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Physiology 1 > 63) Disorders of adrenocortical function > Flashcards

63) Disorders of adrenocortical function Flashcards

1
Q

What is the adrenal gland?

A
  • It is a pyramidal gland that sits above the kidney
  • It consists of a medulla (which is a separate organ) in the middle surrounded by a cortex (which is glandular in nature)
  • The medulla is a modified neural ganglion where the neurones synapse onto blood vessels where they release their neurotransmitters into the blood stream
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2
Q

What hormones are made in the cortex?

A
  • Glucocorticoids (e.g. cortisol)
  • Mineralocorticoids (e.g. aldosterone)
  • Sex steroids (e.g. testosterone)
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3
Q

What hormones are made in the medulla?

A
  • Epinephrine

- Norepinephrine

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4
Q

What are the actions of cortisol?

A
  • Increases plasma glucose levels: This is done by increasing gluconeogenesis, decreasing glucose utilisation, increasing glycogenesis and increasing glycogen storage (in the liver)
  • Increases lipolysis: This provides energy when glycogen stores are depleted
  • Non-essential proteins are catabolised: Which releases Amino Acids to repair essential structures that may be damaged (e.g. blood vessels)
  • Na+ and H2O Retention: Which maintains BP
  • Anti inflammatory: This is because during an inflammatory response strong enzymes are released to damage pathogens but can cause damage to normal tissues if uncontrolled. Therefore inflammatory response controlled to the site of infection only
  • Increased gastric acid production: Allows for a physical barrier to bad food that may be eaten (e.g. if we are hunting and have not much food)
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5
Q

What is Cushing’s syndrome?

A
  • Excess cortisol within the blood
  • It is very rare and occurs mainly in females (along with many other endocrine diseases)
  • It is often found in ages 20-40
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6
Q

What is Cushing’s disease?

A
  • Excess cortisol in the blood due to ATCH secreting pituitary tumour
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7
Q

What are the symptoms of Cushing’s syndrome as a result of changes in fat and protein metabolism?

A
  • Change in body shape
  • Central obesity
  • Moon face
  • Buffalo hump
  • Thin skin, easy bruising (this is because the skin is a non essential tissue and so is broken down)
  • Osteoporosis/ brittle bones (this is because the bones are non essential tissues and so is broken down)
  • Diabetes (This is because glucose is being mobilised)
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8
Q

How do normal stretch marks differ to those found in someone with Cushing’s syndrome?

A
  • Normally when people get stretch marks they are white as only the top layer of the skin cracks and so only the top layer of the epidermis is visible
  • However in Cushing’s syndrome, because the skin is so thin, it gets cracked down to the deep epidermal layers and so have a purplish colour
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9
Q

What are the symptoms of Cushing’s syndrome as a result of changes in sex hormones?

A
  • Excess hair growth
  • Irregular periods
  • Problems conceiving
  • Impotence (erectile dysfunction in males)
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10
Q

What are the symptoms of Cushing’s syndrome as a result of changes in salt and water retention?

A
  • High blood pressure

- Fluid retention

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11
Q

What are the psychiatric symptoms of Cushing’s syndrome?

A
  • Depression and anxiety
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12
Q

How do we investigate Cushing’s disease?

A
  • There are three steps
  • Screening: To test if the patient suffers from Cushing’s disease or not
  • Confirmation of diagnosis: To test if patients have gotten a false positive test
  • Differentiation of cause:
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13
Q

What tests do we use during the screening stage when investigating Cushing’s disease?

A
  • Urinary free cortisol: Measure the amount of cortisol in the urine. If there is excess cortisol then there is a problem
  • Diurnal rhythm: We test cortisol levels at midnight. If cortisol levels are detectable then there is a problem
  • Overnight dexamethasone suppression test: We give a tablet of dexamethasone to provide negative feedback to the brain. The next day a normal person will not have any detectable cortisol in their blood stream. If cortisol is detectable then there is a problem
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14
Q

What are the different possibilities if the screening tests for Cushing’s syndrome comes back positive?

