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Endocrinology > Week 4 > Flashcards

Week 4 Flashcards

1
Q

What is plasma osmolality?

A

The ratio of solutes to water in the plasma

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2
Q

By what 2 mechanisms are water status regulated?

A

Thirst

ADH

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3
Q

What is ADH released in response to and how are these stimuli picked up?

A

Decreased plasma volume -
baroreceptors (heart/vessels)
Increased plasma osmolality - osmoreceptors (hypothalamus)

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4
Q

What receptor does ADH mainly act on and where is this located?

A

AVPR2

Basolateral membrane of kidney collecting duct

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5
Q

What is the action of ADH in the kidney collecting duct?

A

Inserts aquaporins (2) into the apical membrane to increased water reabsorption

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6
Q

What is the normal homeostatic osmolarity of blood?

A

300 mosmoles/L

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7
Q

By what 3 mechanisms is arterial volume regulated?

A

RAAS (AT II release)
Carotid/aortic baroreceptors (sympathetic stimulation)
Cardiac receptors (ANP release)

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8
Q

What are the actions of angiotensin II?

A

Vasoconstriction

Promotes aldosterone release

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9
Q

What is the main action of aldosterone?

A

Insertion of epithelial Na channels in the apical surface of DCT/CD cells of the kidney to increase Na and water reabsorption and K excretion
BP also increased

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10
Q

At what serum Na concentration is a patient considered hyponatraemic?

A

< 135 mmol/L

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11
Q

What are the possible causes of hyponatraemia?

A 
Na and water deficit (hypovolaemia)
Water excess (euvolaemia)
Na and water excess (hypervolaemia)
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12
Q

Why might a patient be hypovolaemic?

A

Renal losses - excess diuretic, deficiency in mineralocorticoids, bicarbonaturia, ketonuria, osmotic diuresis, renal tubular acidosis, salt-losing nephritits
Extra-renal losses - vomiting, diarrhoea, burns, pancreatitis, traumatised muscle

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13
Q

Why might a patient be euvolaemic?

A

Glucocorticoid deficiency, hypothyroidism, pain, psychiatic disorders, drugs, inappropriate ADH secretion

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14
Q

Why might a patient be hypervolaemic?

A

Nephrotic syndrome, cardiac failure, cirrhosis

Acute/chronic renal failure

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15
Q

What is SIADH?

A

Syndrome of inappropriate ADH

Most common cause of low plasma Na due to increased water in the body

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16
Q

What are the possible causes of SIADH?

A

Cancer, pneumonia, CNS infection, drugs (opiates, thiazides, PPIs, anti-depressants)

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17
Q

How is SIADH diagnosed based on test results?

A

Hyponatraemia with inappropriately low plasma osmolality
Urine osmolality > plasma osmolality
Urine Na > 20 mmol/L
Absence of adrenal/thyroid/pituitary/renal insufficiency
No use of diuretics

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18
Q

What is the consequence of sudden hyponatraemia to the brain?

A

If serum Na concentration is low, water will move into cells to increase plasma osmolality which cerebral oedema

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19
Q

What is the consequence of sudden hypernatraemia to the brain?

A

Osmotic demyelination

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20
Q

What are the clinical features of hyponatraemia?

A

Often asymptomatic, symptoms worsen as plasma Na falls

Mild confusion, gait instability, marked confusion, drowsiness, seizures

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21
Q

How is severe/acute hyponatraemia managed?

A

Infusion of hypertonic (3%) saline

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22
Q

How is less severe/chronic hyponatraemia managed?

A

Establish cause
Usually best to restrict fluid and slowly increase Na
(AVPR2 receptor antagonists controversial)

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23
Q

What are the possible causes of hypernatraemia?

A

Very rare; ultimately dehydration

Severe burns, sepsis, urine/faeces, diabetes insipidus, osmotic diuresis in hyperglycaemia

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24
Q

How is hypernatraemia managed?

A

Treat underlying cause
Estimate water deficit to guide fluid regimen
Avoid rapid correction of Na (decrease of 10 mmol/L per 24 hours) due to cerebral oedema risk
IV 5% dextrose

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25
Q

What are the 3 main sources of Ca in the body?

A

GI tract - absorption from diet in SI, vitamin D dependent
Bones - reservoir, regulation of plasma Ca via osteoclasts/osteoblasts
Kidney - free Ca filtered by glomerulus, 99% reabsorbed

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26
Q

What are the effects of vitamin D in the GI tract, bone and kidneys?

