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46 Cards in this Set

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What are the Mendelian forms of blood pressure abnormality?
- Syndrome of Apparent Mineralocorticoid Excess (AME)
- Liddle Syndrome
- Gitelman and Bartter Syndromes
How does a patient with Syndrome of Apparent Mineralocorticoid Excess (AME) present?
- Low birth weight
- Failure to thrive
- Severe HTN in early childhood
- Extensive organ damage
- Renal failure
Clinically, what lab findings are associated with Syndrome of Apparent Mineralocorticoid Excess (AME)?
- HTN
- Hypokalemia
- Metabolic alkalosis
- Low plasma renin activity
- Low plasma aldosterone levels
How do you diagnose Syndrome of Apparent Mineralocorticoid Excess (AME)?
- Measure urine cortisol to cortisone ratio
* Very low or undetectable urinary free cortisone levels
- Measure urine cortisol to cortisone ratio
* Very low or undetectable urinary free cortisone levels
What mutation is responsible for Syndrome of Apparent Mineralocorticoid Excess (AME)? Normal function?
11β-HSD2 - normally functions to convert cortisol to cortisone
11β-HSD2 - normally functions to convert cortisol to cortisone
How is the mutation in Syndrome of Apparent Mineralocorticoid Excess (AME) inherited?
- Autosomal recessive
- Very rare mutation, so often from consanguineous relationship (same ancestors)
What will a pedigree show for a patient with Syndrome of Apparent Mineralocorticoid Excess (AME)?
- May reveal affected siblings (autosomal recessive mutation - 25% chance)
- Not likely in previous generations
What happens if there is a mutation in 11β-HSD2 gene?
- Syndrome of Apparent Mineralocorticoid Excess (AME)
- Cortisol is not being converted to Cortisone
- Build up of cortisol leads to binding to Mineralocorticoid Receptor (MR)
- Syndrome of Apparent Mineralocorticoid Excess (AME)
- Cortisol is not being converted to Cortisone
- Build up of cortisol leads to binding to Mineralocorticoid Receptor (MR)
What is Liddle Syndrome also known as?
Pseudo-aldosteronism
Clinically, what lab findings are associated with Liddle Syndrome? How does this compare to Syndrome of Apparent Mineralocorticoid Excess (AME)?
- HTN (young onset, severe)
- Hypokalemia
- Metabolic alkalosis
- Low plasma renin activity
- Low plasma aldosterone levels
* Urinary aldosterone

All of the same findings as in AME, except * is new
What mutation is responsible for Liddle Syndrome? Normal function?
- Gain-of-function mutation in renal epithelial Na+ channel (either β or γ subunit): SCNN1G and SCNN1B genes
- Leads to constitutive expression of ENaC
- Normally it is not expressed all of the time, limiting the amount of intracellular Na+
- Gain-of-function mutation in renal epithelial Na+ channel (either β or γ subunit): SCNN1G and SCNN1B genes
- Leads to constitutive expression of ENaC
- Normally it is not expressed all of the time, limiting the amount of intracellular Na+
How do you diagnose Liddle Syndrome?
Gene sequencing of SCNN1G and SCNN1B genes to confirm diagnosis
Gene sequencing of SCNN1G and SCNN1B genes to confirm diagnosis
How is the mutation in Liddle Syndrome inherited?
Autosomal Dominant
Autosomal Dominant
What will a pedigree show for a patient with Liddle Syndrome?
One of the parents will be affected (possibly other siblings) because it is Autosomal Dominant
One of the parents will be affected (possibly other siblings) because it is Autosomal Dominant
What are the transport characteristics in the principal cells of the late distal tubule and cortical collecting duct? Regulation?
- Reabsorbs Na+ (ENaC)
- Secretes K+
- Regulated by aldosterone
- Water permeability regulated by ADH
- Reabsorbs Na+ (ENaC)
- Secretes K+
- Regulated by aldosterone
- Water permeability regulated by ADH
What drugs antagonize aldosterone? What cells / location in nephron do they affect?
