissue level

What are the common and less common causes of thyrotoxicosis? (6 points)

1. Graves’ disease due to autoimmune antibody-mediated stimulation 2. Thyroiditis due to viral or immune attack causing thyroid inflammation 3. Toxic multinodular goitre/nodular disease 4. Stimulation of the TSH receptor by high human chorionic gonadotropin levels 5. TSH-secreting pituitary adenomas 6. Congenital hyperthyroidism

How is hyperthyroidism diagnosed? (6 points)

1. Thyrotoxicosis is confirmed by measuring serum TSH 2. TSH is always suppressed except in rare TSH-secreting tumours 3. Serum free T3 and free T4 are usually raised 4. In T3 thyrotoxicosis, only serum T3 is elevated 5. Once biochemical hyperthyroidism is confirmed, further investigations are needed to determine the cause 6. Dopamine and corticosteroids may suppress TSH, but free T3 and T4 are normal

What abnormalities may accompany hyperthyroidism? (7 points)

1. Mild leukopenia 2. Anaemia 3. Transaminitis 4. Raised alkaline phosphatase from bone 5. Mild hypercalcaemia 6. Low albumin 7. Low cholesterol

Why should hyperthyroidism be treated and what are the main antithyroid medicines? (4 points)

1. Treatment prevents complications such as atrial fibrillation 2. Treatment prevents cardiomyopathy 3. Treatment prevents osteoporosis 4. Thionamides, carbimazole and propylthiouracil, block thyroid hormone synthesis and are equally effective

How is carbimazole used to treat hyperthyroidism? (4 points)

1. Carbimazole is started at 15–40 mg daily until the patient becomes euthyroid 2. Euthyroid state usually occurs after 4–8 weeks 3. Higher doses can be used if needed 4. Dose is reduced to 5–15 mg daily when thyroid function tests improve

How is propylthiouracil used to treat hyperthyroidism? (4 points)

1. Propylthiouracil is given at 200–600 mg daily in divided doses 2. It is used until the patient becomes euthyroid 3. It is then gradually reduced 4. Maintenance dose is usually 50–150 mg daily

What other key treatment details apply to antithyroid therapy? (5 points)

1. Treatment usually continues for 6 months to 2 years 2. Most patients remain euthyroid after 10 years 3. If hyperthyroidism recurs after treatment, a second course has little chance of permanent remission 4. Carbimazole 1 mg is considered equivalent to propylthiouracil 10 mg 5. Lugol’s iodine 0.1–0.3 mL three times daily is an alternative but infrequently used and should be well diluted with milk or water

What additional treatments can be used in hyperthyroidism? (5 points)

1. Beta-blockers, usually propranolol, relieve symptoms and control heart rate 2. Beta-blockers can often be stopped once euthyroid state is achieved 3. Corticosteroids, most commonly prednisolone, are used in thyroiditis to reduce thyroid inflammation 4. Block-and-replace therapy can be used 5. Thyroidectomy is infrequently used but requires pretreatment with antithyroid drugs to achieve euthyroidism

How does block-and-replace therapy work in hyperthyroidism? (5 points)

1. Carbimazole 40–60 mg daily is given alone until euthyroid state is achieved 2. Then levothyroxine 50–100 micrograms daily is added 3. Levothyroxine is adjusted in 25 microgram increments to maintain free T4 in desired range 4. Advantages include fewer hospital visits for thyroid function tests 5. Treatment duration is usually shorter, around 18 months, and propylthiouracil can also be used

What is acute thyroid crisis/thyroid storm? (4 points)

1. Thyroid crisis is also called thyroid storm 2. It is a rare but life-threatening exacerbation of thyrotoxicosis 3. Prompt recognition and treatment are essential because mortality is high 4. Patients are best managed in intensive therapy/ITU and may need antiarrhythmics and potassium replacement

How is acute thyroid crisis treated? (7 points)

1. Aim to completely block thyroid hormone synthesis with large doses of antithyroid drugs 2. Propylthiouracil 200–300 mg every 6 hours is preferred because it blocks T4 to T3 conversion 3. Carbimazole can also be used 4. Potassium iodide 10 drops twice daily inhibits thyroid hormone release 5. Beta-blockers or calcium channel blockers control adrenergic symptoms 6. Glucocorticosteroids such as prednisolone 60 mg daily or hydrocortisone 50 mg four times daily block T4 to T3 conversion 7. Colestyramine reduces enterohepatic recirculation of thyroid hormones

What toxicities are associated with carbimazole and propylthiouracil? (7 points)

1. Both can cause neutropenia 2. Both can cause agranulocytosis 3. Patients should report signs of infection promptly 4. Important warning symptoms include sore throat, mouth ulcers, bruising, fever or malaise 5. White blood count should be checked if symptoms occur 6. Treatment should be stopped if there is clinical or laboratory evidence of neutropenia 7. Propylthiouracil and carbimazole can cause severe hepatic reactions