A
  • True Cushing’s Syndrome
  • Pseudo-Cushing’s Syndrome: Where depression, alcoholism, anorexia or obesity is present. Here the patient is chronically stressed and so may have falsely raised cortisol levels but can regulate it normally
  • Exogenous Steroids: We can take a patient history to make sure they are not taking any steroid products
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15
Q

What tests do we use during the confirmation stage when investigating Cushing’s disease?

A
  • Low dose Dexamethasone Suppression testing: Instead of giving a single tablet of Dexamethasone we give a dose for two days. In normal patients the cortisol levels become undetectable (even if the patient is chronically stressed). If the cortisol levels are still detectable then it confirms that a person truly has Cushing’s syndrome
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16
Q

What are the three sources of True Cushing’s syndrome?

A
  • Cushing’s disease: Pituitary adenoma
  • Adrenal Tumour: This tumour can be benign or malignant
  • Ectopic ACTH production: Where ACTH is produced by a tumour that is not in the pituitary. Can be benign or malignant
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17
Q

How do we differentiate the cause of True Cushing’s Syndrome?

A
  • High dexamethasone suppression test: Dexamethasone is given for two days in much higher doses and cortisol levels are observed at the end of the test. If the person has a pituitary adenoma the cortisol level falls by half.
  • ACTH: If ACTH levels remain low after the dexamethasone suppression test then it may be an adrenal tumour . If ACTH levels are high after the dexamethasone suppression test then it may be ectopic ACTH (where ACTH is produced by a tumour that is not in the pituitary)
  • Imaging: After localising Cushing’s Syndrome based on the biochemistry we can then look at the imaging of the tumour
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18
Q

What is the enterochromaffin system?

A
  • Small clusters of neuroendocrine cells that can produce hormones
  • It differs from the endocrine system as hormones are made in tissues rather than in glands
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19
Q

What is POMC?

A
  • Proopiomelanocortin (POMC) is the gene for ACTH
  • POMC can undergo post-translational transformation to alter the genes expressed and so can code for many proteins (one of which is the steroid ACTH)
  • POMC is quite commonly activated in cancers as its promoter is easily turned on.
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20
Q

How does ectopic ACTH production occur?

A
  • When neuroendocrine cells become malignant.
  • POMC is quite commonly activated in cancers as its promoter is easily turned on.
  • Most cells within the body do not have the necessary equipment to transcribe POMC into ACTH
  • However if the neuroendocrine cells within the enterochromaffin system becomes malignant it already has the machinery to produce active ACTH hormone
  • This means that ectopic ACTH production can occur in a carcinoma of the lung
21
Q

What are the symptoms of ectopic ACTH production?

A
  • Hypokalaemia
  • Metabolic alkalosis
  • Hyperglycaemia
22
Q

What is the action of aldosterone?

A
  • Under normal conditions aldosterone binds to the mineralocorticoid receptors (found on the kidney) retains Na+
  • To compensate for the retention of this positive charge is by loosing a positive charge (in this case K+ or even H+ when K+ runs out)
  • Hence overstimulation of the mineralocorticoid receptor can lead to hypernatremia, hypokalaemia and metabolic alkalosis
23
Q

What is the effect of cortisol on the kidneys in day to day living?

A
  • Normally cortisol is unable to bind to the mineralocorticoid receptors
  • This is because there is an enzyme on the receptor complex (11-Beta-Hydroxysteroid Dehydrogenase 2) which destroys cortisol
  • Hence as cortisol reaches the mineralocorticoid receptors it is deactivated
24
Q

What is the effect of cortisol on the kidney in extremis (extreme circumstances?

