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46 Cards in this Set
- Front
- Back
What are the Mendelian forms of blood pressure abnormality?
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- Syndrome of Apparent Mineralocorticoid Excess (AME)
- Liddle Syndrome - Gitelman and Bartter Syndromes |
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How does a patient with Syndrome of Apparent Mineralocorticoid Excess (AME) present?
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- Low birth weight
- Failure to thrive - Severe HTN in early childhood - Extensive organ damage - Renal failure |
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Clinically, what lab findings are associated with Syndrome of Apparent Mineralocorticoid Excess (AME)?
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- HTN
- Hypokalemia - Metabolic alkalosis - Low plasma renin activity - Low plasma aldosterone levels |
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How do you diagnose Syndrome of Apparent Mineralocorticoid Excess (AME)?
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- Measure urine cortisol to cortisone ratio
* Very low or undetectable urinary free cortisone levels |
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What mutation is responsible for Syndrome of Apparent Mineralocorticoid Excess (AME)? Normal function?
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11β-HSD2 - normally functions to convert cortisol to cortisone
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How is the mutation in Syndrome of Apparent Mineralocorticoid Excess (AME) inherited?
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- Autosomal recessive
- Very rare mutation, so often from consanguineous relationship (same ancestors) |
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What will a pedigree show for a patient with Syndrome of Apparent Mineralocorticoid Excess (AME)?
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- May reveal affected siblings (autosomal recessive mutation - 25% chance)
- Not likely in previous generations |
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What happens if there is a mutation in 11β-HSD2 gene?
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- Syndrome of Apparent Mineralocorticoid Excess (AME)
- Cortisol is not being converted to Cortisone - Build up of cortisol leads to binding to Mineralocorticoid Receptor (MR) |
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What is Liddle Syndrome also known as?
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Pseudo-aldosteronism
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Clinically, what lab findings are associated with Liddle Syndrome? How does this compare to Syndrome of Apparent Mineralocorticoid Excess (AME)?
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- 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 |
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What mutation is responsible for Liddle Syndrome? Normal function?
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- 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+ |
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How do you diagnose Liddle Syndrome?
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Gene sequencing of SCNN1G and SCNN1B genes to confirm diagnosis
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How is the mutation in Liddle Syndrome inherited?
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Autosomal Dominant
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What will a pedigree show for a patient with Liddle Syndrome?
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One of the parents will be affected (possibly other siblings) because it is Autosomal Dominant
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What are the transport characteristics in the principal cells of the late distal tubule and cortical collecting duct? Regulation?
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- Reabsorbs Na+ (ENaC)
- Secretes K+ - Regulated by aldosterone - Water permeability regulated by ADH |
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What drugs antagonize aldosterone? What cells / location in nephron do they affect?
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- Spironolactone and Eplerenone
- Target Principal cells of Late Distal Tubule and Cortical Collecting Duct |
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What drugs antagonize Na+ Channels (ENaC)? What cells / location in nephron do they affect?
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- Amiloride and Triamterene
- Target Principal cells of Late Distal Tubule and Cortical Collecting Duct |
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What is the action of Aldosterone? Location of action?
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- Increases NaCl reabsorption
- Increases K+ secretion - Increases H2O reabsorption - Acts in principal cells of late distal tubule and collecting duct |
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What hormones bind the Mineralocorticoid Receptor?
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- Aldosterone
- Cortisol (but not cortisone) |
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What are the effects of Aldosterone or Cortisol binding to the Mineralocorticoid Receptor (MR)?
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Movement of ENaC to apical membrane of principal cells (which causes more reabsorption of Na+)
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How do you treat Apparent Mineralocorticoid Excess (AME)?
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- Reduce endogenous cortisol production
- Decrease Na+ channel activity: Amiloride or Triamterene - Block mineralocorticoid receptor: Spironolactone or Eplerenone - K+ repletion - Dexamethasone for ACTH suppression |
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What is the prognosis for Apparent Mineralocorticoid Excess (AME)?
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Poor because of advanced progression of disease at time of diagnosis
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How do you treat Liddle Syndrome?
