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Phase 2- Endocrine > Week 4 > Flashcards

Week 4 Flashcards

1
Q

What is the principle electrolyte in the intracellular fluid?

A

Potassium (K+)

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2
Q

What is the principle electrolyte in the extracellular fluid?

A

Sodium (Na+)

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3
Q

What is ADH produced in response to?

A

Reduced plasma voluma (sensed by barocepters in atria/veins/carotids), and increased plasma osmolality (sensed by osmoreceptros in hypothalamus)

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4
Q

What triggers the renin-angiotensin axis?

A

Reduced arterial volume, sensed by the juxta-glomerula apparatus of the kidney

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5
Q

What is the action of angiotensin II?

A

Vasoconstriction, and promotion of aldosterone release

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6
Q

How does aldosterone affect the kidney?

A

Aldosterone increases sodium reabsorption and potassium excretion in the distal nephron- increasing sodium status also increases plasma volume, and raises BP

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7
Q

How can hyponatraemia be classified?

A

By ECF volume status: hypovolaemia (Na and water deficit), euvolemia (water excess), and hypervolemia (Na and water excess)

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8
Q

What is the most common cause of low plasma sodium?

A

Syndrome of inappropriate ADH (commonly caused by cancer, chest disease (pneumonia), CNS disorders (infections and injury), drugs: opiates, thiazides, anti-convulsants, PPIs, anti-depressants)

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9
Q

How is SIADH diagnosed?

A

Hyponatraemia with inappropriate low plasma osmolality, urine osmolality>plasma osmolality, urine sodium >20mmol/l, absence of adrenal, thyroid, pituitary or renal insufficiency, no recent use of diuretic agents

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10
Q

What happens in the brain in hyponatraemia?

A

When serum [Na+] is low, water moves into cells to increase plasma osmolality causing cell swelling. If this happens rapidly, cerebral oedema occurs

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11
Q

What happens when there is a sudden rise in [Na+] in the brain?

A

Osmotic demyelination syndrome- sodium must therefore be normalised over 1-2 days

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12
Q

What are the clinical features of hyponatraemia?

A

Symptoms worsen as plasma Na falls: asymptomatic -> mild confusion -> gait instability -> marked confusion -> drowsiness -> seizures

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13
Q

How is very severe and very acute hyponatraemia treated?

A

Normally healthy patients presenting with seizures are given infusion of hypertonic (3%) saline. This is the only time sodium can be given quickly

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14
Q

How is less severe and/or chronic hyponatraemia treated?

A

Establish cause, usually fluid restriction is correct management, increase sodium slowly. 2nd line treatment is controversial- AVPR2 antagonists

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15
Q

What is hypernatraemia due to?

A

Mostly due to water loss, and inability to access water, often caused by insensible/sweat losses (severe burns/sepsis), GI losses, diabetes insipidus, and osmotic diuresis due to hyperglycaemia

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16
Q

How is hypernatraemia managed?

A

Treat underlying cause. Estimate total body water deficit, avoid overly rapid correction. Use IV 5% dextrose

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17
Q

What are the 3 main sources of calcium?

A

GI tract (absorbed throughout small intestine, via D dependent), bones (calcium reservoir, regulated by osteoblasts and osteoclasts) and kidney (free Ca filtered by glomerulus, 97-99% absorbed)

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18
Q

Where are parathyroid glands found?

A

One in each pole of the thyroid gland

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19
Q

What is the effect of PTH?

A

Increases bone resorption, increases vitamin D formation, increases kidney calcium reabsorption and increases phosphate excretion

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20
Q

What is the most physiologically relevant calcium?

A

‘Free’ or ‘ionised’ calcium (55% bound to albumin and 45% free)

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21
Q

What are the clinical features of hypercalcaemia?

A

Moans (fatigue, depression, confusion), bones (bone pain, osteopenia/osteoporosis), stones (nephrolithiasis, nephrocalcinosis), and abdominal groans (pancreatitis, anorexia, nausea and vomiting) as well as increased thirst

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22
Q

What are the two causes of hypercalcaemia?

