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Endocrinology > Disorders of Adrenocortical Dysfunction > Flashcards

Disorders of Adrenocortical Dysfunction Flashcards

1
Q

Where is the adrenal gland located?

A

Adrenal gland sits above kidney

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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

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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)

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4
Q

What is the adrenal medulla?

A

The adrenal medulla is a modified ganglion

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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

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6
Q

Which hormones are produced at the inner regional medulla?

A

adrenaline (epinephrine)

noradrenaline (norepinephrine)

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7
Q

Which areas of the body produce noradrenaline?

A

Inner regional medulla and Sympathetic nervous system

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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

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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

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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.

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11
Q

What is the role of aromatase enzyme?

A

Aromatase enzyme is also produced in the ovary converting testosterone → oestradiol (oestrogens)

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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

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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)

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14
Q

Apart from the gonads, where else are androgens expressed?

A

Androgen enzymes are also expressed in adrenals

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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

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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

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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
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18
Q

What is the cortisol effect on lipids?

A

Increases lipolysis

- Provides energy

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19
Q

What effect does cortisol have on proteins?

A

Proteins are catabolised

- Releases Amino Acids

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20
Q

How does cortisol effect BP?

A

Na+ and H2O Retention

- Maintains BP

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21
Q

What other systemic effects does cortisol produce?

A

Anti inflammatory

Increased gastric acid production

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22
Q

What is Cushing’s syndrome?

A

Chronic exposure to excessive levels of CORTISOL in the blood

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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

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24
Q

What is Cushing’s disease?

A

Excess cortisol in blood due to ACTH secreting pituitary tumour (adenoma) -> cause of Cushing’s syndrome

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25
Q

What are the clinical features of Cushing’s disease?

A

Excess hair growth
Irregular periods
Problems conceiving
Impotence

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26
Q

What is the effect of Cushing’s disease on Sat and water retention?

A

Salt and water retention occurs causing:
High blood pressure
Fluid retention

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27
Q

What are the 3 stages of Cushing’s disease investigation?

A

Screening
Confirmation of the Diagnosis
Differentiation of the Cause

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28
Q

How do we screen and confirm diagnosis of Cushing’s?

A

Urinary free cortisol
Diurnal Rhythm
Overnight dexamethasone suppression testing

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29
Q

How does cortisol production vary over 24 hours?

A

Normal Cortisol response: variable hormone
Peaks in morning
At night is undetectable

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30
Q

How can we use circadian rhythm of cortisol to detect abnormality?

A

If cortisol present at midnight (lowest point) can tell abnormal production is occurring

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31
Q

How is urine used to determine abnormality in cortisol production?

A

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

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32
Q

Why is more cortisol not administered to negatively feedback and stop production?

A

we can’t differentiate between the administered cortisol and the cortisol produced by the body so we use dexamethasone

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33
Q

Describe the Overnight low dose dexamethasone suppression test

A

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

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34
Q

What are the potential differential diagnosis?

A
  • True Cushing’s Syndrome
  • Pseudo Cushing’s Syndrome
  • Exogenous Steroids
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35
Q

Which daily products (exogenous steroids) could be causing Cushing’s effects?

A 
Any one of the following products can contain steroids:
Inhalers
Eyedrops
Nasal Drops
Skin Creams
Health Food Shops
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36
Q

How are exogenous steroids ruled out?

A

Take a history of steroid containing substances to rule out exogenous steroids leaving with possibility of Pseudo Cushing’s / True Cushing’s syndrome

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37
Q

What is pseudo cushing’s syndrome?

A

High cortisol due to:

  • Depression
  • Alcoholism
  • Anorexia Nervosa
  • Obesity
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38
Q

How is pseudo Cushing’s syndrome ruled out?

A

A low dose of dexamethasone is instead given to rule out people with chronic stress and pseudocushing’s dexamethasone suppression test

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39
Q

Outline the LOW DOSE dexamethasone suppression test

A

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

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40
Q

What could be the potential causes of the True Cushing’s syndrome?

A

Cushing’s Disease
Pituitary Adenoma producing ACTH → adrenal producing cortisol

Adrenal Tumour (Benign/Malignant)

Ectopic ACTH production (Benign/Malignant)

41
Q

What is the enterochromaffin system?