A
  • The active site of the enzyme (11-Beta Hydroxysteroid Dehydrogenase) has a saturation point which is set a level that is higher than cortisol levels in day to day living but is lower than cortisol level produced in extremis (extreme conditions).
  • For example if we are bleeding to death and are very stressed we need the cortisol to act on mineralocorticoid receptors to retain Na+
  • This is because as there is not enough aldosterone in the circulation.
  • Hence in extremis cortisol takes over from aldosterone and causes Na+ retention.
25
Q

How does cortisol action on the kidneys differ during Cushing’s Syndrome?

A
  • In Cushing’s syndrome cortisol levels are high enough to saturate the enzyme during day to day living
  • This allows cortisol levels to stimulate the mineralocorticoid receptor without being broken down.
  • This leads to hypernatremia and hypokalaemia
26
Q

How do we determine the localisation of the cause of the Cushing’s syndrome?

A
  • Pituitary: First we look for a tumour on the MRI. If we can’t find the tumour we then do a Inferior Petrosal sinus sampling (IPSS) which uses chemical testing to look at the amount of ACTH coming from the pituitary
  • Adrenal: CT or MRI to look for the tumour
  • Ectopic: Octreotide (Nuclear) Scan and ACTH Sampling
27
Q

How do we treat the different causes of Cushing’s syndrome?

A
  • Adrenal adenoma: Surgery to remove it. To make the surgery smoother we use Cortisol Production Blockers (enzyme blockers) such as Metyrapone (inhibits 11-Beta-Hydroxysteroid Dehydrogenase) and Ketoconazole (inhibits Cytochrome P450)
  • Adrenal cancer: Radiotherapy (DXT, three field or gamma knife) or chemotherapy (CXT Mitotane)
  • Pituitary: transsphenoidal hypophysectomy (TSS) and radiotherapy (DXT) if that does not work. Following treatment patients may require replacement of other pituitary hormones too.
28
Q

Why do we need to give steroid replacement to patients with adrenal tumours?

A
  • Adrenal tumours causes reduction in ACTH production which causes the normal glands to shrink
  • When the tumour (and the source of cortisol) is removed there will be a long period of time where the gland remains too small to produce enough cortisol for the body
  • Hence we have to give steroid replacement until the body (and glands) recover
29
Q

What are the symptoms of Addison’s disease?

A 
Tiredness and Weakness
Anorexia and Weight loss
Postural hypotension
Nausea and Vomiting
Hyperpigmentation
Hyponatraemia 
Hyperkalaemia
Acidosis
Hypercalcaemia
Hypoglycaemia
30
Q

What are the causes of Addison’s disease?

A
  • Autoimmune
  • Steroid Withdrawal: When steroid therapy is given the negative feedback of the steroids and ACTH production means adrenal glands will shrink. If steroid therapy is withdrawn too quickly the gland is too small to produce cortisol for the body and the person can suffer from Addison’s disease
  • Metastases
  • Infection: For example HIV or TB
  • Enzyme defect: For example congenital Adrenal hyperplasia
  • Drugs
31
Q

How do we investigate the cause of adrenal insufficiency?

A
  • Checking cortisol and ACTH levels: If a person has primary adrenal failure cortisol levels will be low and ACTH levels will be high
  • Adrenal imaging: For example CT scans
  • Adrenal anti-bodies: To see what the cause is
  • Infection screen
  • Imaging for cancer
  • Biochemical testing for enzyme deficiency
32
Q

How do we test for adrenal insufficiency?

A
  • Short Synacthen Test: We stimulate adrenal directly by giving the patient synthetic ACTH. We measure how high the cortisol level goes. It is used to diagnose primary adrenal failure (Addison’s disease)
  • Long Synacthen Test: We stimulate the adrenal gland for a prolonged period of time by giving them synthetic ACTH and then we measure how high the cortisol level goes. Used to diagnose secondary adrenal failure (due to pituitary failure)
  • Insulin tolerance test: We make someone hypoglycaemic and observe whether that stress stimulates the release of cortisol. This stimulates the hypothalamus directly and is the gold standard for assessing adrenal axis
  • Glucagon test: We make someone hyperglycaemic and observe whether that stress stimulates the release of cortisol. It stimulates the hypothalamus directly and is performed when insulin tolerance test is contraindicated (i.e. too dangerous and cannot be carried out)
33
Q

How do we treat Addison’s disease?

