Physiology Correlations for Mendelian Forms of Hypertension Flashcards
How does the Syndrome of Apparent Mineralcorticoid Excess (AME) present? How is it different from priamry aldosteronism?
- 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
How do we diagnose AME?
- 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
what is the pathogenesis of AME?
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
What is the clinical picture of liddle syndrome? what is it also known as?
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
what is the pathogenesis of liddle syndrome?
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
how do you treat mineralcorticois excess?
- 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
How do you treat liddle syndorme?
- agents that decrease sodium channel activity
- amiloride
- triamterene
- with treatment prognosis is good
- without treatment cardiovascular and renal complications from uncontrolled hypertension often occur
Compare and contrat AME Syndorme and Liddel Syndrome: what is it a result of
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
Compare and contrast AME Syndrome and Liddle Syndrome:
presentation
AME: early childhood
Liddle Syndrome: childhoos-mostly
Compare and contrast AME Syndrome and Liddle Syndrome: symptoms
AME: hypertension-severe , failure to thrive, short stature
Liddle Syndorme: hypertension-severe
Compare and contrast AME Syndrome and Liddle Syndrome: Biochemistries
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
Compare and contrast AME Syndrome and Liddle Syndrome: molecular
AME: ENzyme conversion of cortisol to cortisone (11B-HSD2)
Liddle: ENaC channel (SCNN1A, SCNN1G, and SCNN1B)
Compare and contrast AME Syndrome and Liddle Syndrome: treatment
AME: spironolactone/eplerenone, amiloride/triamterene, dexamethasone
Liddle: Amiloride/triamterene
Compare and contrast AME Syndrome and Liddle Syndrome: inheritance
AME: autosomal recessive (loss of function)
Liddle: autosomal domniant (gain of function)
What kind of diseases of Gitelman syndrome, and barterr
renal tubular salt-wasting disroders
Compare Bartter Syndrome and Gitelman Syndrome: Defect location
Bartter: ascending limb of loop of henle (site of loop diuretic action)
Gitelman syndrome: distal tubule (side of thiazide diuretic action)
Compare Bartter Syndrome and Gitelman Syndrome: Presentation
Barterr: early onset: potential, infancy, childhood
Gitelman Syndorme: adolescence/ adulthood
Compare Bartter Syndrome and Gitelman Syndrome: symptoms
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
Compare Bartter Syndrome and Gitelman Syndrome: Biochemistries
Barterr: hypokalemic metabolic alkalosis, elevated renin, alodsterone, serum magnesium normal/low, hypercalciuria
Gitelmann: hypokalemic metabolic alkalosis, elevated renin and aldosterone, serum magnesium low, hypocalciuria
Compare Bartter Syndrome and Gitelman Syndrome: Molecular
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)
Compare Bartter Syndrome and Gitelman Syndrome: functional defect
Barterr: concentrating capacity severly impaired
Gitelmann: concentrating capacity normal or mildly impaired
Compare Bartter Syndrome and Gitelman Syndrome: Inheritance
Barterr: autosomal recessive (loss of function)
Gitelmann: autosomal recessive (loss of function)
SO what leads to AME and why
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
Gain of function mutations in ENaC lead to _______-
Liddle syndrome
