Plasma sodium concentration reflects the balance between the sodium content and the water content of plasma. Sodium holds water in the extracellular fluid, so the concentration is a ratio, and the water is the side that moves. The concentration falls when the water rises relative to the sodium. That is why the causes of hyponatremia can be grouped by which side of the balance moves.
In practice the causes fall into three groups. In the first, the body has lost intravascular volume. In the second, hypotonic fluid is taken in faster than the kidney can excrete water. In the third, the kidney keeps water when it should not, and this is called the antidiuresis group. Each group is a different route to the same low number.
How does low volume dilute the blood?
The first group starts with loss of intravascular volume (hypovolemia). Low volume overrides the usual switch-off of ADH at low tonicity, so the posterior pituitary gland releases vasopressin (AVP, the same hormone as ADH).
The nephrons then reabsorb more pure water. ADH makes the collecting duct let water through, but salt stays behind. The same sodium is therefore spread through more water: the water content rises and the plasma sodium concentration falls.
Once hyponatremia appears, AVP production does not stop. It continues despite the falling sodium. The low volume does not correct itself, so ADH keeps bringing water back and the sodium keeps falling. This is why hyponatremia worsens in patients who remain hypovolemic.
Why can a full body still act as if it is short of fluid?
If volume depletion drives this, what about patients who are full of fluid? The same mechanism is triggered by conditions that reduce effective circulating volume even when total body volume is high. The body judges volume by how well the arteries are filled, not by how much water it holds in total. When the arteries are poorly filled, the baroreceptors and the kidney read that as low volume.
Heart failure shows this. Tissue perfusion is poor, especially in the kidney, so the body senses hypovolemia despite an increased total body volume. AVP is then overproduced, water over-accumulates, and the hyponatremia worsens.
Portal hypertension acts similarly.
Hypoalbuminemia acts similarly because a fall in osmotic pressure reduces the water held within the vessels.
What if water comes in faster than the kidney can clear it?
The second group moves the water side of the balance directly. The kidney can clear a limited amount of water in a given time. When hypotonic fluid is taken in faster than that, the water content rises and the sodium is diluted.
Examples include:
- Oral fluid over-intake in patients with dipsogenic diabetes insipidus. Here the thirst drive itself is disordered, so the person keeps drinking more than the kidney can clear.
- Intravenous fluid therapy. A hypotonic infusion puts more water into the blood than sodium, and the surplus stays because the kidney cannot clear it fast enough.
- Absorption of hypotonic fluid used during colonoscopy or surgery of the lower urinary tract. The fluid irrigating the operative field is hypotonic, so the water it carries dilutes the sodium once it is absorbed.
What if ADH stays on when it should switch off?
The third group keeps the antidiuretic effect active. In the syndrome of inappropriate antidiuresis (SIAD), vasopressin release is not suppressed completely when osmolarity falls below the threshold that should inhibit it. The continuous AVP action leads to hyponatremia through over-accumulation of water in the body.
SIAD is not the same as SIADH, and the difference lies in the emphasis. SIAD emphasises the antidiuretic effect itself. That effect may come from over-secretion of ADH or from an abnormality at the level of the kidney, which may respond too strongly to the hormone. In SIADH the emphasis is on over-production of ADH, so SIADH is a subgroup of SIAD. SIADH is the most common cause of hyponatremia.
Which drugs and diseases keep ADH on?
With the antidiuresis group defined, the next question is what switches ADH on. The main causes of SIAD are:
- Drugs:
- antidepressants (tricyclics, SSRIs)
- dopamine antagonists (metoclopramide, prochlorperazine, antipsychotics)
- anticonvulsants (carbamazepine, phenytoin, sodium valproate)
- opiates
- CNS disturbances: stroke, hemorrhage, infection, trauma.
- Malignancies: small cell lung cancer, and pancreatic, duodenal and head and neck cancers.
- Surgery: abdominal, thoracic or pituitary surgery.
- Pulmonary disease: pneumonia, pneumothorax.
- Idiopathic.
One drug example has a proposed mechanism: carbamazepine is thought to raise ADH levels, so the kidney holds water.
How is the antidiuresis group confirmed?
The laboratory picture of SIAD is shared with conditions that reduce renal water loss for other reasons. The diagnosis rests on exclusion. Causes of volume depletion must be excluded. Low volume drives ADH up by itself and gives the same blood and urine picture.
Endocrine causes of reduced water loss from the kidney, other than ADH, must also be excluded. They are listed as:
- hypotension and hypovolemia
- adrenal failure, which is linked to altered vasopressin release and to hyponatremia
- non-osmotic stimuli for AVP
- oedema
- hypothyroidism
Can the kidney itself be the problem?
The ruled-out causes leave the kidney. Vasopressin acts on the kidney through the V2 receptor, and the receptor can be lost or stuck on.
A loss-of-function mutation in the V2 receptor gene causes X-linked diabetes insipidus. Without a working receptor the kidney cannot hold water, so water is lost.
A gain-of-function mutation does the opposite. It makes the V2 receptor constitutively active, meaning active without needing vasopressin. The receptor acts as if ADH were present, so the kidney keeps water whether or not ADH is there. The result is chronic hyponatremia.
Is there a look-alike where the volume really is low?
Central salt wasting is a rare acquired cause of hyponatremia. The patient has natriuresis, which leads to hyponatremia with hypovolemia. It develops in several neurosurgical conditions in which cerebral blood flow is disturbed.
A slight reduction in systemic blood flow has a significant effect on blood flow in the central nervous system. These patients may therefore over-produce AVP after only a small fall in blood flow, rather than after a true fall in blood volume. Under the broad definition of SIAD, central salt wasting is placed in the antidiuresis group.
It is not SIADH, because the patient is genuinely hypovolemic. Central salt wasting produces hyponatremia concurrent with clinical and laboratory signs of hypovolemia. The patient with SIADH is clinically euvolemic. The excess in SIADH is water, not salt, so sodium content and volume stay normal and the patient looks normal.
Why does sodium end up low whichever way it happens?
Whichever group is responsible, plasma sodium ends up low. How the patient presents depends on how low plasma sodium falls and how quickly it developed. So what does that low number do to the patient, and why does the speed of the fall matter so much?