Catecholamines

Question 1

What supplies the adrenal medulla?

Answer 1

1. Superior
2. Middle
3. Inferior arteries

• These divide to form medullary, cortical and capsular arterioles
• Cortical arteries also supply medulla to deliver corticosteroids

Question 2

What veins drain the adrenal gland?

Answer 2

1. Medullary venules drain to central vein
2. Left adrenal vein drains to left renal vein
3. Right adrenal vein to inferior vena cava

Question 3

What do the granules of chromaffin cells contain?

Answer 3

1. ATP
2. POMC products
3. Chromoganin
4. Catecholamines

Question 4

Describe the formation of catecholamines?

Answer 4

1. Tyrosine is taken up into the cell and converted to DOPA by tyrosine hydroxylase (occurs in cytoplasm –> rate limiting step)
2. DOPA is converted to dopamine by DOPA decarboxylase (cytoplasm)
3. Dopamine converted to NA by dopamine hydroxylase (granules –> store for future use)
4. NA released back into cytoplasm and converted to adrenaline by PNMT

• PNMT expression depends on high [cortisol] that are only present in adrenal medulla because of the drainage of venous blood from outer adrenal cortex*
• (cortical arteries passing blood to central vein)*

Question 5

What is PNMT expression increased by?

Answer 5

1. Sympathetic neural outout
2. Glucocorticoids

NB. NA neurones lack PNMT

Question 6

What induces the rate limiting step of synthesis?

Answer 6

Acute sympathetic stimulation

Question 7

What activates an increase in tyrosine hydroxylase :. increases catecholamines production

Answer 7

Chronic stimulation

Question 8

What are NA and A broken down by and what are their waste products?

Answer 8

1. MOA and COMT
2. Metanephrine and VMA (adrenaline and NA)

When look at excess production of catecholamines look at conc. of these waste products as easily detected in urine and blood (broken down quickly)

Question 9

What do adrenaline and NA conc. depend on:

Answer 9

1. Synthesis and secretion
2. Uptake and metabolism - controlled by post-ganglionic endocytosis

Uptake is more imp. than metabolism because syntheses and secretion not on as high metabolic control (as NA and A are pre-formed)

Question 10

What would you give after an adrenalectomy or destruction of medulla?

Answer 10

1. Corticosteroid replacement

Adrenaline is short term axis with short half life so easier to administer cortisol as long half life and is a long term axis

Question 11

What kind of hormones can pheochromocytomas secrete?

Answer 11

• NA
• Adrenaline
• Dopamine
• VMA
• Metanephrines

NB. See increase in both NA and A (as can overproduce both)

Question 12

What is the difference between an extra-adrenal paraganglioma and intra-adrenal paraganglioma?

Answer 12

1. Chromaffin cells outside medulla
2. Chromafin cells inside medulla (e.g. pheochromocytoma)

Question 13

Where do extra-adrenal pheochromocytomas arise?

Answer 13

1. in abdomen arise around inferior mesenteric artery (organ of Zuckerland)
2. Aortic bifurcation

Question 14

What is the epidemiology of pheochromocytomas?

Answer 14

1. Most are sporadic, unicentric and unilateral when in medulla
2. 20-30% are familial, multicentric and bilateral

Question 15

How would you diagnose pheocytochromas?

Answer 15

1. Release is episodic so do assay of 24hr urine sample
2. Imaging with uptake scans with meta-iodobenzylguanidine (mIBG)
3. Also MRI/PET scanning

Question 16

What are the steps for surgical prep for pheochromocytoma removal?

Answer 16

Question 17

Why do you use phenoxybenzamine for preoperative management?

Answer 17

• Non-competitive alpha blockade
• Doxazosin is competitive so can be displaced by high conc. of endogenous catecholamines
• Side effects of phenoxybenzamine:

1. Nasal congestion
2. Drowsiness
3. Fatigue
4. Postural hypotension

Question 18

What are medications which can provoke hypertensive crisis in patients with pheochromocytoma?

Answer 18

1. D2 dopamine receptor antagonists
2. Non cardioselective beta blockers
3. TCAs
4. NT uptake blockers
5. Sympathomimetics

Question 19

Why is fluid replacement done 10 days before surgery?

Answer 19

1. Blood volume depletion as a result of continued high BP can contribute to hypotension and shock
2. Clamping venous drainage of the tumour during surgery can cause abrupt reversal of catecholamines-induced vasoconstriction

Question 20

What else must be considered before doing surgery?

Answer 20

1. Catecholamine-induced cardiomyopathy
2. Arrythmias

Question 21

What are MEN?

Answer 21

1. Autosomal dominant mutations
2. MENIN gene - tumour supressor gene
3. RET gene - proto-oncogene

Question 22

What is MEN type I defined by?

Answer 22

• 4 parathyroid glands
• Pancreatic islets – e.g. gastrinoma, insulinoma, glucagonoma, vasoactive intestinal peptide tumor (VIPoma), pancreatic polypeptide– producing tumor (PPoma)
• Anterior pituitary – e.g. prolactinoma, somatotropinoma, corticotropinoma, nonfunctioning tumors
• Other associated tumors include lipomas, angiofibromas, and those located in the adrenal gland cortex (rarely, in the adrenal medulla).

Question 23

What is MEN type IIa defined by?

Answer 23

1. Medullary thyroid carcinoma (MTC)
2. Pheochromocytoma (~50% of cases)
3. Hyperparathyroidism caused by parathyroid gland hyperplasia (~20% of cases).

However, familial MTC is also recognized. Familial MTC is hereditary MTC without other associated endocrinopathies

Question 24

What is MEN type IIb defined by?

Answer 24

1. MTC and pheochromocytoma
2. Associated abnormalities include:
   
   • mucosal neuromas
   • medullated corneal nerve fibers
   • marfanoid habitus.

Question 25

What is the most common manifestation of Type 1 MEN?

Answer 25

Hyperparathyroidism

Question 26

What are the symptoms of a pheochromocytoma?

Answer 26

1. Extreme hypertension
2. Sweating
3. Flushing
4. Palpitations
5. Nausea

Question 27

What should be evaluated when diagnosing pheocytochromocytomas?

Answer 27

1. Plasma free metanephrines
2. 24 hour urine for catecholamines/metanephrines