Disorders of Adrenocortical Dysfunction Flashcards
(98 cards)
1
Q
Where is the adrenal gland located?
A
Adrenal gland sits above kidney
2
Q
What is the adrenal cortex composed of?
A
The adrenal cortex is glandular tissue and has 3 layers that surround and envelop the adrenal medulla
3
Q
What are the 3 layers of the adrenal cortex?
A
Outermost - zona glomerulosa : aldosterone (mineralocorticoids)
Medial layer- zona fasciculata : cortisol (glucocorticoids)
Innermost - zona reticularis : testosterone (sex steroids)
4
Q
What is the adrenal medulla?
A
The adrenal medulla is a modified ganglion
5
Q
What is the function of the adrenal medulla cells?
A
Adrenal medulla cells (like posterior pituitary) are neuronally derived and secrete their neurotransmitters directly into circulation
6
Q
Which hormones are produced at the inner regional medulla?
A
adrenaline (epinephrine)
noradrenaline (norepinephrine)
7
Q
Which areas of the body produce noradrenaline?
A
Inner regional medulla and Sympathetic nervous system
8
Q
Why is adrenaline only formed in the inner adrenal medulla?
A
O’methyltransferase enzyme only present in adrenal medulla to methylate noradrenaline to form adrenaline
9
Q
Which enzyme is responsible for the production of aldosterone and cortisol?
A
21 hydroxylase is only produced in the adrenal so aldosterone and cortisol are only produced in adrenals
10
Q
Which hormone is produced in the ovaries during the first half of the menstrual cycle?
A
In 1st half of menstrual cycle large quantities of testosterone are formed as the enzymes required are available.
11
Q
What is the role of aromatase enzyme?
A
Aromatase enzyme is also produced in the ovary converting testosterone → oestradiol (oestrogens)
12
Q
What is the major hormone produced in the second half of the menstrual cycle?
A
Progesterone:
In 2nd half of menstrual cycle 17’OH enzyme is down-regulated => progesterone is major outcome not cortisol
13
Q
Why is testosterone not the major androgen in males?
A
Testosterone isn’t a major androgen in males; 5-alpha reductase converts testosterone → dihydrotestosterone which is the major male androgen (reducing testosterone quantity)
14
Q
Apart from the gonads, where else are androgens expressed?
A
Androgen enzymes are also expressed in adrenals
15
Q
What causes Congenital Adrenal Hyperplasia? (CAH)
A
Defects in the synthesis pathway in the ovaries due to 11-beta’OH defect -> decreased aldosterone or cortisol production
- androgens produced instead as only other available pathway
16
Q
What is the effect of CAH on female?
A
will become genetically XY even though female as adrenal glands can’t produce aldosterone and cortisol ∴ produce androgens
=> virilized genitals
17
Q
What are the actions of cortisol on glucose levels?
A
Increases plasma glucose levels
- Inc gluconeogenesis
- Dec glucose utilisation
- Increases glycogenesis
- Inc glycogen storage
18
Q
What is the cortisol effect on lipids?
A
Increases lipolysis
- Provides energy
19
Q
What effect does cortisol have on proteins?
A
Proteins are catabolised
- Releases Amino Acids
20
Q
How does cortisol effect BP?
A
Na+ and H2O Retention
- Maintains BP
21
Q
What other systemic effects does cortisol produce?
A
Anti inflammatory
Increased gastric acid production
22
Q
What is Cushing’s syndrome?
A
Chronic exposure to excessive levels of CORTISOL in the blood
23
Q
What is the occurrence of Cushing’s syndrome?
A
Incidence is 2/1 000 000 population
3-15:1 female : male
Onset at 20-40 years old
24
Q
What is Cushing’s disease?
A
Excess cortisol in blood due to ACTH secreting pituitary tumour (adenoma) -> cause of Cushing’s syndrome
25
What are the clinical features of Cushing's disease?
Excess hair growth
Irregular periods
Problems conceiving
Impotence
26
What is the effect of Cushing's disease on Sat and water retention?
Salt and water retention occurs causing:
High blood pressure
Fluid retention
27
What are the 3 stages of Cushing's disease investigation?
Screening
Confirmation of the Diagnosis
Differentiation of the Cause
28
How do we screen and confirm diagnosis of Cushing's?
Urinary free cortisol
Diurnal Rhythm
Overnight dexamethasone suppression testing
29
How does cortisol production vary over 24 hours?
