Physiology Correlations for Mendelian Forms of Hypertension

Question 1

How does the Syndrome of Apparent Mineralcorticoid Excess (AME) present? How is it different from priamry aldosteronism?

Answer 1

• Presentation:
  
  • low birth weight
  • failure to thrive
  • severe hypertension in early childhood
  • extensive organ damage
  • renal failure
• Clinical picture:
  
  • hypertension
  • hypokalemia
  • metabolic aclkalosis
  • low plasma renin activity
  • low plasma and urine aldosterone levels
• similar to primary alodteronism: differential elevated plasma aldosterone levels

Question 2

How do we diagnose AME?

Answer 2

• measure urine cortisol to cortisone ratio
• in most patients with a defective enzyme, the urinary free cortisone levels are very low or undetectable
• gene sequencing of the 11B-HSD2 gene is available to confirm diagnosis
• loss of function mutation
• autosomal recessive inheritance of a rare mutation, often from consanguineous relationship. pedigree may reveal affected sibs but not likely to be in previous generations

Question 3

what is the pathogenesis of AME?

Answer 3

cortisol binds to MR receptor on the nucleus and leads to more cortisol release, the mutation in 11BHSD prevents cortisol from being metabolized to cortisone. So increased cortisol leads to increased cortisol release aka excess mineralocorticoid

Question 4

What is the clinical picture of liddle syndrome? what is it also known as?

Answer 4

aka pseudoaldosteronism

clinical picture:

• hypertension-young onset, severe
• hypokalemis
• metabolic alkalosis
• low plasma renin activity findings similar to other mineralcorticoid excess syndromes
• low plasms and urinary aldosterone

Question 5

what is the pathogenesis of liddle syndrome?

Answer 5

mutation in the renal epithelial sodium channel (alpha, beta, or gamma subunit) leading to constituitive expression

gene sequencing of the SCNN1A, SCNN1B, and SCNN1G genes is available to confirm diagnosis

gain of funciton mutation

increased absorption of sodium leads to hypertension

Question 6

how do you treat mineralcorticois excess?

Answer 6

• block mineral corticoid receptor (aldosterone antagonists)
  
  • spironolactone
  • eplernone
• sodium channel blockers
  
  • amiloride
  • triamterene
• K supplementation
• Dexamethasone for ACTH suppression (reduces endogenous cortisol production)
• prognosis is usually poor because of advanced diseas at time of diagnosis

Question 7

How do you treat liddle syndorme?

Answer 7

• agents that decrease sodium channel activity
  
  • amiloride
  • triamterene
• with treatment prognosis is good
• without treatment cardiovascular and renal complications from uncontrolled hypertension often occur

Question 8

Compare and contrat AME Syndorme and Liddel Syndrome: what is it a result of

Answer 8

AME: cortisol not converted to cortisone, avid cortisol binding to MR induces a mineralocorticoi excess state

Liddle Syndrome: constituitively active ENaC channel leads to persistent unregulated reabsorption of sodium and increased secretion of potassium

Question 9

Compare and contrast AME Syndrome and Liddle Syndrome:

presentation

Answer 9

AME: early childhood

Liddle Syndrome: childhoos-mostly

Question 10

Compare and contrast AME Syndrome and Liddle Syndrome: symptoms

Answer 10

AME: hypertension-severe , failure to thrive, short stature

Liddle Syndorme: hypertension-severe

Question 11

Compare and contrast AME Syndrome and Liddle Syndrome: Biochemistries

Answer 11

AME: hypokalemia, metabolic alkalosis, low plasma renin activity, low plasma and urinary aldosterone

Liddle Syndrome: hypokalemia, metabolic alkalosis, low plasma renin activity, low plasma and urinary aldosterone

Question 12

Compare and contrast AME Syndrome and Liddle Syndrome: molecular

Answer 12

AME: ENzyme conversion of cortisol to cortisone (11B-HSD2)

Liddle: ENaC channel (SCNN1A, SCNN1G, and SCNN1B)

Question 13

Compare and contrast AME Syndrome and Liddle Syndrome: treatment

Answer 13

AME: spironolactone/eplerenone, amiloride/triamterene, dexamethasone

Liddle: Amiloride/triamterene

Question 14

Compare and contrast AME Syndrome and Liddle Syndrome: inheritance

Answer 14

AME: autosomal recessive (loss of function)

Liddle: autosomal domniant (gain of function)

Question 15

What kind of diseases of Gitelman syndrome, and barterr

Answer 15

renal tubular salt-wasting disroders

Question 16

Compare Bartter Syndrome and Gitelman Syndrome: Defect location

Answer 16

Bartter: ascending limb of loop of henle (site of loop diuretic action)

Gitelman syndrome: distal tubule (side of thiazide diuretic action)

Question 17

Compare Bartter Syndrome and Gitelman Syndrome: Presentation

Answer 17

Barterr: early onset: potential, infancy, childhood

Gitelman Syndorme: adolescence/ adulthood

Question 18

Compare Bartter Syndrome and Gitelman Syndrome: symptoms

Answer 18

Barterr: severe hypotension, growth and developmental delays, polyuria and polydipsia

Gitelman syndrome: may be asymptomatic, hypotension cramping of arms and legs, fatigue, polyuria and nocturia

Question 19

Compare Bartter Syndrome and Gitelman Syndrome: Biochemistries

Answer 19

Barterr: hypokalemic metabolic alkalosis, elevated renin, alodsterone, serum magnesium normal/low, hypercalciuria

Gitelmann: hypokalemic metabolic alkalosis, elevated renin and aldosterone, serum magnesium low, hypocalciuria

Question 20

Compare Bartter Syndrome and Gitelman Syndrome: Molecular

Answer 20

Barterr: Na-K-2Cl cotransporter (SLC12A1), apical K channel (KCNJ1), Cl Channel (CLCNKB and CLCNKA) Beta subunit (bartinn) for CL channels (BSND)

Gitelmann: Na-Cl cotransporter (SLC12A3)

Question 21

Compare Bartter Syndrome and Gitelman Syndrome: functional defect

Answer 21

Barterr: concentrating capacity severly impaired

Gitelmann: concentrating capacity normal or mildly impaired

Question 22

Compare Bartter Syndrome and Gitelman Syndrome: Inheritance

Answer 22

Barterr: autosomal recessive (loss of function)

Gitelmann: autosomal recessive (loss of function)

Question 23

SO what leads to AME and why

Answer 23

loss of function mutations in 11BHS2D2 leads to syndrome of AME due to over-activation of ENaC in late distal tubule and cortical colelcting duct

Question 24

Gain of function mutations in ENaC lead to _______-

Answer 24

Liddle syndrome

Question 25

what leads to Gitelman and Barterr syndormes?

Answer 25

loss of function mutations in transporters or channels for Na, K, and/or Cl in thick ascending limb of the loop of Henle or early distal tubule lead to Gitelman and Bartter syndromes