Mineralocorticoid Disorders & Endocrine Hypertension

Question 1

What is the StAR protein regulated by in the zona glomerulosa

Answer 1

A2 and potassium (reduces plasma sodium)

Question 2

What is blood pressure?

Answer 2

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

Question 3

What are the 3 main physiological factors regulating blood pressure?

Answer 3

** 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**

Question 4

What is Phaeochromocytoma?

Answer 4

• 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

Question 5

How is cardiac output regulated by hormones?

Answer 5

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

Question 6

How is vascular tone/ vasoconstriction regulated by hormones?

Answer 6

increased by:

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

Question 7

How is extracellular fluid volume regulated by hormones?

Answer 7

increased by:

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

Question 8

What is endocrine hypertension?

Answer 8

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

Question 9

When is renin released in response?

Answer 9

-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

Question 10

What are the rapid effects of RAS and aldosterone?

Answer 10

-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

Question 11

What are the physiological actions of aldosterone at the DCT?

Answer 11

• 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

Question 12

What are the long term effects of RAS and aldosterone?

Answer 12

-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

Question 13

What are inhibitors of the adrenal gland?

Answer 13

• Low plasma K+
• High plasma Na+
• ANP

Question 14

What are trophic factors of the adrenal gland?

Answer 14

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

Question 15

What happens in long term exposure to aldosterone?

Answer 15

-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

Question 16

How is heart failure linked to aldosterone?

Answer 16

• Plasma aldosterone elevated in patients with heart failure

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

Question 17

What are the benefits of spironolactone in heart failure therapy?

Answer 17

-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

Question 18

What are the causes of hypertension?

Answer 18

• ~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)

Question 19

What are causes of secondary hypertension?

Answer 19

• 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)

Question 20

What are the causes of primary hyperaldosteronism?

Answer 20

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

Question 21

Describe Conn’s Syndrome

Answer 21

=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

Question 22

Describe Bilateral adrenal hyperplasia

Answer 22

=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

Question 23

Describe Glucocorticoid-Remediable Aldosteronism

Answer 23

=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)

Question 24

What genes are involved in GRA?

Answer 24

-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

Question 25

What are the causes of secondary hyperaldosteronism?

Answer 25

- Renin-secreting JG cell tumour | - Renal arterial stenosis

Question 26

Describe renin-secreting JG cell tumour

Answer 26

``` =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 ```

Question 27

Describe renal arterial stenosis

Answer 27

``` =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 ```

Question 28

How does Cushing's present?

Answer 28

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

Question 29

Describe the Cushing's phenotype

Answer 29

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

Question 30

How does elevated plasma cortisol cause hypertension?

Answer 30

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)

Question 31

What is eNOS involved in?

Answer 31

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

Question 32

Why is cortisol binding to MR receptors in excess?

Answer 32

- 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

Question 33

What are the causes of glucocorticoid hyperactivity?

Answer 33

- Apparent mineralocorticoid excess | - Drugs and liquorice ingestion

Question 34

Describe apparent mineralocorticoid excess

Answer 34

``` =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 ```

Question 35

Describe how drugs and liquorice ingestion leads to glucocorticoid hyperactivity

Answer 35

``` =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! ```

Question 36

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

Answer 36

- freeze, fight & flight response - ↑ heart rate, vasoconstriction, peripheral resistance - ↑ glucagon secretion, ↓ insulin secretion - ↑ glycogen & lipid breakdown

Question 37

What is pheochromocytoma?

Answer 37

- chromaffin cell tumour of adrenal medulla - secrete catecholamines - noradrenaline and/or adrenaline

Question 38

What are the symptoms of pheochromocytoma?

Answer 38

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

Question 39

How is pheochromocytoma diagnosed and treated?

Answer 39

- 24 hour urinary metanephrines & catecholamines | - α-blockers, β-blockers, surgical resection

Question 40

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

Answer 40

-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

Question 41

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

Answer 41

- Low plasma renin status | - Aldosterone-Renin Ratio (ARR)

Question 42

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

Answer 42

-< 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!

Question 43

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

Answer 43

-<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 … ?

Question 44

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

Answer 44

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