Case 19

Question 1

Explain the Hypothalmus-Pituitary-Thyroid axis

Answer 1

The hypothalamus, specifically the paraventricular nucleus, secrete TRH (Thyotropin-releasing hormone), TRH then travels to the anterior pituitary gland and stimulates endocrine cells called Thyrotropes to secrete TSH (Thyroid-stimulating hormone), TSH then travels in the blood goes to a thyroid follicular cell.

Question 2

Explain what TSH does

Answer 2

TSH is a glycoprotein hormone that travels to the thyroid follicular cell in the thyroid gland and attaches to a G-coupled receptor, this activates cAMP (cyclic AMP) which leads to the transcript and translation of a protein called Thyroglobulin

Question 3

Explain iodide trapping

Answer 3

Iodine is present in the blood in its ionic form called Iodide (I-), it enters the thyroid follicular cell via secondary active transport (cotransport) with the help of Na+ and the Sodium-Iodide transporter (NIS Sodium-Iodide symporter) which relies on the Na+ gradient created by the Na/K ATPase pump

Question 4

Explain how thyroid hormones are produced after iodide enters the thyroid follicular cell

Answer 4

After iodide ions enter via secondary active transport, the iodide ions get transported outside the cell into the colloid via a protein called pendrin.

An enzyme called Thyroid Peroxide converts iodide into iodine (removes the electron which is oxidation) this process is called iodide oxidation.

Thyroid peroxide then attaches iodine onto the tyrosine amino acids found on the Thyroglobulin protein that was just synthesised. In a process called iodination.

Depending on whether thyroid peroxide (TP) attached 4 or 3 iodine molecules to the the tyrosine amino acids (comes in pairs where each tyrosine can hold 2 iodine molecules). TP can either form 1 DIT (Di-iodotyrosine) and 1 MIT (mono-iodotyrosine) and fuse them to form a T3 (Triodothyronine) or form and fuse two DITs forming T4 (Thyroxine)

Question 5

After T3 and T4 are formed but confined in a bigger protein how do we get T3 and T4 into the bloodstream

Answer 5

The whole Thyroglobulin protein containing T3 and T4 get pinocytosed into the thyroid follicular cell. Lysosomes vesicles then fuse with the big protein and T3 and T4 hormones are cut out and released. T3 and T4 cannot travel in the blood alone so the liver produces a protein called Thyroxine-binding globulin (TBG) to transport them

Question 6

What is the difference between T3 and T4

Answer 6

The thyroid mainly produces 80% T4 and 20% T3

T3 has a greater potency but shorter half-life (1-3 days) while T4 has a much longer-term response and a half life of 5-7 days but much less potent.

In the the peripheral tissues such as the liver and kidneys T4 will be deiodinated to T3 to make it more potent and active

Question 7

How does being cold affect thyroid hormone production

Answer 7

Being cold have a positive effect on TRH meaning it stimulates the release of Thyrotropin-releasing hormone from the paraventricular nucleus in the hypothalamus which travels to the thyrotropes in the anterior pituitary and leads to increased TSH being produced which leads to increased tissue metabolism and heat to be produced

Question 8

What does the secretion of thyroid stimulating hormone promote/increases

Answer 8

• Increases proteolysis of stored thyroglobulin
• Increases activity of iodide pump which increases iodide trapping rate
• Increases iodination of tyrosine
• Increases size and secretory activity of thyroid cells
• Increases number of thyroid cells and infolding of follicle thyroid epithelium

Question 9

What negatively impacts secretion of TSH by the Thyrotropes

Answer 9

• Thyroid hormones (T3, T4)
• Increased tissue metabolism
• Somatostatin

Question 10

What Thyroid hormone’s mechanism of action in cells

Answer 10

T3 and T4 enter the cell via MCT8 transporter or diffusion, once it is inside the cell T4 is converted into T3 and the T3 enters the nucleus and binds to Thyroid hormone receptor which activates a complex to either turn off or turn on gene expression, depending on what the cell needs. The turning on of gene expression leads to gene transcription and translation forming proteins such as (Na/K pumps, respiratory enzymes, differing receptors, etc.)

