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Endocrine & Diabetes > Mineralocorticoid Disorders & Endocrine Hypertension > Flashcards

Mineralocorticoid Disorders & Endocrine Hypertension Flashcards

1
Q

What is the StAR protein regulated by in the zona glomerulosa

A

A2 and potassium (reduces plasma sodium)

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2
Q

What is blood pressure?

A

Force pushing against blood vessel walls as blood is pumped out by the heart

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3
Q

What are the 3 main physiological factors regulating blood pressure?

A

** Cardiac output **
=volume of blood pumped out by the heart
=stroke volume x heart rate (beats/min)

** Vascular tone **
=‘stiffness’ or resistance of blood vessels
=balance between vasoconstrictor & vasodilator influences

** Extracellular fluid (ECF) volume
=Interstitial fluid in tissues
=intravascular fluid in the plasma
=increased by kidney water resorption**

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4
Q

What is Phaeochromocytoma?

A
  • Catecholamine-producing tumour of the chromaffin cells, primarily affecting the cardiovascular system (vasoconstriction, episodes of rapid heart beat & hypertension, sweating & palpitations).
  • Treated by receptor blockade & surgery
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5
Q

How is cardiac output regulated by hormones?

A

-increased by:
=catecholamines (SNS) (alpha adrenergic receptors)
=cortisol potentiation (HPA)= long term sustained

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6
Q

How is vascular tone/ vasoconstriction regulated by hormones?

A

increased by:

  • angiotensin II (AII; RAS)
  • aldosterone (RAS)
  • catecholamines (SNS)
  • cortisol potentiation (HPA)
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7
Q

How is extracellular fluid volume regulated by hormones?

A

increased by:

  • aldosterone (RAS)
  • cortisol (HPA)= affects water resorption, not seen in normal homeostasis (pathophysiologically altered)
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8
Q

What is endocrine hypertension?

A

-caused by excess:
=aldosterone from ZG
=cortisol or precursors from ZF
=catecholamines from medulla

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9
Q

When is renin released in response?

A

-JG cell baroreceptors
=reduced ECF & renal perfusion pressure in afferent arteriole
=directly activates renin release from granules
-Macula densa cell Na+ sensing
=decreased Na+ load to distal tubule (↓ECF/plasma Na+)
=activates sympathetic innervation of JG apparatus
-Carotid arch baroreceptors in periphery
=Low systemic arterial pressure (reduced ECF, cardiac output, vascular tone)
=activates sympathetic innervation of JG apparatus

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10
Q

What are the rapid effects of RAS and aldosterone?

A

-Vasculature rapid (secs)
=Increased vasoconstriction, postural regulation of BP
-Adrenal rapid (mins)
=Increased aldosterone synthesis (ZG), increased catecholamine synthesis
-Kidney 6-48hr
=Increased sodium and water reabsorption via RAAS

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11
Q

What are the physiological actions of aldosterone at the DCT?

A
  • Aldosterone binding promotes AR (mineralocorticoid) receptor relocation from cytoplasm to nucleus
  • Increased uptake of Na+ via apical ENaC protein and increased basolateral Na+/K+ exchange
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12
Q

What are the long term effects of RAS and aldosterone?

A

-Vasculature
=Smooth muscle, increased cell hyperplasia, increased cell hypertrophy, long-lasting change in vascular tone (stiffer)
-Adrenal
=Increased aldosterone synthase enzyme expression, increased glomerulosa cell proliferation
-CNS
=Increased thirst, increased salt appetite, increased ADH release

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13
Q

What are inhibitors of the adrenal gland?

A
  • Low plasma K+
  • High plasma Na+
  • ANP
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14
Q

What are trophic factors of the adrenal gland?

A
  • High plasma K+
  • Low plasma Na+
  • Angiotensin 2 (RAS)
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15
Q

What happens in long term exposure to aldosterone?

A

-Pathophysiological changes to adrenal, kidney, heart and peripheral vascular smooth muscle
=Vascular smooth muscle hyperplasia
=Cardiac fibrosis, left ventricular hypertrophy
=Increased blood pressure

Aldosterone direct damage to heart (hyperplasia, fibrosis) not consequence of hypertension

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16
Q

How is heart failure linked to aldosterone?

A
  • Plasma aldosterone elevated in patients with heart failure

- Standard HF therapy: ACE inhibitor + loop diuretic + digoxin

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17
Q

What are the benefits of spironolactone in heart failure therapy?

A

-Mineralocorticoid receptor antagonist
-Spironolactone (MR antagonist) blocks aldosterone action in kidney AND other tissues (e.g. heart)
-Which otherwise leads to:
=myocardial remodelling,
=Na+ retention & vascular dysfunction
-Decreases all-cause mortality in heart failure patients

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18
Q

What are the causes of hypertension?