A

clusters of neuroendocrine cells throughout the body

42
Q

How can Enterochromaffin cells cause increased Cortisol?

A

These can sometimes express the gene for ACTH (if malignant) that can lead to cortisol production not initiated from the brain

43
Q

How can we determine the cause of Cushing’s syndrome?

A
  • High dose Dexamethasone Suppression testing
  • ACTH
  • Imaging
44
Q

Outline the HIGH DOSE dexamethasone suppression test

A

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
Q

How can we differentiate between ectopic ACTH or an Adrenal tumour?

A

Low ACTH:

  • Adrenal Tumour
  • Benign
  • Malignant

High ACTH:

  • Ectopic ACTH Production
  • Benign
  • Malignant
46
Q

What are the metabolic effects of Cushing’s?

A

Hypokalaemia
Metabolic Alkalosis
Hyperglycaemia

47
Q

How does aldosterone achieve its effects in the kidneys?

A

By binding to mineralocorticoids receptors to retain Na+ in exchange for K+.

48
Q

How are metabolic effects achieved via aldosterone?

A

H+ can also be removed with K+ using the same mechanism (mineralocorticoid receptor) => metabolic changes

  • Hypernatremia
  • Metabolic alkalosis
  • Hypokalaemia
49
Q

Explain how cortisol is a competitive agonist of aldosterone?

A

Cortisol is 10x more abundant in plasma and can also bind to mineralocorticoid receptor with equal affinity to aldosterone

50
Q

How is aldosterone the major hormone bound to mineralocorticoid receptors despite cortisol having same affinity?

A

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
Q

How does cortisol bind to the mineralocorticoid receptor when levels are high?

A

The active site saturation point is set to a higher level than normal cortisol levels but is just below extreme cortisol levels

52
Q

How is everyday BP controlled?

A

BP control achieved by aldosterone day to day

53
Q

How does cortisol aid BP regulation during haemorrhage?

A

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
Q

When else does Cortisol aid Na+ retention?

A

During Cushing’s syndrome

55
Q

What is the precursor of ACTH?

A

POMC

56
Q

What are the products of POMC?

A

ACTH -> alpha-MSH / CLIP

Beta-LPH -> beta-MSH/Beta-endorphin

57
Q

What are the functions of beta-LPH?

A

beta-LPH increases action of T-helper cells and Natural killer cells

58
Q

What is the function of alpha-MSH?

A

Alpha-MSH appetite suppressant hormone and causes pigmentation

59
Q

How much alpha-MSH is produced for every mol of ACTH?

A

1 mol ACTH released = 1 mol alpha-MSH

60
Q

How is a CRH test used to identify Pituitary dependent Cushing’s Syndrome?

A

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
Q

What is the normal response to ACTH administration?

A

Normal response to CRH administration => ACH in blood doubles

62
Q

If an adrenal tumour is present, what would CRH administration show?

A

Adrenal Tumour: CRH causes ACTH suppression => overproduction of cortisol means they cannot respond to CRH so remains suppressed

63
Q

What would the result of CRH on ectopic ACTH?

A

Ectopic ACTH = ↑ACTH but doesn’t respond to CRH as not in pituitary

64
Q

How can we use imaging to localise the tumour causing ↑ACTH ?

A

Pituitary

  • MRI
  • IPSS

Adrenal
- CT or MRI

Ectopic

  • Octreotide Scan
  • ACTH Sampling
65
Q

How is Cushing’s syndrome treated?

A 
SURGERY
Cortisol Production Blockers
Metyrapone
Ketoconazole
DXT  three field or  gamma knife
Following treatment patients may require replacement of other pituitary hormones too
66
Q

How is a pituitary tumour causing Cushing’s treated?

A

Pituitary

surgery: Transsphenoidal Hypophysectomy

67
Q

How is an adrenal source causing Cushing’s treated?

A

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
Q

What are the clinical features of Addison’s disease?

A

*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
Q

What are the causes of Addison’s disease?