Normal Cortisol response: variable hormone
Peaks in morning
At night is undetectable
30
How can we use circadian rhythm of cortisol to detect abnormality?
If cortisol present at midnight (lowest point) can tell abnormal production is occurring
31
How is urine used to determine abnormality in cortisol production?
Renal threshold for cortisol is 3-5% freely filtered in urine
With tumours, urine would show increased cortisol in urine as more production during the day
32
Why is more cortisol not administered to negatively feedback and stop production?
we can’t differentiate between the administered cortisol and the cortisol produced by the body so we use dexamethasone
33
Describe the Overnight low dose dexamethasone suppression test
Cortisol is measured at 8am
Dexamethasone 1mg is given at 11pm
Cortisol is measured at 8am the next morning
Cortisol suppression to <50 nmol/l is normal
34
What are the potential differential diagnosis?
- True Cushing's Syndrome
- Pseudo Cushing's Syndrome
- Exogenous Steroids
35
Which daily products (exogenous steroids) could be causing Cushing's effects?
```
Any one of the following products can contain steroids:
Inhalers
Eyedrops
Nasal Drops
Skin Creams
Health Food Shops
```
36
How are exogenous steroids ruled out?
Take a history of steroid containing substances to rule out exogenous steroids leaving with possibility of Pseudo Cushing's / True Cushing’s syndrome
37
What is pseudo cushing's syndrome?
High cortisol due to:
- Depression
- Alcoholism
- Anorexia Nervosa
- Obesity
38
How is pseudo Cushing's syndrome ruled out?
A low dose of dexamethasone is instead given to rule out people with chronic stress and pseudocushing’s dexamethasone suppression test
39
Outline the LOW DOSE dexamethasone suppression test
LOW DOSE :
0.5 mg Dexamethasone six-hourly, 48 hrs
Result: complete suppression in normal subject
If cortisol detectable then patient has CUSHING’S SYNDROME
40
What could be the potential causes of the True Cushing's syndrome?
Cushing’s Disease
Pituitary Adenoma producing ACTH → adrenal producing cortisol
Adrenal Tumour (Benign/Malignant)
Ectopic ACTH production (Benign/Malignant)
41
What is the enterochromaffin system?
clusters of neuroendocrine cells throughout the body
42
How can Enterochromaffin cells cause increased Cortisol?
These can sometimes express the gene for ACTH (if malignant) that can lead to cortisol production not initiated from the brain
43
How can we determine the cause of Cushing's syndrome?
- High dose Dexamethasone Suppression testing
- ACTH
- Imaging
44
Outline the HIGH DOSE dexamethasone suppression test
HIGH DOSE
2 mg Dexamethasone six-hourly for 48 hrs
RESULTS:
If cortisol suppresses to < 50% of baseline then the patient has Pituitary dependent Cushing’s Disease
If the Cortisol does not suppress then the patient has ectopic ACTH production or an adrenal tumour
45
How can we differentiate between ectopic ACTH or an Adrenal tumour?
Low ACTH:
- Adrenal Tumour
- Benign
- Malignant
High ACTH:
- Ectopic ACTH Production
- Benign
- Malignant
46
What are the metabolic effects of Cushing's?
Hypokalaemia
Metabolic Alkalosis
Hyperglycaemia
47
How does aldosterone achieve its effects in the kidneys?
By binding to mineralocorticoids receptors to retain Na+ in exchange for K+.
48
How are metabolic effects achieved via aldosterone?
H+ can also be removed with K+ using the same mechanism (mineralocorticoid receptor) => metabolic changes
- Hypernatremia
- Metabolic alkalosis
- Hypokalaemia
49
Explain how cortisol is a competitive agonist of aldosterone?
Cortisol is 10x more abundant in plasma and can also bind to mineralocorticoid receptor with equal affinity to aldosterone
50
How is aldosterone the major hormone bound to mineralocorticoid receptors despite cortisol having same affinity?
11-beta Hydroxysteroid Dehydrogenase 2 is part of the mineralocorticoid receptor complex and converts cortisol → cortisone during normal physiology allowing only aldosterone to bind
51
How does cortisol bind to the mineralocorticoid receptor when levels are high?
The active site saturation point is set to a higher level than normal cortisol levels but is just below extreme cortisol levels
52
How is everyday BP controlled?
BP control achieved by aldosterone day to day
53
How does cortisol aid BP regulation during haemorrhage?
maximum stimulation of mineralocorticoid receptor to retain maximum Na+. Cortisol levels rise so high blocking active site of the enzyme, allowing cortisol to access the receptor itself - stress response activates all mineralocorticoid receptors to achieve maximum Na+ retention
54
When else does Cortisol aid Na+ retention?