A

GI - increases absorption
Bone - increases resorption
Kidneys - increases reabsorption

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27
Q

What is parathyroid hormone released in response to?

A

Low plasma Ca

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28
Q

What are the effects of PTH?

A

Overall - increased serum Ca and phosphate

Bone - increased Ca and phosphate release
Kidney - increased phosphate excretion, calcium reabsorption and calcitriol formation
Small intestine - increased absorption of dietary Ca and phosphate

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29
Q

How much circulating Ca is bound and free and which of these is more physiologically relevant?

A

Bound - 55%

Free - 45%; more important

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30
Q

What are the clinical features of hypercalcaemia?

A

Moans, bones, stones and groans

Renal - polyuria, polydipsia, kidney stones, nephrocalcinosis, renal tubular acidosis, nephrogenic diabetes insipidus, acute/chronic renal insufficiency
GI - anorexia, nausea, vomiting, constipation, pancreatitis, peptic ulcer disease
Musculoskeletal - muscle weakness, bone pain, osteopenia/osteoporosis
Neurologic - decreased concentration, confusion, fatigue, stupor/coma

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31
Q

What ECG changes would be seen in hypercalcaemia?

A

Shortened QTc interval

Bradycardia

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32
Q

What can cause hypercalcaemia?

A

Primary hyperparathyroidism - parathyroid adenoma

Malignancy - PTH-related peptide, direct osteolysis (bone metastases)

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33
Q

How can the cause of hypercalcaemia be distinguished between primary hyperparathyroidism and malignancy?

A

Measure PTH
Increased/normal - primary hyperparathyroidism
Decreased - malignancy

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34
Q

How is hypercalcaemia classified?

A

Mild < 3 mmol/L
Moderate 3-3.5 mmol/L
Severe >3.5 mmol/L

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35
Q

What are the 2 main routes by which hypercalcaemia is managed?

A 
Rehydration - hypovolaemia impairs renal Ca clearance
Bisphosphonate therapy (e.g. zolendronate) - inhibit bone resorption, 2-4 days to have full effect
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36
Q

What additional management can be used to treat hypercalcaemia?

A

Calcitonin - increases renal Ca excretion and decreases bone resorption, only has 48 hour effect
Glucocorticoids - inhibit vitamin D production
Parathyroidectomy - only if resistant to treatment, rare

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37
Q

What hormone is released when serum Ca is high and where is it released from?

A

Calcitonin

Thyroid gland

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38
Q

What are the actions of calcitonin?

A

Increases renal Ca excretion

Decreases bone resorption

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39
Q

What are the effects of acute hypocalcaemia?

A

Tetany
Cardiac arrhythmia
Hypotension

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40
Q

What are the consequences of tetany?

A

Increased neuromuscular excitability
Peri-oral numbness, muscle cramps, tingling of hands/feet
Severe - carpopedal spasm, laryngospasm, seizures

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41
Q

What ECG changes would be seen in hypocalcaemia?

A

Lengthened QTc

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42
Q

What can cause hypocalcaemia?

A

Low PTH - surgery, autoimmune
High PTH - vit D deficiency, chronic renal failure, Ca loss
Drugs
Hypomagnesaemia - PTH resistance

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43
Q

How can hypocalcaemia be treated?

A

IV Ca replacement - tetany/cardiac problems
Mg infusion
Chronic - vit D, oral Ca salts
Treat underlying cause

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44
Q

In terms of fluids, how would hypovolaemia, euvolaemia and hypervolaemia be treated?

A

Hypo - isotonic saline
Eu - water restriction
Hyper - Na and water restriction

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45
Q

What are the main causes of primary adrenal insufficiency?

A

Addison’s disease
Adrenal TB/malignancy
Congenital adrenal hyperplasia

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46
Q

What is adrenal insufficiency?

A

Inadequate adrenocortical function

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47
Q

What is congenital adrenal hyperplasia?

A

A genetic autosomal recessive disorder in which there is a lack of 21-hydroxylase activity, leading to a deficiency in cortisol and aldosterone accompanied by an excess of adrenal androgens

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48
Q

What are the main causes of secondary adrenal insufficiency?

A

Iatrogenic (excess exogenous steroid)

Pituitary/hypothalamic disease/tumour

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49
Q

What is Addison’s disease?

