CHEMPATH: Thyroid

Question 1

A. TSH < 0.01, Free T3 15.6, Free T4 38.0.

• 1. Consistent with clinical primary hypothyroidism
• 2.Consistent with euthyroid status in a patient complaining of tiredness.
• 3.Consistent with pituitary driven thyrotoxicosis
• 4.Consistent with secondary or pituitary hypothyroidism.
• 5.Consistent with sub-clinical hypothyroidism with risk of later clinical hypothyroidism.
• 6.Consistent with thyrotoxicosis.
• 7.To screen for medullary thyroid carcinoma
• 8.To screen for recurrence of differentiated thyroid carcinoma.

Normal ranges TSH 0.33-4.5mU/L Free T3 (3.2-6.5pmol/L) Free T4 (10.2-22.0pmol/L) Thyroglobulin <5 ug/L

Answer 1

6

Question 2

TSH 8.4, Free T4 11.7, Thyroid peroxidase (thyroid antibodies) positive

• 1. Consistent with clinical primary hypothyroidism
• 2.Consistent with euthyroid status in a patient complaining of tiredness.
• 3.Consistent with pituitary driven thyrotoxicosis
• 4.Consistent with secondary or pituitary hypothyroidism.
• 5.Consistent with sub-clinical hypothyroidism with risk of later clinical hypothyroidism.
• 6.Consistent with thyrotoxicosis.
• 7.To screen for medullary thyroid carcinoma
• 8.To screen for recurrence of differentiated thyroid carcinoma.

Normal ranges TSH 0.33-4.5mU/L Free T3 (3.2-6.5pmol/L) Free T4 (10.2-22.0pmol/L) Thyroglobulin <5 ug/L

Answer 2

5

Question 3

TSH 1.4, Free T4 12.1.

• 1. Consistent with clinical primary hypothyroidism
• 2.Consistent with euthyroid status in a patient complaining of tiredness.
• 3.Consistent with pituitary driven thyrotoxicosis
• 4.Consistent with secondary or pituitary hypothyroidism.
• 5.Consistent with sub-clinical hypothyroidism with risk of later clinical hypothyroidism.
• 6.Consistent with thyrotoxicosis.
• 7.To screen for medullary thyroid carcinoma
• 8.To screen for recurrence of differentiated thyroid carcinoma.

Normal ranges TSH 0.33-4.5mU/L Free T3 (3.2-6.5pmol/L) Free T4 (10.2-22.0pmol/L) Thyroglobulin <5 ug/L

Answer 3

2

Question 4

TSH 22. 4, Free T4 6.3.

• 1. Consistent with clinical primary hypothyroidism
• 2.Consistent with euthyroid status in a patient complaining of tiredness.
• 3.Consistent with pituitary driven thyrotoxicosis
• 4.Consistent with secondary or pituitary hypothyroidism.
• 5.Consistent with sub-clinical hypothyroidism with risk of later clinical hypothyroidism.
• 6.Consistent with thyrotoxicosis.
• 7.To screen for medullary thyroid carcinoma
• 8.To screen for recurrence of differentiated thyroid carcinoma.

Normal ranges TSH 0.33-4.5mU/L Free T3 (3.2-6.5pmol/L) Free T4 (10.2-22.0pmol/L) Thyroglobulin <5 ug/L

Answer 4

1

Question 5

Thyroglobulin 254

• 1. Consistent with clinical primary hypothyroidism
• 2.Consistent with euthyroid status in a patient complaining of tiredness.
• 3.Consistent with pituitary driven thyrotoxicosis
• 4.Consistent with secondary or pituitary hypothyroidism.
• 5.Consistent with sub-clinical hypothyroidism with risk of later clinical hypothyroidism.
• 6.Consistent with thyrotoxicosis.
• 7.To screen for medullary thyroid carcinoma
• 8.To screen for recurrence of differentiated thyroid carcinoma.

Normal ranges TSH 0.33-4.5mU/L Free T3 (3.2-6.5pmol/L) Free T4 (10.2-22.0pmol/L) Thyroglobulin <5 ug/L

Answer 5

8

Question 6

What naturally occurring compound blocks TSH?

Answer 6

Perchlorate

Question 7

Describe the molecular mechanisms of T3/4 production.