A
  • Hydrocortisone: This is used to replace cortisol in adrenal failure. We try to mimic the diurnal rhythm by giving a large dose in the morning and a smaller dose during the day. There is no dose given in the evening and night time. This allow cortisol levels to fall to allow for sleep
  • Fludrocortisone: Used to replace aldosterone in primary adrenal failure.
34
Q

What is 21-hydroxysteroid deficiency?

A
  • Commonest form of Congenital Adrenal Hyperplasia (CAH)
  • It is autosomal recessive and linked with the HLA complex
    The enzyme defect occurs in the steroid synthesis pathway which causes the build up of intermediate products
  • The only end product available for these intermediate compounds to be turned into is the sex steroids (testosterone)
  • Because cortisol is not being produced there is no negative feedback to ACTH so ACTH levels become very high which means a lot of cholesterol enters the pathway and a lot of testosterone is formed
35
Q

What are the problems of having excess testosterone?

A
  • In males there are no problems caused
  • However in females there maybe virilisation of genitalia, hirsutism (excess body hair), premature adrenarche (early puberty), infertility.
  • Since there is no aldosterone being produced they have a salt-loosing crisis. They are unable to retain sodium in the kidney. As a result loose lots of sodium and water follows it into the urine. This can cause hyperkalaemia and hypertension.
36
Q

Why are there different symptoms seen in 21-hydroxylase deficiency?

A

There are milder genetic defects which reduce the action of the enzyme but don’t stop it completely
- This produces different clinical patterns (symptoms)

37
Q

What is 11-Beta hydroxylase Deficiency?

A
  • A very rare form of Congenital Adrenal Hyperplasia (CAH)
  • It is autosomal recessive and is linked to the HLA complex
  • The enzyme defect is lower in the pathway (than in 21-hydroxysteroid deficiency) and so levels of deoxycorticosterone levels are raised along with testosterone
  • Deoxycorticosterone has a partial action (like aldosterone) so is a partial mineralocorticoid receptor agonist.
  • There is no cortisol production which results in high ACTH so large amounts of testosterone and 17-OHP (leading to hypertension, hypernatremia and hypokalaemia in childhood)
38
Q

How do we investigate for 11-Beta hydroxylase Deficiency?

A
  • Synacthen Test: We would see that the cortisol levels would not rise. We can also see an increased 17OH Progesterone levels
39
Q

How do we treat 11-Beta hydroxylase Deficiency?

A
  • We aim to replace the cortisol which inhibits ACTH production and so the testosterone production reduces
  • We use long acting steroids to stop testosterone production
  • We can perform surgery on the virilised female genitalia
  • We can treat mothers during pregnancy to prevent virilisation of the foetus
  • If aldosterone is not being produced we use fludrocortisone to replace mineralocorticoids lost
40
Q

What is aldosterone?

A
  • It is a hormone that is produced in the zona glomerulosa of the adrenal cortex
  • It acts on the kidney via receptor binds glucocorticoids with equal affinity
  • It is an intranuclear receptor (type 1)
41
Q

How do the different cells within the kidneys help produce renin?

A
  • Afferent arterioles: Senses blood pressure and controls production of renin
  • Macula Densa: Detects the amount of Na+ in the glomerular filtrate and produces renin
  • Juxtaglomerular cells: Responsible for producing renin
  • These cells are all very close to each other and can effectively coordinate the production of renin
42
Q

What are the stimuli for renin secretion?