A

Primary adrenal insufficiency

Autoimmune destruction of adrenal cortex (>90% before symptomatic)

50
Q

What are the clinical features of Addison’s disease?

A

Anorexia, weight loss, fatigue, lethargy, dizziness, low BP, abdominal pain, vomiting, diarrhoea, skin pigmentation

51
Q

How is adrenal insufficiency diagnosed?

A 
Biochemistry 
Short synacthen test
ACTH levels 
Renin/aldosterone levels
Adrenal autoantibodies
52
Q

What biochemistry results would be indicative of adrenal insufficiency?

A

Decreased Na
Increased K
Hypoglycaemia

53
Q

What is the short synacthen test and what results would be indicative of adrenal insufficiency?

A

Measurement of plasma cortisol before and 30 minutes after an IV ACTH injection
Normal baseline - >250 mmol/L
Normal post-ATCH - >480 mmol/L

54
Q

How would ACTH levels be affected in adrenal insufficiency?

A

Increased

55
Q

Outline the axis for cortisol

A

Hypothalamus - corticotrophin releasing hormone (CRH)
Anterior pituitary - adrenocorticotrophic hormone (ACTH)
Adrenal cortex - cortisol
Cortisol exerts negative feedback on the anterior pituitary and hypothalamus

56
Q

How would renin and aldosterone levels be affected by adrenal insufficiency?

A

Renin - greatly increased

Aldosterone - decreased

57
Q

How is adrenal insufficiency managed?

A

Treatment should not be delayed until diagnosis is confirmed
Hydrocortisone - cortisol replacement, 15-30mg tablets in divided doses to mimic diurnal rhythm
Fludrocortisone - aldosterone replacement, monitor BP/K

58
Q

What education must be given regarding steroid treatment?

A

Sick day rules - adjustment, immunosuppression
Cannot stop suddenly - if taking for >3 weeks
Need to wear identification - steroid treatment card, medic alert bracelet

59
Q

What is the commonest cause of secondary adrenal insufficiency and how?

A

Iatrogenic

Exogenous steroid use will exert negative feedback on the release of CRH and ACTH, as cortisol normally does

60
Q

What is the physiological cause of secondary adrenal insufficiency?

A

Lack of CRH or ACTH

61
Q

What factors stimulate the hypothalamus to set off the cortisol axis?

A

Stress
Illness
Time of day

62
Q

What are the clinical features of secondary adrenal insufficiency?

A

Similar to Addison’s except pale skin (no increased ACTH) and aldosterone production is intact (RAAS regulated)

63
Q

How is secondary adrenal insufficiency treated?

A

Hydrocortisone - cortisol replacement

64
Q

What is Cushing’s syndrome?

A

A rare disease of excess cortisol secretion which mostly affects women aged 20-40 and has a high mortality rate

65
Q

What are the clinical features of cortisol excess/Cushing’s syndrome?

A

Easy bruising, facial plethora, striae, proximal limb myopathy, increased abdominal/central fat, poor wound healing, skin thinning, buffalo hump back

66
Q

What are the 2 types of Cushing’s syndrome?

A

ACTH dependent - pituitary adenoma (68%), ectopic ATCH (12%), ectopic CRH (<1%)
ACTH independent - adrenal adenoma (10%), adrenal carcinoma (8%), nodular hyperplasia (1%)

67
Q

How is Cushing’s syndrome diagnosed?

A

Establish cortisol excess

Establish source of cortisol excess

68
Q

How can cortisol excess be established in Cushing’s syndrome?

A

Dexamethasone suppression test
24 hour urinary free cortisol
Late night salivary cortisol

69
Q

How can the source of cortisol excess be established in Cushing’s syndrome?

A

Measure ACTH
Normal/high - CRH stimulation test; no change = chest/abdominal/pelvic CT; exaggerated rise = pituitary MRI
Undetectable - adrenal CT scan

70
Q

How is Cushing’s syndrome managed?

A

Surgical - transphenoidal pituitary surgery, laparascopic adrenalectomy, removal of ACTH source
Medical - metyrapone/ketoconazole (inhibition of cortisol production); short term measure

71
Q

What is the commonest cause of Cushing’s syndrome and how does it occur?

A

Iatrogenic
Prolonged high dose steroid therapy (e.g. asthma, RA, IBD, transplant) chronically suppresses pituitary ACTH production and causes adrenal atrophy

72
Q

What are the implications of adrenal atrophy due to long term steroid use adrenal suppression?