Answer 7

This occurs in thyrocytes in thyroid follicles.

• Iodide goes through the membrane via Na+/K+ ATPase
• Iodide –> iodine by thyroid peroxidase (TPO)
• The iodine is then taken up by thyroglobulin(TG) and –> thyroxine through a number of processes involving TPO –>MIT and TIT via iodination of tyrosine residues in thyroglobulin
• There is coupling of monoiodotyrosine (MIT) and DIT to form T3 and 2 diiodotyrosine (DIT) to form T4
• Once the thyroxine (T4) is produced, it is stored within the thyroid gland (and taken up by BM again and secreted into the lumen when required)
  
  • In the periphery, T4 –> T3

Question 8

Which form is thyroxine most commonly found in the periphery?

Answer 8

• A very small proportion is active thyroxine (fT4)
• Only 0.03% of thyroxine in the circulation is active
• Thyroxine can bind to thyroxine-binding pre-albumin (TBPA) & albumin
• Most of the thyroxine is bound to thyroxine binding globulin (TBG) – 75%
• NOTE: if lacking albumin in diet, you TBG levels will go down

Question 9

Describ the axis.

Answer 9

• Hypothalamus produces TRH à stimulates production of TSH from pituitary gland à stimulates T4 production
  
  • T4 converted to T3 in peripheries (active component of thyroxine)
• Too much T4 –> feedback to the hypothalamus to prevent it from producing too much TRH
  
  • So, if you have low T4, you should have high TRH and high TSH

NB: hCG and TSH have similar structures (hCG has 1/10,000 activity of TSH) and so can stimulate same actions I.E. a string around the neck is used as a pregnancy test in Africa (hCG –> goitre)

Question 10

List the most common causes of hypothyroidism.

Answer 10

Most hypothyroidism is PRIMARY

• Hashimoto’s thyroiditis (autoimmune)
• Atrophic thyroid (congenital or age)
• Post-Graves’ disease (radioactive iodine, surgery, natural history or thionamines)
• Other minor causes:
  
  • Post-thyroiditis
  • Drugs (amiodarone, lithium)
  • Thyroid agenesis or dysgenesis
  • Iodine deficiency and dyshormonogenesis
  • 2^nd hypothyroidism (pituitary disease)
  • Peripheral thyroid hormone resistance

Question 11

What are the clinical features of hypothyroidism?

Answer 11

• Metabolic rate - reduced –> weight gain
• Cardiovascular - bradycardia
• Gastrointestinal - constipation
• Respiratory- laboured breathing
• Reproductive - oligomenorrhoea
• Other:
  
  • Weight gain (metabolic rate issues) and poor appetite
  • Cold/dry hands/feet
  • Hyponatraemia (thyroxine is involved with Na transport in kidneys)
  • Normocytic anaemia + pernicious anaemia)
  • Myxoedema, goitre
  • Subtle in the elderly

Question 12

What investigations should be done for primary hypothyroidism? What other conditions should you test for?

Answer 12

• High TSH + Low T4 if primary
• Thyroid peroxidase autoantibodies (suggests autoimmune hypothyroidism / Hashimoto’s thyroiditis)
• Remember to consider any other autoimmune conditions that the patient may also have (e.g.
  
  • pernicious anaemia
  • coeliac disease
  • Addison’s disease

Question 13

What is the management of primary hypothyroidism?

Answer 13

• Perform an ECG:
  
  • If there is co-cardiac failure alongside the hypothyroidism, giving levothyroxine will exacerbate any myocardial ischaemia and MAY worsen the heart failure à start at a VERY low dose and titrate
• Levothyroxine (T4), 50-125-200 mcg/day -
  
  • Titrated to a normal TSH
  • Titrated by BMI, most patients are on about 100mcg,
• Liothyronine (T3)

Question 14

What is the problem with overtreating patients with T4? Is there evidence for T3 rather than T4?

Answer 14

• NO evidence base for over-treating patients with too much T4
  
  • Some patients prefer to take too much thyroxine because it helps them lose weight
  • Excessive thyroxine can cause osteopaenia and AF
• There is NO evidence base for giving T3 rather than T4
  
  • T4 is sometimes converted to T3 in some tissues; patients think that T3 is more natural.

Question 15

What type of hypothyroidism is associated with normal T4 but high TSH?