A
  • Decrease blood pressure: If perfusion pressure of the kidney decreases aldosterone levels rise to try and retain Na+ to increase blood pressure. This is detected by the afferent arterioles
  • Decrease Na+ levels: If there is a decrease in Na+ levels (sensed by the macula densa) then aldosterone levels are increased to increase circulating volume and pressure in the kidney
  • Sympathetic Nervous System activity: If the sympathetic nervous system (SNS) is activated, the body assumes that there is shock occurring and so blood pressure needs to be raised which causes aldosterone to be produced
43
Q

Describe the mechanism by which aldosterone is released

A
  • The stimuli is received by the kidneys which triggers the release of renin
  • Angiotensinogen produced in the liver is converted (by renin) to angiotensin I
  • Angiotensin Converting Enzyme (ACE) found in the blood vessels of the lungs and kidneys converts angiotensin I to angiotensin II
  • Angiotensin II acts on the adrenal gland to release aldosterone (there is also a minor control of aldosterone release by ACTH and high K+ levels)
  • Aldosterone causes expansion of extracellular fluid (extracellular fluid volume increases) and hypokalaemia
  • The effects of aldosterone reverses the stimuli to aldosterone production (however it is not a direct negative feedback mechanism) so is called a physiological negative feedback (action of the hormone takes away the stimulus)
44
Q

What are the different types of aldosterone syndromes?

A
  • Primary Excess (Conn’s Syndrome): This causes high aldosterone and low renin. This is normally caused by a benign adenoma of the adrenal gland (causing increased production of aldosterone). There are sometimes hyperplasia of the gland that does this along with aldosterone producing cancers
  • Secondary Excess: This causes high aldosterone and high renin. These can either be with hypertension or with normal blood pressure. When there is hypertension occuring there is either a renal artery stenosis, a renin secreting tumour or a malignant nephrosclerosis. When there is normal blood pressure there is either congestive cardiac failure (CCF), liver cirrhosis, nephrotic syndrome and dehydration. These are conditions associate with oedema and although the body has excess water, it is sitting in the tissue and not in the blood vessels. Which means plasma fluid levels are reduced and the kidney can only read the volume of water in the blood stream
45
Q

How is Conn’s Syndrome treated?

A
  • Surgery to remove the adenoma
  • To make it safer we might treat the aldosterone levels to make sure the potassium levels are high enough to make sure the anaesthetic is safe
  • Spironolactone/Eplerenone are used to antagonise the action of aldosterone
  • Potassium Supplementation
46
Q

What is Phaeochromocytoma?

A
  • A tumour of the enterochromaffin cells of the adrenal medullar
  • Extra adrenal pheochromocytoma occurs in sympathetic ganglia or organ of Zuckerkandl (which lies behind the aorta)
  • They produce catecholamines such as epinephrine, norepinephrine and dopamine
  • They are most commonly due to inherited germline mutations or associated with somatic mutations
47
Q

What are the symptoms of Phaeochromocytoma?

A
  • Sweating
  • Headache
  • Tachycardia
  • Anxiety
  • Fever
  • Hypertension
  • Constipation and abdominal pain
  • Fits
  • Visual disturbance
  • Hypotension (in some cases)
48
Q

How do we investigate Constipation phaeochromocytoma?

A
  • We look at the breakdown products of the catecholamines and the metanephrines in the urine.
  • Once these levels are raised we look at imaging to try and find out where the tumour is
  • This can be done via a CT or an MRI
49
Q

How do we manage pheochromocytoma?

A
  • Alpha blockade: Alpha receptors cause an increase in blood pressure when stimulated (can lead to stroke). We can use non-competitive alpha antagonist which destroy the receptor and so if there is a large rise in adrenaline they will have no effect. Competitive alpha antagonists may also be given
  • Beta blockade: Beta receptors cause an increase in heart rate. We can use non-selective beta blockers
  • Fluid resuscitation
  • Surgery: To remove the gland with the tumour

Physiology 1 (64 decks)

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