SIADH

Alexander Usorov, MD
July 31, 2007
SIADH


Most frequent cause of hyponatremia
First described by Schwartz et al in 1957 in 2 pts with
bronchogenic carcinoma
Arginine vasopressin was then identified
ADH


Synthesized in hypothalamus
Transported down to posterior pituitary
Released in response to hyperosmolality (major stimuli,
mediated through osmoreceptors in hypothalamus) or
hypovolemia (via baroreceptors in left atrium, aortic arch, etc)
ADH


Binds to V2 receptors in collecting tubules
stimulates cyclic adenosine monophosphate
leads to insertion of aquaporin-2 channels into apical
membranes
The goal is to facilitate the transport of solute-free water





























Figure Freeze-fracture appearance of
vasopressin-induced intramembrane particle
(IMP) aggregates in toad urinary bladder (A),
toad epidermis (B), and rat kidney collecting
duct (C). The morphology of the aggregates is
different in all three vasopressin target cells. In
the bladder, the aggregates are tightly packed
linear arrays, in the skin they form orthogonally
packed square arrays, and in the collecting
duct principal cell they form loose clusters that
are often located in shallow depressions on the
cell surface. Bar = 0.25 m.

























Figure Aquaporin-2 (AQP2) is internalized by clathrin-coated pits. A and B, Immunogold
labeling of AQP2 in clathrin-coated pits (arrows) at the apical plasma membrane of
collecting duct principal cells. An antibody against an external epitope of AQP2 was
used. C and D, Label-fracture images of LLC-PK1 cells expressing AQP2. Immunogold
label for AQP2 is located in intramembrane particle (IMP) clusters on the membrane (C,
arrows; and is associated with membrane invaginations that resemble clathrin-coated
pits (D, arrows). For more details, see Sun TX, et al. Bars = 0.25 m.

SIADH => SIAD
A slight misnomer
The name implies inappropriate secretion
1/3
rd
of pts do secrete AVP independent of plasma osmolality
Others exhibit reset osmostat AVP is fully supressed, but
serum Na level is lower than nl
AVP levels may be undetectable in some pts
Some aquaporin mutations lead to concentrated urine in the
absence of AVP
Therefore, the new term, Syndrome of Inappropriate
Antidiuresis (SIAD) has been proposed

Patterns of plasma levels of arginine vasopressin (AVP; also known as the antidiuretic hormone), as
compared with plasma sodium levels in patients with SIAD, are shown. Type A is characterized by
unregulated secretion of AVP, type B by elevated basal secretion of AVP despite normal regulation by
osmolality, type C by a "reset osmostat," and type D by undetectable AVP. The shaded area
represents normal values of plasma AVP. Adapted from Robertson


Disorders associated with SIAD
Malignancies
Carcinomas, lymphomas, sarcoma
Pulmonary disorders
Infectious, asthma, CF
CNS disorders
Infectious, bleeding, masses, MS
Drugs
Chlorpropramide, SSRIs, cyclophosphomide, ecstasy
Diagnosis of SIAD

Essential features
hyponatremia
plasma osm<275
urine osm>100
clinical euvolemia
urinary Na>40
nl thyroid/adrenal fxn, no recent diuretic use
Dx of SIAD

Supplemental features
uric acid<4
BUN<10
failure to correct hypoNa after NS infusion
correction of hypoNa after fluid restriction
Volume status assesment

Sometimes, clinical assesment of volume status is
imprecise. Dr. Berl suggests the following:
Rule out volume contraction by infusing 2L of NS over 24-48
hours.
Urine osm has to be less than 500 (to avoid severe worsening of
hypoNa)
If hypoNa corrects, this suggests volume depletion
NEJM 356:2064-2072
Why 500 osms?

Where did Berl come up with that magic number?
Goldfarb and Rose both tell me that osmolality of
administered IVF must exceed osmolality of urine
Who is right?

Goldfarb-Rose Hypothesis


Prior acceptance that isotonic saline (308 osms) infusion in
SIAD is useless
Electrolytes are excreted in urine
Urine osmolality in SIAD is typically >300
water is retained => worsening hypoNa
Example

Our patient
Urine osms=892
NaCl=308
Excess NaCl to be excreted after 1L infusion
308/892=345cc of urine
655cc of water is retained, hence a reduction in plasma Na
concentration

How much lower?
Total body osmoles=TBW x Posm
Posm is equal to 2 x plasma Na
Total effective osmoles= 0.6 x 50kg x 2 x 129
= 7740 mosmol
655 cc of water is retained, hence TBW is 30.655L
New plasma Na = total effective osmoles / (2 x TBW)
7740 / 61.2 = 127 meq/L
Our pts Na went down to 127

Berls Axiom

Previous study showed an increase in plasma Na of pts with
SIADH from 124 to 127 mEq/l after IV NS (Musch et al Am J
Med 1995;99: 348-55)
Mean initial urinary osmolality was 429 mosm/kg
So why not give SIAD pts isotonic saline?

Treating SIADH with isotonic saline
Musch et al conducted a prospective study of 17 pts with
SIADH (Q J Med 1998; 91:749-753)
Goal to predict the response to isotonic saline based on either
Uosm and UNa+K
2L infusion over 24 hours
Initial plasma Na 115-130
All pts met the criteria for SIADH
Water restriction (<750cc/day)
Stable Na intake (70-120 mEq per day)
Results
11 men, 6 women
mean age 64+13
Underlying conditions of 17 pts
Lung cancer (6)
Other pulm diseases (4)
Cerebral traumatism (2)
Ovarian CA/sarcoma/cortical atrophia (1 each)
Idiopathic SIADH (2)

Results cont.
t0
t24
Sodium
126+5 127+6
Potassium
4+0.4 3.9+0.5
UNa+K
128+61 163+41
Uosm
502+128 497+113
Weak correlation
Strong correlation
Discussion
11 / 17 pts increased their plasma Na after 2L infusion
Uosms exceeded the osmolality of isotonic saline

6 / 17 pts aggravated their hypoNa
mean Uosm > 538 mosm/kg



Prvs assumption that rise in plasma Na by 5 mEq/L after 2L
NS infusion/24h suggests hypovolemia may be incorrect
This response can be observed in SIAD pts as well
Differentiate by high urinary salt excretion
salt-depleted hypovolemic pts conserve salt

Conclusion

Response to NS in SIAD can be predicted from Uosm
Study conducted in older pts
decreased urine concentrating ability
Younger pts are likely to have a slight decrease in serum Na
I believe in Berl