A
  • ~30%= lifestyle/ environmental (poor diet, lack of exercise)
  • ~70% major familial/genetic mono- or polygenic component

-85-90% classified as ‘Primary’ or ‘Essential’ hypertension
=all cases without any identifiable cause
-10-15% classified as ‘secondary’ hypertension
=neoplasia, vascular damage & endocrine causes (primary aldosteronism common cause of secondary hypertension)

19
Q

What are causes of secondary hypertension?

A
  • Renal: chronic renal failure, renal artery stenosis, renin-secreting tumour of the kidney (very rare)
  • Vascular: atherosclerosis, co-arctation of the aorta
  • Pregnancy: hormonal and heamodynamic changes
  • Drugs: alcohol, glucocorticoids, oestrogen-containing oral contraceptives, non-steroidal anti-inflammatory drugs
  • Endocrine: adrenal disorders, thyroid disease, pituitary disease (Cushings, acromegaly), primary hyperparathyroidism, diabetes mellitus (secondary to vascular damage)
20
Q

What are the causes of primary hyperaldosteronism?

A
  • Conn’s syndrome
  • Bilateral adrenal hyperplasia
  • Glucocorticoid-Remediable Aldosteronism (GRA)
21
Q

Describe Conn’s Syndrome

A 
=unilateral adrenal tumour ZG
=aldosterone-producing adenoma
-Phenotype:
=high aldosterone, MR activation
=high Na+, low K+, ECF expansion
=hypertension, low renin (RAS)
-Treatment – surgical (encapsulated, low chance of metastasis, slow growing):
=venous sampling and/or CT scan
=unilateral adrenalectomy
22
Q

Describe Bilateral adrenal hyperplasia

A 
=bilateral adrenal hyperplasia
=most common form (60-70%) of PA
-Phenotype:
=high aldosterone, MR activation, 
=high Na+, low K+, ECF expansion, 
=hypertension, low renin (RAS)
-Treatment – pharmacological:
=anti-hypertensives,
=e.g. MR anatgonists
=spironolactone, eplerenone
23
Q

Describe Glucocorticoid-Remediable Aldosteronism

A 
=Autosomal dominant genetic disorder (human chromosome 8)
=ACTH-driven hyperaldosteronism
-Phenotype:
=high aldosterone, MR activation, 
=high Na+, low K+, ECF expansion, 
=hypertension, low renin (RAS)
-Treatment:
=suppress pituitary ACTH secretion
=synthetic glucocorticoid (Dex)
24
Q

What genes are involved in GRA?

A

-Genes for Aldo synthase & 11β-OHase
=95% identity in protein-coding regions, sticky in hydridisation

-BUT gene promoters different:
=Aldo synthase regulated by AII & K+
=11β-OHase regulated by ACTH

-GRA hybrid gene :
=Unequal meiotic exchange
=11β-OHase promoter (ACTH-driven, more active)
=aldo synthase coding region

25
Q

What are the causes of secondary hyperaldosteronism?

A
  • Renin-secreting JG cell tumour

- Renal arterial stenosis

26
Q

Describe renin-secreting JG cell tumour

A 
=renin hyper-secretion, ↑RAAS
=severe hypertension
-Phenotype:
=high plasma renin, high aldosterone
=MR activation, high Na+, low K+
=ECF expansion, hypertension
-Treatment:
=surgical removal of tumour
27
Q

Describe renal arterial stenosis

A 
=low perfusion pressure, renin
=secretion, ↑RAAS, hypertension
-Phenotype:
=high plasma renin, high aldosterone
=MR activation, high Na+, low K+,
=ECF expansion, hypertension
-Treatment:
=anti-hypertensive, e.g. MR blockers
=statins, anti-platelet agents;
=balloon angioplasty +/- stent
28
Q

How does Cushing’s present?

A
  • weight gain, stretch marks, easy bruising, proximal muscle weakness
  • diabetes mellitus (high plasma glucose), menstrual irregularities, depression
29
Q

Describe the Cushing’s phenotype

A
  • hypertension due to multiple effects of elevated plasma cortisol - …
  • high cortisol, high Na+, low K+ (=MR activation?), low renin & low aldosterone
30
Q

How does elevated plasma cortisol cause hypertension?

A
  1. Glucocorticoids inhibit vascular nitric oxide production by eNOS
    =increases vasoconstriction, resistance and blood pressure
  2. Glucocorticoids potentiate catecholamine action in heart (B1) and vasculature (A1)
    =increases adrenaline activation (increased PNMT), vasoconstriction and cardiac output
  3. Glucocorticoids can inappropriately activate kidney MR (moderate affinity for MR, 11betaHSD2 enzyme usually protects)
31
Q

What is eNOS involved in?