Question 11

What is thyroid hormone’s metabolic effect

Answer 11

Question 12

Where is thyroid hormone stored?

Answer 12

Stored within the follicular lumen (colloid)

Question 13

What fundamentally causes primary hypothyroidism

Answer 13

Primary hypothyroidism is when you have a lack of T3 and T4 production because of problems in the thyroid gland such as thyroid destruction or iodine deficiency

Question 14

Describe autoimmune thyroiditis (specifically Hashimoto) and how it leads to primary hypothyroidism

Answer 14

Hashimoto’s disease is an autoimmune disease where the body produces antibodies against thyroglobulin protein (Anti-TG antibodies) and Thyroperoxidase enzyme (Anti-TPO) called Hashimoto antibodies. This usually occurs because of HLA mutations (HLA DR-3 and HLA DR-4)

SIDENOTE: Post partum can also cause primary hypothyroidism

Question 15

Common symptoms of hypothyroidism

Answer 15

Question 16

What is secondary hypothyroidism

Answer 16

In secondary hypothyroidism the problems lies with the hypothalamus or anterior pituitary gland meaning that both TSH and T3+T4 levels would be low

Question 17

How can you differentiate between primary and secondary hypothyroidism

Answer 17

In primary hypothyroidism you have low T3 & T4 levels but high TSH levels

In secondary hypothyroidism you have both low T3 & T4 levels and low TSH levels

Question 18

Example of a disease that can cause secondary hypothyroidism

Answer 18

A pituitary adenoma

Question 19

What investigations do you do for hypothyroidism (Important, especially read last part at the bottom)

Answer 19

Thyroid function test (TFTs), Initially always only test for TSH and then if it’s high test for TSH and fT4

Question 20

What is a Goiter and why does it appear in hypothyroidism

Answer 20

An enlargement of a thyroid gland that occurs because in hypothyroidism you have low T3 & T4 levels which causes TSH to increase, this leads to the thyroid follicular cells to increase in number (to compensate). TSH can also produce and store more Thyroglobulin which increases colloid amount in the thyroid gland and ultimately leads to a larger thyroid gland (Goitre)

Question 21

How do you treat hypothyroidism

Answer 21

• lifelong treatment. oral levothyroxine which is given once daily on an empty stomach, first thing in the morning, which increases T3 and T4 levels
• In adults ages 18-49 you initially give 50 - 100 micrograms once daily then increase in steps every 3-4 weeks to maintain 100 - 200 micrograms daily
• In older patients (>50 yrs) or with severe hypothyroidism you initially give 25 micrograms once daily and increase in steps of 25 micrograms every 4 weeks to maintain 50 - 200 micrograms once daily

Question 22

What fundamentally causes primary hyperthyroidism

Answer 22

• Hyper function of thyroid
• Follicle destruction (causes follicle content to be released into the blood which increases T3 and T4 levels)
• Also happens if you take too much thyroid hormone (Levothyroxine)

Question 23

What would a thyroid function test show in primary hyperthyroidism

Answer 23

High T3 and T4 levels
Low TRH and TSH levels

Question 24

Explain what happens in Grave’s disease and how it causes hyperthyroidism

Answer 24

Graves’ disease is an autoimmune disease where the bodies produce antibodies against the TSH receptors on the thyroid follicular cells, these antibodies are called Thyroid-stimulating antibodies. These antibodies bind to the TSH receptors and act like TSH which causes the follicular cells to produce T3 and T4. These antibodies are produced because of mutations in the HLA genes (HLA-DR3 and HLA-B8)

Question 25

Hashimotos disease can also cause hyperthyroidism explain how

Answer 25

Because the hashimoto antibodies are attacking the follicular cells they can eventually cause them to leak the choroid contents into the blood which leads to hyperthyroidism