- Spironolactone and Eplerenone
- Target Principal cells of Late Distal Tubule and Cortical Collecting Duct
- Spironolactone and Eplerenone
- Target Principal cells of Late Distal Tubule and Cortical Collecting Duct
What drugs antagonize Na+ Channels (ENaC)? What cells / location in nephron do they affect?
- Amiloride and Triamterene
- Target Principal cells of Late Distal Tubule and Cortical Collecting Duct
- Amiloride and Triamterene
- Target Principal cells of Late Distal Tubule and Cortical Collecting Duct
What is the action of Aldosterone? Location of action?
- Increases NaCl reabsorption
- Increases K+ secretion
- Increases H2O reabsorption
- Acts in principal cells of late distal tubule and collecting duct
- Increases NaCl reabsorption
- Increases K+ secretion
- Increases H2O reabsorption
- Acts in principal cells of late distal tubule and collecting duct
What hormones bind the Mineralocorticoid Receptor?
- Aldosterone
- Cortisol (but not cortisone)
What are the effects of Aldosterone or Cortisol binding to the Mineralocorticoid Receptor (MR)?
Movement of ENaC to apical membrane of principal cells (which causes more reabsorption of Na+)
Movement of ENaC to apical membrane of principal cells (which causes more reabsorption of Na+)
How do you treat Apparent Mineralocorticoid Excess (AME)?
- Reduce endogenous cortisol production
- Decrease Na+ channel activity: Amiloride or Triamterene
- Block mineralocorticoid receptor: Spironolactone or Eplerenone
- K+ repletion
- Dexamethasone for ACTH suppression
What is the prognosis for Apparent Mineralocorticoid Excess (AME)?
Poor because of advanced progression of disease at time of diagnosis
How do you treat Liddle Syndrome?
Agents that decrease ENaC activity: Amiloride or Triamterene
What is the prognosis for Liddle Syndrome?
- Good prognosis w/ treatment w/ Amiloride or Triamterene (block ENaC)
- Without tx, cardiovascular and renal complications from uncontrolled HTN
How does a patient with Bartter Syndrome present?
- Early childhood
- Growth and mental retardation
- Polyuria and polydipsia (great thirst)
- Hypercalciuria
How does a patient with Gitelman Syndrome present?
- Adolescence / adulthood
- Cramping of arms and legs
- Fatigue
- Hypomagnesemia
- Polyuria and nocturia
Clinically, what lab findings are associated with Bartter and Gitelman Syndromes? How does this compare to AME and Liddle Syndrome?
- Hypokalemia (same)
- Metabolic alkalosis (same)
* Hyper-reninemia (vs low renin activity)
* Hyper-aldosteronism (vs low aldosterone activity)
How is the mutation in Bartter and Gitelman Syndromes inherited?
- Autosomal recessive
- Often from consanguineous relationship (same ancestors)
What will a pedigree show for a patient with Bartter and Gitelman Syndromes?
- May reveal affected siblings (autosomal recessive mutation - 25% chance)
- Not likely in previous generations

(same as AME)
What are the transport characteristics in the principal cells of the thick ascending loop of Henle? Regulation?
- Rabsorbs 25% of filtered Na+ by Na+/K+/2Cl- transporter
- Lumen positive potential drives paracellular reabsorption of Na+, K+, Mg2+, Ca2+
- Impermeable to H2O (dilutes tubular fluid)
- Rabsorbs 25% of filtered Na+ by Na+/K+/2Cl- transporter
- Lumen positive potential drives paracellular reabsorption of Na+, K+, Mg2+, Ca2+
- Impermeable to H2O (dilutes tubular fluid)
What drugs target the Na+/K+/2Cl- transporter? Location?