What liver toxicity counselling is needed for antithyroid medicines? (5 points)

1. Severe hepatic reactions may require transplantation 2. Severe hepatic reactions may be fatal 3. Patients and carers should report anorexia, nausea, vomiting, fatigue, abdominal pain, jaundice, dark urine or pruritus 4. If significant hepatic enzyme abnormalities develop, the medicine should be stopped immediately 5. Early withdrawal increases the chance of complete recovery

What learning outcomes are reviewed at the end of the lecture? (5 points)

1. Review the anatomy, function and control of the thyroid gland, including the hypothalamic-pituitary-thyroid axis 2. Discuss the functions of thyroid hormone 3. Describe signs and symptoms of hypothyroidism and hyperthyroidism 4. Outline pathophysiology and diagnosis of hypothyroidism and hyperthyroidism 5. Detail therapies and treatment regimens for hypothyroidism and hyperthyroidism

Thyroid hormone synthesis is dependent on which chemical element?

 

Magnesium

 

Selenium

 

Iodine

Iron

 

Calcium

Iodine: The synthesis of both T3 and T4 requires iodine and the hormones are transported in the serum bound to carrier proteins, namely thyroxine-binding globulin, albumin and thyroxine-binding prealbumin.

 

Which of the following statements about triiodothyronine (T3) and tetraiodothyronine (T4) is correct?

 

Increasing levels of these hormones supress the release of thyrotropin-releasing hormone (TRH)

 

 

Increasing levels of triiodothyronine (T3) result in enhanced conversion of T3 to tetraiodothyronine (T4)

 

Increasing level of these hormones supress the activity of the hypothalamic-pituitary-adrenal (HPA) axis

 

Decreasing levels of these hormones supress the release of thyroxine-binding globulin

 

Increasing levels of these hormones stimulate the release of thyroid-stimulating hormone (TSH)

Increasing levels of these hormones supress the release of thyrotropin-releasing hormone (TRH)

Like all things in endocrinology, thyroid hormones are controlled by negative feedback. As triiodothyronine (T3) and tetraiodothyronine (T4) levels rise and exert their metabolic effects, they simultaneously exert negative feedback on the hypothalamus and anterior pituitary, thus inhibiting the release of stimulatory hormones such as thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH). This then results in reduced secretion of T3 and T4 (which in turn stimulates the release of TRH and TSH to increase levels).

Which of the following is an action of thyroid hormones?

 

They produce a general increase in the metabolism of carbohydrates, fats and proteins

 

They increase bone turnover

 

They supress basal metabolic rate

 

They are responsible for stimulating the breakdown of glycogen into glucose

 

They stimulate the conversion of inactive to active vitamin D in the kidney

They produce a general increase in the metabolism of carbohydrates, fats and proteins

 

Which of the following statements about thyroid replacement therapy is correct?

 

Patients with primary hypothyroidism should be offered treatment with a combination of liothyronine and levothyroxine

 

The management of primary hypothyroidism requires short to medium term treatment with thyroid hormones whilst the underlying cause is investigated and treated.

 

Pregnancy usually requires a decrease in the dose of thyroid replacement

 

Desiccated thyroid extracts (e.g. Armour Thyroid®) are recommend for patients who fail to respond to first line therapy

 

Levothyroxine should be taken on an empty stomach

Levothyroxine should be taken on an empty stomach

Levothyroxine has a poor interaction profile, with absorption being impaired by the presence of food, caffeine and other medicines and should therefore be taken 30 minutes before breakfast, caffeine-containing products or other medication.

Mr Simpson is a 45 year old patient with Grave's disease who you are seeing in your thyroid clinic today. You are planning to prescribe him carbimazole 20mg once daily to manage this condition. Thinking specifically about the toxicology of this drug, what counselling points would you cover with Mr Simpson?

Your answer:

Carbimazole (and propylthiouracil) are associated with neutropenia and agranulocytosis and it is important to counsel patients to promptly report any signs suggestive of a a blood disorder.

You should inform the patient to report any signs of infection such as especially a sore throat, mouth ulcers, bruising, fever or malaise.

If he experiences any of the above, a white blood count should be performed and treatment stopped if there is clinical or laboratory evidence of neutropenia.

Although associated more strongly with propylthiouracil, carbimazole is also known to cause severe hepatic reactions which may necessitate transplantation or even result in death.

Patients and their carers should be advised to recognise and report any signs of liver dysfunction such as anorexia, nausea, vomiting, fatigue, abdominal pain, jaundice, dark urine or pruritus.

If significant hepatic enzyme abnormalities develop, the drug should be discontinued immediately.