A 
Autoimmune
TB
Steroid Withdrawal
Metastases
Infiltration
- Amyloid/Haemochromatosis 
Waterhouse- Freidrichson
Apoplexy 
Infection: Fungal/viral
Enzyme defect
- Congenital Adrenal hyperplasia
- Adrenolucodystrophy
- Adrenomyolneuropathy
Drugs
70
Q

How do we investigate Addison’s?

A

Investigate by administering synthetic ACTH and seeing if gland produces cortisol
- This doesn’t take into account brain activity (stress → cortisol)

71
Q

What other tests are used to determine Addison’s disease?

A

Insulin tolerance test → test hypothalamic function at cortisol production

Glucagon regulates hypoglycemic effects so glucagon tolerance test can also be used

72
Q

How is Addison’s treated?

A

Hydrocortisone

Fludrocortisone

73
Q

Outline the dose of Fludrocortisone administered for Addison’s?

A

50-200 mcg o.d.

74
Q

What would be the dosage of Hydrocortisone administered for Addison’s disease?

A

Hydrocortisone

  • 10mg 5mg 5mg
  • Mimics the diurnal rhythm
  • Last dose before 6pm
75
Q

What is classical CAH?

A 
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
Q

How does 21’OH deficiency cause clinical CAH?

A

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
Q

How does sexual differentiation occur ?

A

Genetically - XY

To be male, foetus testus has to produce testosterone to masculine the genitalia

78
Q

How does 21’Oh deficiency (CAH) cause a defect in sexual differentiation?

A

Child genetically XX overproduces testosterone during genital differentiation becoming XY

79
Q

What are the effects of 21’OH deficiency (classical CAH)?

A

Excess sex steroids cause:
virilisation, hirsutism, premature adrenarche, infertility

No aldosterone, hence salt-losing crisis
- hyperkalaemia, hypotension

80
Q

What is non-classical CAH?

A 
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
Q

How does 11β-hydroxylase deficiency cause CAH?

A

17’OHP levels raised producing excess sex steroids masculinisaing body

Deoxycorticosterone is also raised and has partial aldosterone action

82
Q

What is the major symptom of non-classical CAH in children?

A

Instead of presenting with circulatory collapsing in infancy present with hypertension in childhood

83
Q

What are the clinical effects of non-classical CAH?

A

Excess sex steroids
virilisation, hirsutism, premature adrenarche, infertility

No aldosterone but high DOC, which is an agonist at MC receptors
hypertension and hypokalaemia

84
Q

What are the 2 ways of investigating CAH?

A

Synacthen

  • No cortisol rise
  • Increased 17OH Progesterone levels

Prednisolone suppression
- Androgens should fall into normal range

85
Q

How is CAH treated?

A

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
Q

Outline the features of aldosterone

A

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
Q

How is aldosterone release regulated?

A

Control of aldosterone is va renin production in kidneys

88
Q

Where is renin produced?

A

JGA cells

89
Q

What stimulates aldosterone release?

A

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
Q

Summarise the production and effects of aldosterone

A

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
Q

What is the effects of primary excess of aldosterone?

A

Conn’s Syndrome
Bilateral Adrenal Hyperplasia
Steroid Treatable hypertension
Aldosterone producing adrenal carcinoma

92
Q

What are the effects of secondary excess aldosterone with hypertension?

A

Renal artery stenosis
Renin Secreting Tumour
Malignant nephrosclerosis

93
Q

What are the effects of secondary excess aldosterone with normal BP?

A

CCF
Cirrhosis
Nephrotic syndrome
Dehydration

94
Q

What is the treatment for Conn’s syndrome?

A

Spironolactone
Amiloride / Triampterine
Potassium Supplementation
Treatment of the Primary Tumour

95
Q

What is Pheochromocytoma?

A

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
Q

What are the sympotms and side effects of Pheochromocytoma?

A 
Constipation
Abdominal Pain
Headache
Fits
Visual disturbance
Pallor or Flushing
Sweating
Anxiety
Fever
Paroxysmal hypertension
Palpitation
(Hypotension)
Angor aminii
97
Q

What are the metabolic effects of pheochromocytoma?

A 
Eosinophilia
Hyperglycaemia
Hypercalcaemia
Raised urinary 
Metanephrines
Catecholamines
98
Q

How is pheochromocytoma managed?

A 
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

Endocrinology (12 decks)

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