- Loop diuretic: Furosemide, Ethacrynic Acid, Bumetanide
- Thick Ascending Loop of Henle
- Loop diuretic: Furosemide, Ethacrynic Acid, Bumetanide
- Thick Ascending Loop of Henle
What are the transport characteristics in the principal cells of the early distal tubule? Regulation?
- Reabsorbs Na+, Cl-, Ca2+, and Mg2+
- Not permeable to H2O
- Reabsorbs Na+, Cl-, Ca2+, and Mg2+
- Not permeable to H2O
What drugs target the Na+/Cl- transporter? Location?
- Thiazide diuretics
- Early Distal Tubule
- Thiazide diuretics
- Early Distal Tubule
Where are the mutations for Bartter Syndrome?
All in Thick Ascending Loop of Henle
- Type 1: Na+/K+/2Cl- transporter
- Type 2:  K+ channel 
- Type 3: Cl- channel
All in Thick Ascending Loop of Henle
- Type 1: Na+/K+/2Cl- transporter
- Type 2: K+ channel
- Type 3: Cl- channel
Where are the mutations for Gitelman Syndrome?
Early Distal Tubule (Convoluted)
- Na+/Cl- transporter
Early Distal Tubule (Convoluted)
- Na+/Cl- transporter
Mutations in Na+/Cl- transporter cause what? What diuretic acts like this?
- Gitelman Syndrome
- Thiazide Diuretics
- Gitelman Syndrome
- Thiazide Diuretics
Mutations in Na+/K+/2Cl- transporter cause what? What diuretic acts like this?
- Bartter Syndrome Type 1
- Loop Diuretics: Furosemide, Ethacrynic Acid, Bumetanide
- Bartter Syndrome Type 1
- Loop Diuretics: Furosemide, Ethacrynic Acid, Bumetanide
Mutations in K+ channel of thick ascending limb of loop of Henle cause what?
Bartter Syndrome Type 2
Bartter Syndrome Type 2
Mutations in Cl- channel of thick ascending limb of loop of Henle cause what?
Bartter Syndrome Type 3
Bartter Syndrome Type 3
How do Bartter and Gitelman Syndromes affect salt conc., BP, Renin-Ang system? Implications?
- Salt wasting
- Hypotension
- Activation of Renin-Angiotensin-Aldosterone system:
→ Movement of ENaC channels to membrane to reabsorb Na+ (inhibits salt wasting)
→ K+ secretion (hypokalemia)
→ H+ secretion (metabolic alkalosis)
- Salt wasting
- Hypotension
- Activation of Renin-Angiotensin-Aldosterone system:
→ Movement of ENaC channels to membrane to reabsorb Na+ (inhibits salt wasting)
→ K+ secretion (hypokalemia)
→ H+ secretion (metabolic alkalosis)
Why do Bartter and Gitelman Syndromes cause hypokalemia?
Activation of Renin-Angiotensin-Aldosterone system leads to K+ secretion
Activation of Renin-Angiotensin-Aldosterone system leads to K+ secretion
What acid-base disturbance do Bartter and Gitelman Syndromes cause? Why?
Metabolic Alkalosis because activation of Renin-Angiotensin-Aldosterone system causes H+ secretion
Metabolic Alkalosis because activation of Renin-Angiotensin-Aldosterone system causes H+ secretion
What are the mutations in Bartter Syndrome?
- BSND
- CLCNKA
- CLCNKB
- KCHJ1
- SLC12A1
(genes that encode proteins in ascending part of Henle's loop)
What are the mutations in Gitelman Syndrome?
- SLC12A3 gene (thiazide-sensitive Na-Cl cotransporter)
- CLCNKB (less commonly)
What does Bartter Syndrome mimic? Gitelman Syndrome?
- Bartter: chronic Loop diuretic ingestion
- Gitelman: chronic Thiaxide diuretic ingestion
What is the prognosis for Bartter and Gitelman Syndromes?
- Bartter: reduced in severe cases, prognosis is poor
- Gitelman: good prognosis w/ proper treatment