A

Unable to respond to stress/illness/surgery
Need extra doses of steroid when ill/undergoing surgery
Cannot stop treatment suddenly (gradual withdrawal if on steroids for >4-6 weeks)

73
Q

How is the adrenal gland involved in hypertension?

A

90% of hypertension is idiopathic (essential) but <10% are secondary to another disorder (e.g. renal disease, aldosterone excess, iatrogenic)
Investigate for secondary cause, especially in young, resistant hypertension

74
Q

What is primary aldosteronism?

A

Production of aldosterone independent of its regulators (e.g. angiotensin II, K+)

75
Q

What is the commonest secondary cause of hypertension?

A

Primary aldosteronism

76
Q

What are the 2 possible causes of primary aldosteronism?

A

Single adrenal adenoma

Bilateral adrenal nodules/hyperplasia

77
Q

What are the clinical features of primary aldosteronism?

A

Significant hypertension
Hypokalaemia
Alkalosis

78
Q

How is primary aldosteronism diagnosed?

A

Biochemistry - plasma aldosterone increased, plasma renin decreased
Suppression testing - IV saline load
Adrenal CT scan

79
Q

How is primary aldosteronism managed?

A

Surgical (if adrenal ademona) - unilateral laparascopic adrenalectomy ; hypertension only cured in 30-70%
Medical (if bilateral adrenal hyperplasia) - mineralocorticoid receptor antagonist (e.g. spironolactone, eplerenone, amiloride)

80
Q

What is a phaeochromocytoma?

A

A rare catecholamine-secreting tumour of the adrenal medulla causing episodic hypertension, headache, palpitations, pallor and sweating

81
Q

How is a phaeochromocytoma diagnosed?

A

Measure urinary catecholamines and metabolites

CT scan of adrenals

82
Q

How is a phaeochromocytoma treated?

A

Adrenalectomy - pre-operative treatment with α1/β1 antagonists to block effects of catecholamine surge

83
Q

Where are the enzymes involved in steroid hormone production from cholesterol found?

A

Mitochondria

Smooth endoplasmic reticulum

84
Q

Which carrier protein transports cortisol in the blood?

A

Corticosteroid binding globulin

85
Q

What is the size and weight of an average adrenal gland?

A

4-6 cm

6-8 g

86
Q

Why are the adrenal glands yellow in colour?

A

High cholesterol levels (for synthesis of steroid hormones)

87
Q

What is the arterial supply of the adrenal glands?

A

Superior, middle and inferior suprarenal arteries

88
Q

What type of blood flow occurs in the adrenal gland?

A

Centripetal - blood reaches the outer surface of the gland and then enters each layer

89
Q

What is the venous drainage of the adrenal glands?

A

Medullary veins emerge from the hilum and form the suprarenal veins which drain into the IVC on the right and left renal vein on the left

90
Q

What is the nerve supply of the adrenal glands and which cell type do they innervate?

A

Coeliac plexus
Thoracic splanchnic nerves
Supply the chromaffin cells of the adrenal medulla

91
Q

What are the zones of the adrenal cortex?

A

Zona glomerulosa
Zona fasiculata
Zona reticularis

92
Q

What are the main histological features of the zona glomerulosa and what hormones are produced here?

A

Clusters of small cells, fewer lipids

Mineralocorticoids - aldosterone, deoxycorticosterone

93
Q

What are the main histological features of the zona fasiculata and what hormones are produced here?

A

Large cells arranged in cords

Glucocorticoids - cortisol, corticosterone

94
Q

What are the main histological features of the zona reticularis and what hormones are produced here?

A

Small cells, haphazard arrangement

Adrenal androgens - DHEA, androstenedione

95
Q

What are the contents of the adrenal medulla and what hormones are produced here?

A

Chromaffin cells, numerous capillaries and veins

Catecholamines - adrenaline, noradrenaline

96
Q

Where is cholesterol sourced for steroid hormone synthesis?

A

Taken up from circulation (e.g. LDL) or synthesised from acetyl CoC

97
Q

What is the rate limiting enzyme in cholesterol biosynthesis?

A

HMG-CoA reductase

98
Q

What enzyme catalyses the conversion of cholesterol to pregnenolone?

A

Cytochrome P450 on the inner mitochondrial membrane

Cholesterol side-chain cleavage

99
Q

What is the rate limiting step in cellular localisation of cholesterol and what molecule is responsible for its regulation?