Question 26

Why does a goiter appear during hyperthyroidism

Answer 26

Increased TSH hormone (or antibodies in case of Graves’ disease) can overstimulate the follicular cells to constantly produce thyroid hormones, this causes the cells to get enlarged and have small colloids, this eventually leads to hypertrophy and hyperplasia of these cells and leads to the formation of a goiter

Question 27

How does hyperthyroidism cause cardiovascular dysfunction and compare it to hypothyroidism

Answer 27

Increased T3 and T4 levels can increase the sensitivity of Beta 1 receptors on the muscles of the heart (thyroxine can lead to more beta receptors to be produced and expressed on the myocardia), this means that noradrenaline has a stronger effect on the muscles leading to higher heart rate and stronger contractility, this leads to increased systolic blood pressure and potentially diseases like AFib and Supraventricular tachycardia. In hypothyroidism low thyroid hormone levels causes decreased sensitivity and so you have lowered heart rate. Low T3 and T4 can also cause blood vessels to constrict too much leading to increased systemic resistance and DIASTOLIC HYPERtension

Question 28

What happens in secondary hyperthyroidism and how does it compare to primary hyperthyroidism

Answer 28

The issue with secondary hyperthyroidism is usually in the pituitary gland where it increases the TSH levels and causes hyperthyroidism. This means in secondary hyperthyroidism you have increased TSH and increased T3 and T4 levels whereas in primary hyperthyroidism you have increased T3 and T4 levels but low TSH levels.

Question 29

What clinical features are special to Graves’ disease

Answer 29

- Thyroid bruit which is a vascular sound of the turbulent flow of blood around the thyroid gland. This is caused by the proliferation of the blood supply to the thyroid gland when it enlarges - Thyroid eye disease (Graves’ orbitopathy) which is a swelling of the tissue in the orbit which create a bulging of the eye - Pretibial myxoedema is a skin condition where you have thick plaques of skin that are waxy or scaly as well as swelling. Typically appears on the shin

Question 30

Can hyperthyroidism be transient

Answer 30

Yes, in cases of infection the release of the contents of the choroid into the blood may cause hyperthyroidism but it can eventually go back to normal

Question 31

What are the signs and symptoms of hyperthyroidism

Answer 31

Question 32

What are the less common symptoms of hyperthyroidism

Answer 32

- Oligo/Amenorrhoea (infrequent or absent periods) - Hair loss - Sore throat

Question 33

What do you look for when potential examining someone for hyperthyroidism

Answer 33

Question 34

How would you do thyroid function test for hyperthyroidism

Answer 34

- Initially test for only serum TSH - test for BOTH fT4 and fT3 if TSH is below range - suspect subclinical hyperthyroidism if TSH is below range and T3 & T4 levels are within normal range - Repeat TFTs in 3 months to exclude transiently suppressed TSH and to confirm diagnosis (IMPORTANT)

Question 35

What further investigation can you do for hyperthyroidism

Answer 35

Question 36

How do you treat hyperthyroidism

Answer 36

The aim is to block thyroid hormonogenesis and try to restore normal thyroid hormone levels Thionamide such as: Carbimazole (main one) (which blocks actions of thyroid peroxidase) or propylthiouracil (use this if trying for pregnancy) Or u can do definitive treatment options like: Radioiodine (using radioactive iodine to destroy thyroid cells) or surgery Can also give propranolol to treat increased sympathetic effect such as tremor, anxiety, increased heart rate etc.