A

Primary hyperparathyroidism (usually single parathyroid adenoma) and malignancy (usually due to cancer secretion of PTH-related peptide- breast, lung and multiple myeloma are comments tumours, also seen in bone metastases due to direct osteolysis)

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23
Q

How can you distinguish between the two causes of hypercalcaemia?

A

Measure PTH: if decreased then malignancy likely, if normal or increased then primary hyperparathyroidism

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24
Q

What does management of hypercalcaemia depend on?

A

Severity:

  • mild <3 mmol/l
  • moderate 3-3.5 mmol/l
  • severe > 3.5 mmol/l
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25
Q

How is hypercalcaemia managed?

A

Patients are often hypovolaemic, which impairs renal clearance of calcium. Isotonic (0.9%) saline infusion corrects hypovolaemia, though will not normalise calcium unless only mildly elevated

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26
Q

How are bisphosphonates used to treat hypercalcaemia?

A

They inhibit bone resorption by inhibiting osteoclasts- agents of choice for treating hypercalcaemia of malignancy. Delayed effect, maximal at 2-4 days after treatment

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27
Q

What other agents are used to treat hypercalcaemia?

A

Calcitonin- increases renal calcium excretion, decreases bone resorption, only effective for 48 hours
Glucocorticoids- inhibit vitD production
Parathyroidectomy- only if resistant to treatment, rarely indicated urgently

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28
Q

What are the complications of acute hypocalcaemia?

A

Tetany:
- increased neuromuscular excitability
- peri-oral numbness, muscle cramps, tingling or hands/feet
- if severe: carpopedal spasm, laryngospasm, seizures
Cardiac complications:
- dysrhythmia
- hypotension

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29
Q

What causes hypocalcaemia?

A 
Low PTH:
- after parathyroid surgery 
- autoimmune hypoPTism
High PTH:
- vitamin D deficiency
- chronic renal failure
- loss of calcium
Drugs
Hypomagnesaemia:
- leads to PTH resistance
30
Q

How is hypocalcaemia treated?

A 
IV calcium replacement if tetany or cardiac manifestations
May also need Mg infusion
Chronic management:
- vitD 
- oral calcium salts
Treat underlying cause
31
Q

What are steroid hormones derived from?

A

Enzymatic modification of cholesterol

32
Q

How is steroidogenesis regulated?

A

By enzymes found in mitochondria and smooth ER

33
Q

What protein carries cortisol?

A

Corticosteroid binding globulin

34
Q

What are the adrenal glands composed of?

A

Outer cortex (3 zones) and inner medulla

35
Q

What blood vessels supply the adrenal glands?

A

Superior, middle and inferior suprarenal arteries

36
Q

What drains the adrenal glands?

A

The medullary vein which flows from the centre of the gland, and emerges from the hilum to form the suprarenal veins, which joins the IVC on the right and the left renal vein on the left

37
Q

What are the zones of the adrenal gland?

A

Fibrous capsule, zona glomerulosa (clusters of small cells, fewer lipids than other layers), zona fasciculata (large cells arranged in cords), zona reticularis (smaller cells- haphazard arrangement) and chromaffin cells as well as numerous veins and arteries

38
Q

In which zone are adrenal androgens produced?

A

ZR; regulated by ACTH (important source of androgens in women)

39
Q

In which zone are glucocorticoids produced?

A

ZF; regulated by ACTH

40
Q

In which zone are mineralocorticoids produced?

A

ZG; regulated by RAS, mineralocorticoids are involved in sodium and BP homeostasis

41
Q

What is the first step in steroidogenesis?

A

Conversion of cholesterol to pregnenolone (enzyme located in inner mitochondria membrane, cytochrome P450)

42
Q

What protein carries out the transport of free cholesterol from cytoplasm to mitochondria?

A

Steroidogenic acute regulatory protein

43
Q

What is the mechanism of action of steroid hormones?