A

-Nitric Oxide Synthase converts arginine to NO which with citrulline leads to vasodilation which reduces blood pressure

32
Q

Why is cortisol binding to MR receptors in excess?

A
  • Increased plasma cortisol exceeds capacity of 11β-HSD2 to convert cortisol to cortisone
  • Active cortisol inappropriately activates the kidney MR receptor, doesn’t bind when inactive
  • Increases Na+ & water retention causing ECF expansion
33
Q

What are the causes of glucocorticoid hyperactivity?

A
  • Apparent mineralocorticoid excess

- Drugs and liquorice ingestion

34
Q

Describe apparent mineralocorticoid excess

A 
=Autosomal recessive ‘loss of function’ mutation in 11β-HSD2 (less active)
=↓conversion of cortisol to cortisone
-Phenotype:
=high local kidney cortisol, low RAS
=MR activation, high Na+, low K+ 
=ECF expansion, hypertension
-Treatment – pharmacological:
=MR antagonists (spironolactone, eplerenone)
=low-Na+ diet & K+ supplements
35
Q

Describe how drugs and liquorice ingestion leads to glucocorticoid hyperactivity

A 
=carbenoxolone, glycyrrhizinic acid inhibitors of kidney 11β-HSD2
=↓conversion of cortisol to cortisone
-Phenotype:
=high local kidney cortisol, low RAS
=MR activation, high Na+, low K+ 
=ECF expansion, hypertension
-Treatment – environmental:
=altered drug treatment
=stop eating liquorice!
36
Q

What are the actions of adrenaline released from the adrenal medulla?

A
  • freeze, fight & flight response
  • ↑ heart rate, vasoconstriction, peripheral resistance
  • ↑ glucagon secretion, ↓ insulin secretion
  • ↑ glycogen & lipid breakdown
37
Q

What is pheochromocytoma?

A
  • chromaffin cell tumour of adrenal medulla
  • secrete catecholamines
  • noradrenaline and/or adrenaline
38
Q

What are the symptoms of pheochromocytoma?

A

-Palpitations, Headache, Episodic sweating
=racing heart, anxiety (~50%),
=hypertension – sustained/paroxysmal (~50%)
=diabetes mellitus (~40%)
*distinctive but variable symptoms

39
Q

How is pheochromocytoma diagnosed and treated?

A
  • 24 hour urinary metanephrines & catecholamines

- α-blockers, β-blockers, surgical resection

40
Q

What recent advances have been made in primary/ essential hypertension?

A

-Monogenic endocrine hypertension accounts for 10-15% of hypertension
-Majority (85-90%) of hypertensive patients have ‘Essential’ hypertension,
=all cases lacking a single identifiable cause
-BUT: RAAS inhibitors can treat some ‘Essential’ Hypertension patients
=MR receptor antagonists
=Renin inhibitors
=A2 receptor antagonists
=ACE inhibitors

41
Q

What are the ways to sub-classify primary/ essential hypertension?

A
  • Low plasma renin status

- Aldosterone-Renin Ratio (ARR)

42
Q

How do we sub-classify patients on low plasma renin status?

A

-< 20% of hypertensive patients display:
-low plasma renin (= expected feedback),
but inappropriately ‘normal’ or high aldo levels

  • are low plasma renin due to high blood pressure? OR ‘excess’ mineralocorticoid feedback?
  • suggests altered aldosterone levels may be involved in essential hypertension after all!
43
Q

How do we sub-classify patients on Aldosterone-Renin Ratio (ARR)?

A

-<15% of hypertensive patients display:
=inappropriately normal or high plasma aldo & raised ARR

  • both renin and aldosterone should be low in hypertension (= expected feedback)
  • ARR = mass concentration of aldosterone divided by plasma renin activity (recommended screening tool for primary hyperaldosteronism)
  • high ARR = evidence of undiagnosed aldosterone-secreting adenomas … ?
44
Q

Describe the two-hit model for functional aldosterone-producing microadenomas

A
  1. Aldo-producing cell clusters (APCCs): somatic mutations in genes controlling, ZG:
    =membrane depolarisation & intracellular Ca2+
    =increased AS expression
    =uncontrolled aldosterone production
  2. Aldo-producing adenomas (APAs): somatic mutations in genes growth:
    =membrane depolarisation & intracellular Ca2+
    =increased AS expression
    =uncontrolled aldosterone production
    =+ cell proliferation & nodule formation

Endocrine & Diabetes (45 decks)

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