Question 37

What is Addison disease also known as

Answer 37

Primary adrenal insufficiency

Question 38

What layer of the adrenal gland produces aldosterone

Answer 38

Zona Glomerulosa

Question 39

What layer of the adrenal gland produces cortisol

Answer 39

Zona Fasciculata

Question 40

What layer of the adrenal gland produces androgens

Answer 40

Zona Reticularis

Question 41

What are the layers of the Adrenal gland

Answer 41

From outer to inner: - Connective tissue capsule - Zona glomerulosa - Zona fasciculata - Zona reticularis - Medulla

Question 42

How to remember what each layer produces

Answer 42

You eat a steak then dessert then have sex Steak - Aldosterone (mineralcorticoids) Dessert - Cortisol (Glucocorticoids) Sex - Androgens (DHEA, which is a precursor to many androgens (testosterone))

Question 43

What does Aldosterone do and what is it regulated by

Answer 43

Increases sodium retention, potassium excretion in the urine and regulates blood pressure Regulated by the Renin-angiotensin-aldosterone system (RAAS)

Question 44

What does cortisol do and what is it regulated by

Answer 44

Released as a stress response, it increases glucose metabolism and is anti-inflammatory Regulated by ACTH (adrenocorticotropic hormone) from anterior pituitary

Question 45

What do androgens (weak ones) do and what is it regulated by

Answer 45

Weak androgens help with pubic and axillary hair growth Regulated by ACTH (adrenocorticotropic hormone) but is less tightly regulated

Question 46

What does the medulla of the adrenal gland release

Answer 46

Adrenaline and noradrenaline (catecholamines)

Question 47

What does Adrenaline and noradrenaline do and what is it regulated by

Answer 47

Fight-or-flight response (increases heart rate, blood pressure and glucose) Regulated by the sympathetic nervous system

Question 48

Explain the Hypothalamic-pituitary-adrenal (HPA) axis

Answer 48

Stress or circadian rhythm activate the hypothalamus to release CRH (corticotropin-releasing hormone) which travels to the anterior pituitary and acts on the Corticotrope to release ACTH (adrenocorticotropic hormone) which travels to the adrenal cortex and stimulates it to release cortisol. Cortisol can then be stored in the cell as its inactive form, cortisone. High levels of cortisol in the blood has a negative effect on the hypothalamus and anterior pituitary to reduce levels of eventual cortisol production

Question 49

What is the mneumonic to help remember the diseases that occur when each layer of the adrenal gland has an overproduction of its hormone

Answer 49

Conn goes to get some Cush then get a tumor Zona glomerulosa: produces mineralcorticoids (aldosterone), in excess it causes Conn syndrome Zona fasciculata: produces glucocorticoids (cortisol) which in excess causes Cushing syndrome Zona reticularis: produces sex serious precursors which in excess cause a tumor in the Zona reticularis

Question 50

What happens when there is an underproduction of hormones in a layer of the adrenal gland and what disease do you usually get because of it (primary and secondary)

Answer 50

If there is an underproduction in any layer there is an underproduction everywhere since all the components produced are interlinked. This under activity usually gives rise to Addison’s disease as the most common disease. Infections of TB or HIV may also cause under activity Secondary underproduction is usually caused by the pituitary gland in a condition called hypopituitarism. This causes loss of ACTH hormone affecting the layers EXCEPT the Zona glomerulosa (aldosterone) because that is influenced by Renin

Question 51

What else can cause disordered production of the adrenal gland

Answer 51

Congenital adrenal hyperplasia which is when you have mutations in creating critical enzymes which can either increase or decrease production of enzymes. (C21-hydroxylase deficiency is found in 90-95% of cases)

Question 52

What’s the main symptoms of Conn’s syndrome

Answer 52

Uncontrollable increase in blood pressure that doesn’t respond to anti hypertensive medications

Question 53

Diagnostic feature of Conn’s syndrome

Answer 53

Question 54

Treatment for conn’s syndrome

Answer 54

If tumor is identified then remove it via Adrenalectomu If not caused by tumor first line treatment is spironolactone second line is eplerenone. These work as mineralcorticoids receptor antagonists

Question 55

Cushing’s syndrome, background, causes and diagnosis

Answer 55

Question 56

Cushing’s syndrome vs Cushing’s disease

Answer 56

Cushing syndrome is primary to the adrenal gland and is when you have high cortisol levels. Cushing’s disease is a subset of Cushing’s syndrome and occurs because of a pituitary tumor (so basically secondary Cushing’s syndrome)