Answer 15

Subclinical hypothyroidism (SH) / “Compensated Hypothyroidism”

• T4 level is NORMAL but TSH is HIGH
• Pituitary gland senses T4 and* thinks the thyroid is NOT producing enough thyroxine so it produces more TSH

Question 16

Which antibody if positive in subclinical hypothyroidism, may indicate thyroid disease?

Answer 16

If TPO antibodies are positive, it suggests that may –> thyroid disease

Question 17

Is there any benefit of treating subclinical hypothyroidism? Does it help with symptoms?

Answer 17

Generally asymptomatic

Subclinical hypothyroidism is UNLIKELY to be the cause of their presenting symptoms – no change in symptoms will occur.

But hypothyroidism is associated with hypercholesterolaemia (may be only benefit of treating SH)

Question 18

How soon after radioiodine treatment do patients become hypothyroid?

Answer 18

Usually hypothyroid within 1 year of receiving treatment

But may take many years in some patients (up to 15yrs) ( 50% of patients)

Question 19

Describe the changes in thyroid function in pregnancy and why they occur.

Answer 19

1. hCG has a similar structure to TSH - so can bind onto THSr and cause thyroid to produce more thyroxine
   
   • Can cause thyrotoxicity if malignancy produces hCG
2. Rise in hCG in the 1^st trimester –> increase in free T4 but this is a normal physiological process
   
   • Normal ranges’ of TSH and T4 in pregnancy are slightly different to non-pregnancy
   • Later in pregnancy, hCG levels will drop –> T4 levels drop and TSH levels will rise slightly
3. TBG levels increase in pregnancy (as TBG is under the control of oestrogen) – but cannot be measured in serum, only T4

If T4 was low or extremely high at the start of pregnancy then this would be abnormal.

Question 20

What is the most thing to remember when testing for neonatal hypothyroidism?

Answer 20

Test must be done at the appropriate time (48-72hrs) after birth otherwise you may be detecting the mother’s TSH and miss the neonatal hypothyroidism (common as occurs in 1 in 3500)

Done using Guthrie test

Question 21

What is sick euthyroid syndorme? How is it managed?

Answer 21

Occurs when severe illness affects the HPT axis and thyroid may shut down to reduce the BMR BUT no hypothyroid symptoms occur and no improvement on giving thyroxine

• Biochemistry
  
  • Low T4 and T3 (and reduced T3 action)
  • Normal/high TSH (later decreased)

Question 22

What are the causes of hyperthyroidism and how can they be divided?

Answer 22

High uptake and low uptake on technetium scan

• HIGH UPTAKE:
  
  • Graves’ disease- 40-60%
  • Toxic multinodular goitre - 30-50%
  • Single toxic adenoma - 5%
• LOW UPTAKE:
  
  • Sub-acute thyroiditis / viral thyroiditis / de Quervain’s thyroiditis (all the same)
  • Postpartum thyroiditis

Rare causes:

• Silent thyroiditis (AI, amiodarone)
• Factitious thyroiditis
• TSH-induced
• Thyroid cancer induced
• Trophoblastic tumour and Struma ovarii (high hCG production)

Question 23

List 2 causes of low and high uptake on technetium scan.

Answer 23

Technetium scan can be used to see which parts of the thyroid are producing excessive thyroid hormone. All three of the above conditions that are high uptake will show increased uptake of technetium

• Graves’ disease
• Toxic multinodular goitre
• Single toxic adenoma

In pregnancy, the body may produce antibodies that stimulate the thyroid gland to release excess amounts of thyroxine. These have low uptake in a technetium scan:

• Postpartum thyroiditis
• Sub-acute thyroiditis, de Quervain’s

Question 24

What are the clinical features of hyperthyroidism?

Answer 24

• Metabolic rate- increased –> weight loss
• Cardiovascular - tachycardia
• Gastrointestinal- diarrhoea
• Respiratory - tachypnoea
• Skeletal - osteopaenia & osteoporosis (thyroxine acts on osteoclasts)
• Reproductive - irregular periods

Question 25

What do investigations show in hyperthyroidism?

Answer 25

* Low TSH, high T3 and T4 * Technetium scan may show high or low uptake depending on the cause * Thyroid autoantibodies (**thyroid microsomal**)

Question 26

What is the management of hyperthyroidism?

