Friday, May 18, 2007

SIADH or SIAD-where did the "h" go and does it matter?

Fifty years ago the syndrome of inappropriate secretion of anti-diuretic hormone was described in a lung cancer patient and the term SIADH (Syndrome of inappropriate anti-diuretic hormone secretion) entered the medical vocabulary. The anti-diuretic hormone was later identified as arginine vasopressin (AVP). I have thought for some time that things would have been simpler and easier to think about if instead of anti-diuretic hormone this water retaining hormone would have actually been called "water retaining hormone" but its too late now.

A recent article in NEJM informs the readers that only about one-third of cases of SIADH have non-suppressed levels of arginine vasopressin so that the term "Syndrome of Inappropriate Antidiuresis " is more correct or appropriate.

I thought this was something new rather than some subtlety I have just missed but a perfunctory Google search leads to more than one not- very- recent article than used that term in the sense of SIADH being a subset of SIAD. So the term has been around for more than a year or two.

So what is the pathophysiology in those cases without levels of ADH that are too high for the situation? In some the "osmostat" is reset.This means that ADH release is suppressed only at a lower level of serum osmolality than normal. In other cases, the vasopressin renal receptor is somehow able to concentrate urine even in the absence of arginine vasopressin.These variation in the aquaporin receptor-recently reported in the NEJM bring about a Nephrogenic syndrome of inappropriate antidiuresis.

The authors of the Clinical Practice Review in the May 17.2007 NEJM (Ellison DH and Berl T, MEJM 356;20 p 2064) state that:

"Measurement of the serum level of arginine vasopressin is not recommended routinely, because urinary osmolality above 100 mOsm per kilogram of water is usually sufficient to indicate excess circulating arginine vasopressin."

I am confused by this. I had considered an osmolality above 100 an important criterion for the diagnosis. Yet we are told that only about 1/3 of cases ( that meet the criteria that include the urine osmolality criterion) a have elevated arginine vasopressin.So the urine osmolality criterion does not mean elevated AVP is about 2/3 of cases. In fact, had the authors of the article that described the aquaporin mutations made that assumption the syndrome might still await description and a entire new avenue of water balance physiology would not have been opened.

In any event, apparently the presence or absence of the "h" seems to make no difference in the recommended therapy which as the authors clearly indicate is fraught with disagreement about the specifics.

Treatment has always seemed to involve avoiding hard places and rocks. One risk is that the cerebral edema induced by the hypo-osmolality is clearly a bad thing and should not be allowed to persist and worsen and on the other hand there is the somewhat mysterious spectre of osmotic demyelination which is typically referred to by one of it forms namely central pontine myelinolysis. Here is an excellent 1997 reference which includes a description of the impressive deductive abilities of the ancient ( circa 1940s and 1950s) neurologists who seemed to be able to see into the brain without benefit of MRIs and described the pontine loss of myelin.

The myelinolysis seems to be caused by too rapid correction of the hyponatremia, at least that is the consensus theory while some authors still blame the severe hyponatremia per se.But how rapid is too rapid?It is thought to be more likely to occur with correction in chronic cases ( the brain cells seems to adapt to hyponatremia by loosing osmotically active molecules and thereby limiting the degree of cerebral edema.)

If most-according to the recent NEJM review) cases do not actually have elevated ADH levels ,what does that mean for the efficacy or safety of the "vaptan" group of drugs. There are at least four vasopressin-receptor antagonists with one intravenous drug (conivaptan-trade name Vaprisol) approved already and oral prparations in the drug pipeline. I wonder if the ADH level is not high what good (harm?) would happen if they are used and the ADH level is not the culprit?