Question 57

Other signs and symptoms of Cushing’s syndrome

Answer 57

Question 58

Classic signs of Cushing’s syndrome

Answer 58

Question 59

How do you diagnose Cushing’s syndrome and what drug do u use for confirm diagnosis

Answer 59

Cortisol dips at night time and peaks in the morning, in Cushing’s it stays high all day. So if you measure 24 hour urinary free cortisol you will be able to see if it’s Cushing’s. To fully diagnose the disease you do a low-dose dexamethadone test where u give that drug and see if it reduces cortisol. If it doesn’t suppress cortisol levels then it confirms the diagnosis

Question 60

Cushing syndrome treatment

Answer 60

Question 61

Addisons disease caused and what it does hormone levels

Answer 61

Question 62

Clinical features of primary hypoadrenalism (acute vs chronic)

Answer 62

Question 63

What are the pigmentation clinical features of addison’s and why do they happen

Answer 63

Because in addisons disease you have low cortisol, the body tries to compensate by increasing ACTH level, this in turn leads to excess of Melonocyte-stimulating hormone (MSH) causing these clinal features

Question 64

How do you diagnose addisons disease

Answer 64

Short synacthen test which is a synthetic version of ACTH, once given wait 30 mins and see if cortisol levels rise, if they don’t that means their adrenal gland isn’t working and they have addisons

Question 65

Treatment for addisons disease

Answer 65

Lifelong hydrocortisone, which is a glucocorticoid that mimics the action of cortisol, give 10 mg on waking and 5mg in mid-afternoon Mineralcorticoids replacement therapy may also be needed in which you give fludrocortisone

Question 66

What is the mutation that causes disordered adrenal production

Answer 66

C21-hydroxylase deficiency. When this enzyme is deficient it can’t convert progesterone to aldosterone which leads to low levels of aldosterone and also increased levels of androgens because the progesterone is instead converted into more androgens

Question 67

What is a phaeochromocytoma and what does it lead to

Answer 67

phaeochromocytoma is a rare catecholaamine-secreting tumor arising from the chromaffin cells in the renal medulla. If underactive it causes no syndrome but if it overactive it causes a triad of classic symptoms which are Hypertension, Throbbing bilateral headache and Palpitations

Question 68

Phaeochromocytoma diagnosis and treatment

Answer 68

Question 69

How do adrenal hormones link to mood

Answer 69

Question 70

How do adrenal hormones link to mood (one of the ILOs of case 19)

Answer 70

Question 71

What does the parathyroid secrete and what does that do

Answer 71

The parathyroid secretes parathyroid hormone from the chief cells of the parathyroid, which increases blood calcium levels by: - Stimulating osteoclasts to break down bone matrix - Increase calcium reabsorption in the kidneys leading to less calcium excretions in the urine, it then decreases phosphate reabsorptions to increase about of phosphate in urine to maintain calcium-phosphate balance - Stimulates the activation of vitamin D (into calcitriol) in the kidneys which increases calcium and phosphate absorption in the intestines -PTH lowers blood phosphate levels by promoting its excretion in the kidney

Question 72

What does calcitonin do and what is it secreted by

Answer 72

Calcitonin is released by the parafollicular cells (C-cells) of the thyroid gland and reduces blood calcium levels by: - Inhibiting osteoclast activity which reduces bone resorption - Increasing excretion of calcium in the urine by reducing calcium reabsorption in the renal tubules

Question 73

Mechanism of action of Carbimazole

Answer 73

Carbimazole blocks thyroid hormonogenesis by inhibiting the action of thyroid peroxidase, organification of iodide and their uptake by tyrosyl radicals as well as the coupling of iodotyrosines with iodothyronine residues (T3 and T4) which in turn suppress the synthesis of thyroid hormones.