During Cushing's syndrome
55
What is the precursor of ACTH?
POMC
56
What are the products of POMC?
ACTH -> alpha-MSH / CLIP
| Beta-LPH -> beta-MSH/Beta-endorphin
57
What are the functions of beta-LPH?
beta-LPH increases action of T-helper cells and Natural killer cells
58
What is the function of alpha-MSH?
Alpha-MSH appetite suppressant hormone and causes pigmentation
59
How much alpha-MSH is produced for every mol of ACTH?
1 mol ACTH released = 1 mol alpha-MSH
60
How is a CRH test used to identify Pituitary dependent Cushing's Syndrome?
0.1 µg/kg of human CRH is given
Blood is assayed for ACTH and cortisol at time -15, 0, 15, 30, 60, 90, 120.
An exaggerated response indicates pituitary dependant Cushing’s Disease
A flat response indicates ectopic ACTH production
61
What is the normal response to ACTH administration?
Normal response to CRH administration => ACH in blood doubles
62
If an adrenal tumour is present, what would CRH administration show?
Adrenal Tumour: CRH causes ACTH suppression => overproduction of cortisol means they cannot respond to CRH so remains suppressed
63
What would the result of CRH on ectopic ACTH?
Ectopic ACTH = ↑ACTH but doesn’t respond to CRH as not in pituitary
64
How can we use imaging to localise the tumour causing ↑ACTH ?
Pituitary
- MRI
- IPSS
Adrenal
- CT or MRI
Ectopic
- Octreotide Scan
- ACTH Sampling
65
How is Cushing's syndrome treated?
```
SURGERY
Cortisol Production Blockers
Metyrapone
Ketoconazole
DXT three field or gamma knife
Following treatment patients may require replacement of other pituitary hormones too
```
66
How is a pituitary tumour causing Cushing's treated?
Pituitary
| surgery: Transsphenoidal Hypophysectomy
67
How is an adrenal source causing Cushing's treated?
Adrenal source
- Removal of adrenal tumour
Patients need steroid replacement tablets at time of and following surgery
Adrenal tumour suppresses gland function
Many won't need steroid tablets long term
68
What are the clinical features of Addison's disease?
*opposite of Cushing's
```
Hyponatraemia
Hyperkalaemia
Acidosis
Hypercalcaemia
Hypoglycaemia
Increased urea and creatinine
Eosinophilia
Lymphocytosis
Tiredness
Weakness
Anorexia
Weight loss
Postural hypotension
Myalgia
Salt Craving
Nausea Vomiting
Hyperpigmentation
Vitiligo
```
69
What are the causes of Addison's disease?
```
Autoimmune
TB
Steroid Withdrawal
Metastases
Infiltration
- Amyloid/Haemochromatosis
Waterhouse- Freidrichson
Apoplexy
Infection: Fungal/viral
Enzyme defect
- Congenital Adrenal hyperplasia
- Adrenolucodystrophy
- Adrenomyolneuropathy
Drugs
```
70
How do we investigate Addison's?
Investigate by administering synthetic ACTH and seeing if gland produces cortisol
- This doesn’t take into account brain activity (stress → cortisol)
71
What other tests are used to determine Addison's disease?
Insulin tolerance test → test hypothalamic function at cortisol production
Glucagon regulates hypoglycemic effects so glucagon tolerance test can also be used
72
How is Addison's treated?
Hydrocortisone
| Fludrocortisone
73
Outline the dose of Fludrocortisone administered for Addison's?
50-200 mcg o.d.
74
What would be the dosage of Hydrocortisone administered for Addison's disease?
Hydrocortisone
- 10mg 5mg 5mg
- Mimics the diurnal rhythm
- Last dose before 6pm
75
What is classical CAH?
```
21-hydroxylase Deficiency
Commonest form of CAH
Incidence 1:10 000 live births
Autosomal recessive
HLA linked: HLA-A3, Bw47,DR7
Increased incidence in Yupik Eskimos
```
76
How does 21'OH deficiency cause clinical CAH?
21’OH deficiency causes a rise in 17’OHP intermediate - can’t produce cortisol
=> no -ve feedback to ACTH
ACTH forces large amounts of cholesterol through synthesis pathway
Pathway converts intermediates to sex steroids as other pathways unavailable to maintain balance
77
How does sexual differentiation occur ?
