Lecture: tolvaptan for the cirrhotic population

Today’s lecture focused on hyponatremia in the cirrhotic population.  It is recognized that nearly 50% of cirrhotics will experience hyponatremia, but just 2% will have severe hyponatremia (<120).  You must first try to exclude cases of hypovolemic hyponatremia, often seen in the setting of overdiuresis, diarrhea and emesis; the hyponatremia here occurs when the volume-depleted patient consumes free water as compensation.  Always consider alternative causes like thyroid disorders, adrenal insufficiency and SIADH.  

That will leave you with the most common cause: hypervolemic hyponatremia.  The problem here is again dilutional in nature, with the osmolar-independent pathway of ADH hyperstimulation counteracting the extreme vasodilation of portal hypertension.  It occurs less frequently before the development of ascites.  We learned that as disease severity progresses (ie. advanced Childs class) these patients lose the ability to concentrate their urine and remain highly sodium-avid.  The first step in treatment is volume restriction, which is usually successful.  When unsuccessful, phamacologics are indicated, not hypertonic fluids, which will only cause worsening of ascites and third spacing of fluid.  

Tolvaptan is the agent of choice, but beware, its reliability is uncertain in the cirrhotic population.  Tolvaptan is a blocker of V2 receptors on the apical membrane of collecting duct cells, and its affinity is higher than ADH.  By inhibiting ADH action on these receptors, intracellular cAMP is decreased along with the number of aquaporin channels on the basolateral membrane.  In sum, water is not reabsorbed into the body and a free-water aquaresis ensues.

In previous phase III clinical trials with tolvaptan, the majority of subjects had heart failure or SIADH and very few were cirrhotic.  The sodium level in cirrhotics did not rise as dramatically as in the other groups.  For all groups, hyponatremia returned when the drug was discontinued.  There have not been any impactful publications on tolvaptan for the cirrhotic population in the past few years.  
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