Warnock's "Liddle Syndrome: Clinical and Cellular Abnormalities" 1994
From Biol557
Contents |
[edit] Abstract
- They suggest that continuously avid sodium channels in the distal tubule are the result of Liddle Syndrome.
- Avid: "enthusiastic; passionate; longing eagerly; eager; greedy" via wikipedia
- This avidity leads to extra retention of water and sodium as well as potassium wasting and eventually hypertension.
[edit] Introduction
- A doctor noticed that a patient and her siblings had hypokalemia (low potassium), metabolic alkalosis, and hypertension.
- She responded to triamterene but not to spironolactone.
- Triamterene: "Triamterene directly blocks the epithelial sodium channel[1] (ENaC) on the lumen side of the kidney collecting tubule." via wikipedia
- Spironolactone: "is a renal competitive aldosterone antagonist in a class of pharmaceuticals called potassium-sparing diuretics." "Spironolactone inhibits the effect of aldosterone by competing for intracellular aldosterone receptors in the distal convoluted tubule cells (it actually works on aldosterone receptors in the collecting duct)." via wikipedia
[edit] The index case
- Patient presents with hypertension, normal urinary excretion, hypokalemic alkalosis.
- They ruled out primary hypoaldosteronism because sodium levels were normal in sweat and saliva and a low salt diet didn't change anything.
- They tried spironolactone (an aldosterone receptor antagonist) and found no change in any mineralocorticoids.
- "Triannterene, in conjunction with a low-sodium diet, normalized serum potassiumm and bicarbonate in GS and her siblings."
- "Liddle and colleagues concluded that their disorder resulted from a tendency of the kidneys to conserve sodiunn and excrete potassium. even in the virtual absence of mineralocorticoids."
- GS's renal function continued to deteriorate over time, however.
- GS got a double liver transplantation and has since controlled her hypertension while her siblings remain hypertensive.
[edit] Original pedigree
- The family tree of GS includes lots of uncontrolled hypertension and premature death from cardiovascular issues and strokes.
- Not everyone with GS's condition (Liddle syndrome) has hypokalemia.
[edit] Clinical features
- "The most striking finding in Liddle syndrome is the absolute suppression of aldosterone and renin secretion-giving rise to the descriptive term 'pseudoaldosteronism'."
- "Definitive diagnosis depends on the measurement of abnormally low urinary aldosterone and normal levels of other corticosteroid metabolites."
- So, we see that sodium levels are high and suspect that aldosterone signaling may be too high.
- Recall that the aldosterone receptor, when activated will put sodium channels on the apical membrane so sodium can go from filtrate to blood.
- Recall that we usually use aldosterone to activate the aldosterone receptor.
- So we see that So we treat with sprionolactone which will competitively bind to the aldosterone receptor such that fewer of the receptors will be activated because they are binding spironolactone instead of aldosterone.
- But then we see that this doesn't work so we suspect that perhaps the sodium channels that are on the apical surface are just always open for sodium when they aren't supposed to be that way.
- So we treat with triamteren or amiloride which block the sodium channels so there is less reabsorption.
- This works, so we realize that these patients don't have aldosterone problems, they have channel problems!
- "Indeed. inappropriate. sustained reabsorption of sodium by the collecting tubule would cause hypertension that mimics that of mineralocorticoid excess. Concomitant potassium wasting would be caused by the delivery of sodium to this distal segment of the nephron and the secretion of potassium via the parallel conductance pathway in the apical membrane of the collecting tubule. Suppressed secretion of renin and aldosterone would simply result from the salt and water excess that are consistent features of any mineralocorticoid excess."
- Though increased sodium avidity was shown on the erythrocyte membrane, it cannot be a systemic trait because saliva and sweat has the correct avidity and a kidney transplant fixed the index case's hypertension issues.