Genetically - XY
| To be male, foetus testus has to produce testosterone to masculine the genitalia
78
How does 21'Oh deficiency (CAH) cause a defect in sexual differentiation?
Child genetically XX overproduces testosterone during genital differentiation becoming XY
79
What are the effects of 21'OH deficiency (classical CAH)?
Excess sex steroids cause:
virilisation, hirsutism, premature adrenarche, infertility
No aldosterone, hence salt-losing crisis
- hyperkalaemia, hypotension
80
What is non-classical CAH?
```
11β-hydroxylase Deficiency
Approx 5% of reported CAH.
Incidence 0.5:100 000 live births
Autosomal recessive
Increased in Moroccan Jews (1:6000 live births)
HLA linked
- HLA-B14,DR1
```
81
How does 11β-hydroxylase deficiency cause CAH?
17’OHP levels raised producing excess sex steroids masculinisaing body
Deoxycorticosterone is also raised and has partial aldosterone action
82
What is the major symptom of non-classical CAH in children?
Instead of presenting with circulatory collapsing in infancy present with hypertension in childhood
83
What are the clinical effects of non-classical CAH?
Excess sex steroids
virilisation, hirsutism, premature adrenarche, infertility
No aldosterone but high DOC, which is an agonist at MC receptors
hypertension and hypokalaemia
84
What are the 2 ways of investigating CAH?
Synacthen
- No cortisol rise
- Increased 17OH Progesterone levels
Prednisolone suppression
- Androgens should fall into normal range
85
How is CAH treated?
Both CAH are s spectrum of disease – partial deficiencies complicate matters
Rx of 11β- and 21'OH deficiency lies mainly in use of glucocorticoid therapy
Surgery to virilised female genitalia
Treatment of Mother to prevent foetal Virilisation
Fludrocortisone is used only in 21'OH deficiency to replace absent mineralocorticoid activity
86
Outline the features of aldosterone
Produced in the zona glomerulosa of the adrenal cortex
Acts on the kidney via receptor binds glucocorticoids with equal affinity
Intranuclear receptor (type 1)
87
How is aldosterone release regulated?
Control of aldosterone is va renin production in kidneys
88
Where is renin produced?
JGA cells
89
What stimulates aldosterone release?
Low BP in afferent arteriole
Low Na in DCT and macula densa
Increased symp. activity => renin release
=> increases flow of blood to kidney to raise BP and Na+ retention
90
Summarise the production and effects of aldosterone
Renin converts angiotensinogen → AG1
AG1 circulate sbody and in lungs ACE converts it to AGII
AGII acts on adrenal to release aldosterone
Aldosterone causes Na+ retention and decreased K+ = -ve feedback
ACTH and K+ can also stimulate aldosterone
91
What is the effects of primary excess of aldosterone?
Conn’s Syndrome
Bilateral Adrenal Hyperplasia
Steroid Treatable hypertension
Aldosterone producing adrenal carcinoma
92
What are the effects of secondary excess aldosterone with hypertension?
Renal artery stenosis
Renin Secreting Tumour
Malignant nephrosclerosis
93
What are the effects of secondary excess aldosterone with normal BP?
CCF
Cirrhosis
Nephrotic syndrome
Dehydration
94
What is the treatment for Conn's syndrome?
Spironolactone
Amiloride / Triampterine
Potassium Supplementation
Treatment of the Primary Tumour
95
What is Pheochromocytoma?
Rare tumour of enterochromaffin cells of the adrenal medulla results in excess release of dopamine, epinephrine and norepinephrine
=> hormones that control HR, metabolism, and BP
96
What are the sympotms and side effects of Pheochromocytoma?
```
Constipation
Abdominal Pain
Headache
Fits
Visual disturbance
Pallor or Flushing
Sweating
Anxiety
Fever
Paroxysmal hypertension
Palpitation
(Hypotension)
Angor aminii
```
97
What are the metabolic effects of pheochromocytoma?
```
Eosinophilia
Hyperglycaemia
Hypercalcaemia
Raised urinary
Metanephrines
Catecholamines
```
98
How is pheochromocytoma managed?
```
Emergency
Alpha blockade as causes Vasoconstriction
Non competitive alpha antagonist
Phenoxybenzamine phentolamine
Beta blockade as normally causes vasodilation
Nonselective beta blocker
Propranolol
Fluid Resuscitation
Surgery
```
*block alpha receptors first