A
  • Steroid hormone diffuses through plasma membrane
  • Binds to intracellularly cytosolic receptor member of steroid receptor superfamily
  • Receptor-Hormone complex enters the nucleus and binds to a glucocorticoid response element in 5’ flanking region of target genes
  • Binding initiates gene transcription to produce mRNA
  • mRNA is translated to protein which mediates the effects-target cell response
44
Q

What problem occurs due to higher glucocorticoid [plasma] and high mineralocorticoid receptor affinity to GCs?

A

Cortisol and other GCs can illicitly occupy MR. 11-beta-HSDII catalyses the conversion of cortisol (active) to cortisone (inactive) in selective tissues, allowing aldosterone to function normally

45
Q

What are the effects of cortisol?

A
  • Stimulates gluconeogenesis in liver
  • Permissive effect on glucagon
  • Stimulation of lipolysis
  • Insulin antagonists
  • Increased breakdown of skeletal muscle protein
  • Immune suppression
46
Q

What are the effects of aldosterone?

A
  • Acts on MR receptors in the principle cells to up-regulate basolateral Na/K pumps
  • Up-regulates ENaC
  • Stimulates secretion K+ into lumen
  • Stimulates secretion H+ via the H+/ATPase in the intercalated cells of the cortical collecting tubules
  • Aldosterone stimulates Na+ and water reabsorption from the gut, salivary and sweat glands in exchange for K+
  • Non-epithelial effects on heart and vascular system
47
Q

How does aldosterone act in the kidney?

A

AL binds to MR
Translocated into nucleus
Acts as a transcription factor- binds to HREs
Repression or induction of aldosterone responsive genes
mRNA transcripts (SGK-1, ENaC, NaK-ATPase)
Results in sodium reabsorption and potassium excretion

48
Q

What is the rhythm of cortisol release?

A

Circadian rhythm (more detail needed)

49
Q

How is cortisol release regulated?

A
  • ACTH binds to 7TMD G-protein receptors
  • Conformational changes in receptor stimulate adenyl cyclase, causing an increase in cAMP, activation of PKA and calcium influx
  • ACTH has rapid and long-term actions
  • Stimulation of cholesterol delivery to the mitochondria (rapid)
  • Increased transcription of genes coding for steroidogenic enzymes e.g. 11B-hydroxulase (long-term)
  • Increased cortisol (androgen) production
50
Q

How is aldosterone regulated?

A

RAS activated in response to decreased BP or plasma sodium, leads to production go Ang II, which causes direct (vasoconstriction) and indirect (aldosterone, thirst) methods of BP elevation

51
Q

How does AngII increase aldosterone production?

A
  • AngII binds to 7TMD G-protein coupled receptor
  • Activates phospholipase C
  • Hydrolyses PIP2 to form 2nd messengers IP3 and DAG
  • IP3 causes stored Ca2+ to be released
  • Rise in [Ca2+]i activates Ca2+-calmodulin dependent protein kinases (CaMKs) which stimulate the transcription of StAR and cholesterol uptake into mitochondria
  • Increased aldosterone production
52
Q

What is congenital adrenal hyperplasia?

A

Autosomal recessive disorder, characterised by deficiency of cortisol and aldosterone due to lack of 21-hydroxylase activity (increased adrenal androgens)

53
Q

What are the causes of adrenal insufficiency?

A

Primary insufficiency (Addison’s disease, CAH, adrenal TB/malignancy) or secondary insufficiency (due to lack of ACTH stimulation, iatrogenic (excess exogenous steroid), pituitary/hypothalamic disorders)

54
Q

What are the clinical features of Addison’s disease?

A

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

55
Q

How is adrenal insufficiency diagnosed?

A

Biochemistry: hypoglycaemia, increased potassium, decreased sodium
Short synACTHen tes:
- measure plasma cortisol before and 30 minutes after IV ACTH injection
ACTH levels:
- should be very increased (causes skin pigmentation)
Renin/aldosterone levels:
- renin increased, aldosterone decreased
Adrenal autoantibodies

56
Q

How is adrenal insufficiency managed?