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Agents that decrease ENaC activity: Amiloride or Triamterene
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What is the prognosis for Liddle Syndrome?
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- Good prognosis w/ treatment w/ Amiloride or Triamterene (block ENaC)
- Without tx, cardiovascular and renal complications from uncontrolled HTN |
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How does a patient with Bartter Syndrome present?
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- Early childhood
- Growth and mental retardation - Polyuria and polydipsia (great thirst) - Hypercalciuria |
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How does a patient with Gitelman Syndrome present?
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- Adolescence / adulthood
- Cramping of arms and legs - Fatigue - Hypomagnesemia - Polyuria and nocturia |
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Clinically, what lab findings are associated with Bartter and Gitelman Syndromes? How does this compare to AME and Liddle Syndrome?
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- Hypokalemia (same)
- Metabolic alkalosis (same) * Hyper-reninemia (vs low renin activity) * Hyper-aldosteronism (vs low aldosterone activity) |
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How is the mutation in Bartter and Gitelman Syndromes inherited?
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- Autosomal recessive
- Often from consanguineous relationship (same ancestors) |
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What will a pedigree show for a patient with Bartter and Gitelman Syndromes?
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- May reveal affected siblings (autosomal recessive mutation - 25% chance)
- Not likely in previous generations (same as AME) |
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What are the transport characteristics in the principal cells of the thick ascending loop of Henle? Regulation?
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- 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) |
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What drugs target the Na+/K+/2Cl- transporter? Location?
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- Loop diuretic: Furosemide, Ethacrynic Acid, Bumetanide
- Thick Ascending Loop of Henle |
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What are the transport characteristics in the principal cells of the early distal tubule? Regulation?
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- Reabsorbs Na+, Cl-, Ca2+, and Mg2+
- Not permeable to H2O |
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What drugs target the Na+/Cl- transporter? Location?
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- Thiazide diuretics
- Early Distal Tubule |
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Where are the mutations for Bartter Syndrome?
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All in Thick Ascending Loop of Henle
- Type 1: Na+/K+/2Cl- transporter - Type 2: K+ channel - Type 3: Cl- channel |
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Where are the mutations for Gitelman Syndrome?
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Early Distal Tubule (Convoluted)
- Na+/Cl- transporter |
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Mutations in Na+/Cl- transporter cause what? What diuretic acts like this?
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- Gitelman Syndrome
- Thiazide Diuretics |
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Mutations in Na+/K+/2Cl- transporter cause what? What diuretic acts like this?
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- Bartter Syndrome Type 1
- Loop Diuretics: Furosemide, Ethacrynic Acid, Bumetanide |
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Mutations in K+ channel of thick ascending limb of loop of Henle cause what?
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Bartter Syndrome Type 2
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Mutations in Cl- channel of thick ascending limb of loop of Henle cause what?
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Bartter Syndrome Type 3
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How do Bartter and Gitelman Syndromes affect salt conc., BP, Renin-Ang system? Implications?
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- 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) |
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Why do Bartter and Gitelman Syndromes cause hypokalemia?
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Activation of Renin-Angiotensin-Aldosterone system leads to K+ secretion
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What acid-base disturbance do Bartter and Gitelman Syndromes cause? Why?
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Metabolic Alkalosis because activation of Renin-Angiotensin-Aldosterone system causes H+ secretion
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What are the mutations in Bartter Syndrome?
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- BSND
- CLCNKA - CLCNKB - KCHJ1 - SLC12A1 (genes that encode proteins in ascending part of Henle's loop) |
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What are the mutations in Gitelman Syndrome?
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- SLC12A3 gene (thiazide-sensitive Na-Cl cotransporter)
- CLCNKB (less commonly) |
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What does Bartter Syndrome mimic? Gitelman Syndrome?
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- Bartter: chronic Loop diuretic ingestion
- Gitelman: chronic Thiaxide diuretic ingestion |
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What is the prognosis for Bartter and Gitelman Syndromes?
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- Bartter: reduced in severe cases, prognosis is poor
- Gitelman: good prognosis w/ proper treatment |