A

Transport of free cholesterol from cytoplasm into mitochondria
Steroidogenic acute regulatory protein (StAR)

100
Q

Outline the biosynthesis of aldosterone from cholesterol

A

Cholesterol → pregnenolone → progesterone → corticosterone → aldosterone

101
Q

Outline the biosynthesis of cortisol from cholesterol

A

Cholesterol → pregnenolone → 17 OH pregnenolone → 17 OH progesterone → 11 deoxycortisol → cortisol

102
Q

What is the C domain of the steroid receptor?

A

Highly conserved DNA binding domain containing 2 zinc fingers which bind to hormone response elements

103
Q

What is the E domain of the steroid receptor?

A

Highly conserved ligand-binding domain which binds steroid

104
Q

Outline the mechanism of action of steroid hormones

A

Steroid hormone diffuses through cell membrane → binds to intracellular cytosolic receptor → complex moves into the nucleus and binds to glucocorticoid response element → gene transcription activated to produce mRNA → translation into protein which mediates effects on target cell

105
Q

Where are glucocorticoid receptors found?

A

Ubiquitous

106
Q

Where are mineralocorticoid receptors found?

A

Distal nephron, salivary glands, sweat glands, large intestine, brain, vasculature, heart

107
Q

What is the affinity of the mineralocorticoid receptor for cortisol, dexamethasone and aldosterone?

A

Aldosterone > cortisol > dexamethasone

108
Q

What is the affinity of the glucocorticoid receptor for cortisol, dexamethasone and aldosterone?

A

Dexamethasone > cortisol = aldosterone

109
Q

What are the normal plasma levels of aldosterone and cortisol?

A

Aldosterone - 100-500 pmol/L

Cortisol - 100-500 nmol/L

110
Q

Why is there a need for a mechanism which stops cortisol from binding to the glucocorticoid receptor and what is this mechanism?

A

Cortisol concentration is much higher than aldosterone and cortisol is able to bind to the mineralocorticoid receptor
11β-hydroxysteroid dehydrogenase converts active cortisol to inactive cortisone in selective tissues (e.g. kidney) to allow normal aldosterone function

111
Q

What is 11β-hydroxysteroid dehydrogenase inhibited by?

A

Liquorice

112
Q

What are the effects of cortisol?

A

Stimulates gluconeogenesis
Permits glucagon activity
Stimulates lipolysis
Antagonises insulin
Increases breakdown of skeletal muscle protein
Involved in memory, learning, mood and immune suppression

113
Q

What are the actions of aldosterone?

A

Na and water reabsorption
K and H excretion
Effects on the heart and vascular system

114
Q

What can result from aldosterone gene transcription?

A

Serum and glucocorticoid-regulated kinase 1 (SGK-1)
Epithelial Na channels (ENaC)
Na/K ATPase

115
Q

Describe the circadian rhythm of cortisol secretion

A

Highest in the morning

Smaller peaks in the evening (5pm) and midnight

116
Q

How is ACTH formed?

A

Cleavage of proopiomelanocortin (POMC) in corticotropes of the anterior pituitary

117
Q

What other peptides are formed with ACTH?

A

Lipotropin - β endorphin precursor
β-endorphin and met-enkephalin - opiod peptides with pain-alleviation and euphoric effects
Melanocyte stimulating hormone (MSH) - controls melanin skin pigmentation

118
Q

Outline the mechanism of action of ACTH

A

ACTH binds to GPCR → adenylate cyclase → increased cAMP → PKA stimulation → Ca influx → increased cortisol/androgen production

119
Q

What are the short-term and long-term effects of ACTH?

A

Short-term - stimulation of cholesterol delivery to the mitochondria
Long-term - increased transcription of genes coding for steroidogenic enzymes (e.g. 11β hydroxylase)

120
Q

What is the RAAS stimulated in response to?

A

Decreased BP/plasma Na

121
Q

What are the direct and indirect effects of angiotensin II on BP?

A

Direct - vasoconstriction

Indirect - aldosterone activation, thirst stimulation

122
Q

Outline the mechanism of action of angiotensin II

A

Angiotensin II bings to GPCR → activation of phospholipase C → hydrolysis of PIP2 to IP3 and DAG → IP3 stimulates Ca release → Ca calmodulin kinase activation → StAR transcription → cholesterol uptake into mitochondria → increased aldosterone production

Endocrinology (4 decks)

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