Answer 26

* Keep safe:give b**eta-blocker if pulse \> 100 bpm** * **Radioactive iodine** – *taken up by the thyroid gland, which then releases radiation to destroy the thyroid gland* Consider other autoimmune conditions (e.g. coeliac disease, Addison's disease) **ECG** - AF **Bone mineral density**

Question 27

What are the side effects of using radioiodine treatment?

Answer 27

¹³¹I is used * Can precipitate a thyroid storm and * Make the thyroid gland underactive (i.e. hypothyroidism) - **good** * Side effects: ophthalmopathy/tracheal compression NB: Stop thionamine if using radioactive iodine

Question 28

What are the clinical features of Graves' disease?

Answer 28

* Diffuse goitre * Thyroid associated ophthalmopathy (TSH-R on muscles of eyes) – *do not give radioiodine* * Thyroid associated dermopathy – pretibial myxoedema * Thyroid acropachy – *bones of fingers affected* * Other AI

Question 29

How can hyperthyroidism be managed medically?

Answer 29

Thionamides (e.g. carbimazole, propylthiouracil / PTU) * **They work by preventing conversion of iodide --\> iodine by thyroid peroxidase** These medications are either: 1. **Titrated** to achieve normal T4 levels or they can be... 2. **‘Block and replaced’** (a high dose of thionamides are used to block the thyroid gland completely, then given thyroxine to maintain normal)

Question 30

What are the side effects of thionamides?

Answer 30

Rash Rare side-effect = agranulocytosis Patients should STOP treatment if they develop a sore throat or fever + seek medical attention

Question 31

What are the two main drug mechanims for hyperthyroidism treatment?

Answer 31

* **Potassium perchlorate** can be given to hyperthyroid patients before surgery to block the uptake of iodide by the thyroid cells * **Thionamides (PTU/carbimazole)** inhibit thyroid peroxidase, thereby preventing the conversion of iodide to iodine

Question 32

What are the types of thyroiditis?

Answer 32

* Silent (painless) thyroiditis (most have some pain in the neck) * Viral / sub-acute thyroiditis * Post-partum thyroiditis (tx for viral or post-partum thyroiditis is different to hyperthyroidism) In most cases this is painful.

Question 33

What is the most common course of thyroiditis? What is the management?

Answer 33

* Initial inflammation --\> release of thyroid hormone --\> hypothyroidism long term. * Most thyroiditis patients present at the stage where their TSH is high and their T4/T3 is low * Long-term treatment of thyroiditis is **thyroid hormone replacement** NB: patients can present at different stages e.g. when TSH and T3 are both low, T3 high and TSH low etc.

Question 34

Name 4 types of thyroid cancer. Which are the most common?

Answer 34

1. Papillary thyroid cancer (pathology = Psammoma body) 2. Follicular thyroid cancer 3. Medullary carcinoma of the thyroid 4. Anaplastic thyroid cancer 1 + 2 are most common. Typically slow progressing.

Question 35

Which thyroid cancer is this associated with?

Answer 35

Papillary thyroid cancer - Psammoma body

Question 36

What is the treatment of thyroid cancer?

Answer 36

1. **Total thyroidectomy ± radioiodine** 2. **Supraphysiological doses of thyroxine** *(to lower the TSH levels so that TSH does NOT stimulate any remaining thyroid cancer cells, as many of these tumours cells are sensitive to TSH and may grow again)* 3. **Measure TG (thyroglobulin)** to monitor if the cancer ever returns *(as everything has been wiped out so no TG should be released)* ## Footnote *\*TG is a protein produced by RER in thymocytes.*

Question 37

What are the causes of medullary thyroid cancer? Which cells are affected?

Answer 37

* Causes: * **sporadic** * **familial** * **MEN 2** This is RARE but can be devastating It is a cancer of the **C-cells of the thyroid gland** (these produce calcitonin so if too much then may be MCC)​

Question 38

What are the tumour markers of medullary thyroid cancer?

Answer 38

Tumour markers: 1. Calcitonin (normally released but at high levels in cancer) 2. CEA (carcinoembryonic antigen)

Question 39

What are the MEN1 and MEN2a/b cancers?

Answer 39