A

Do not delay treatment to confirm diagnosis
Hydrocortisone as cortisol replacement:
- if unwell, give IV first
- then 15-30 mg tablets daily in divided doses
- try to mimic diurnal rhythm
Fludrocortisone as aldosterone replacement:
- careful monitoring of BP and plasma potassium
Need education:
- ‘sick day rules’
- cannot stop suddenly
- need to wear identification

57
Q

What are patients with adrenal deficiency given if sick?

A

Doubled dose of steroid for 3 days

58
Q

How does exogenous steroid cause endogenous steroid deficiency?

A

Exogenous steroid (high dose prednisolone, dexamethasone or inhaled corticosteroid) turns off hypothalamic production of CRH and pituitary production of ACTH, resulting in no endogenous cortisol production

59
Q

What are the clinical features of Cushing’s disease?

A

Easy bruising, facial plethora, striae, proximal myopathy, moon face with red checks, muscle wasting in legs and arms, thinning of skin

60
Q

What causes Cushing’s syndrome?

A

ACTH dependent (pituitary adenoma, ectopic ACTH (carcinoid/carcinoma), ectopic CRH) or ACTH independent (adrenal adenoma, adrenal carcinoma, nodular hyperplasia)

61
Q

How is Cushing’s syndrome diagnosed? (step 1)

A

Establish cortisol excess:

  • dexamethasone suppression testing
  • 24 hr urinary free cortisol
  • late night salivary cortisol
62
Q

How is Cushing’s syndrome diagnosed? (step 2)

A

Establish source of cortisol excess:
- measure ACTH
if normal: CRH stimulation test
no change in ACTH-> CT chest/abdo/pelvis (ectopic ACTH)
exaggerated rise in ACTH -> pituitary MRI (pituitary ACTH source )
if undetectable: adrenal CT scan

63
Q

How is Cushing’s managed?

A 
Surgical:
- transphenoidal pituitary surgery
- laproscopic adrenalectomy
- removal of ACTH source
Medical:
- metyrapone/ketoconazole
  - inhibit cortisol production
- short term measure
64
Q

What does chronic steroid use cause, and what condition is it associated with?

A

Chronic suppression of pituitary ACTH product and adrenal atrophy; iatrogenic Cushing’s disease

65
Q

How is adrenal hypertension caused?

A

Increased aldosterone production, or increased production of adrenaline by phaeochromocytoma

66
Q

What is primary aldosteronism?

A

Autonomous production of aldosterone independent of its regulators (angiotensin II/potassium), due to either single adrenal adenoma or bilateral adrenal nodules

67
Q

What are the clinical features of primary aldosteronism?

A

Significant hypertension, hypokalaemia (in up to 50%) and alkalosis

68
Q

How is primary aldosteronism diagnosed?

A

Biochemical tests:

  • plasma aldosterone elevated
  • plasma renin concentration suppressed
  • suppression testing
    • IV saline load
  • adrenal CT scan
69
Q

How is primary aldosteronism managed?

A 
Surgical:
- unilateral laproscopic adrenalectomy
- only if adrenal adenoma
- cure of hypokalaemia
- cures hypertension in 30-70% of cases
Medical:
- in bilateral adrenal hyperplasia
- use MR antagonists (spironolactone or eplerenone)
- or amiloride (blocks Na reabsorption by kidney)
70
Q

What is phaeochromocytoma?

A

Catecholamine secreting tumours of the adrenal medulla, causing hypertension (intermittent in 50%), and episodes of headache, palpitations, pallor and sweating

71
Q

How is phaeochromocytoma diagnosed?

A

Measurement of urinary catecholamines and metabolites and CT scan of adrenals

72
Q

How is phaeochromocytoma treated?

A

Adrenalectomy is treatment of choice- need pre-operative treatment with alpha1 +/- beta1 antagonists to block effects of catecholamine surge

Phase 2- Endocrine (4 decks)

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