Because the plasma sodium concentration reflects the balance between the sodium content and the water content of the plasma, the causes of hyponatremia can be grouped by which side of that balance moves. In practice they fall into three groups.
Intravascular volume depletion
Loss of intravascular volume, or hypovolemia, leads to release of vasopressin (AVP, the same hormone as ADH) by the posterior pituitary gland. The nephrons then reabsorb more pure water, the water content rises, and the concentration of sodium in the plasma falls. The difficulty is that the process does not stop once hyponatremia appears: despite the falling sodium, AVP production continues, so the hyponatremia worsens in patients who remain hypovolemic.
The same mechanism is triggered by conditions that reduce effective circulating volume even when total body volume is high. In heart failure, poor perfusion of the tissues, especially the kidney, makes the body sense hypovolemia despite an increased total body volume; AVP is overproduced, water over-accumulates, and hyponatremia worsens. Portal hypertension acts similarly, and hypoalbuminemia does so because a fall in osmotic pressure reduces the water held within the vessels.
Hypotonic fluid intake exceeding water excretion
The second group moves the water side of the balance directly. When hypotonic fluid is taken in faster than the kidney can excrete water, the water content rises and the sodium is diluted. This can happen with oral fluid over-intake in patients with dipsogenic diabetes insipidus, with intravenous fluid therapy, and with absorption of the hypotonic fluid used during colonoscopy or surgery of the lower urinary tract.
Syndrome of inappropriate antidiuresis
In the syndrome of inappropriate antidiuresis, or SIAD, there is failure to suppress vasopressin release completely when osmolarity falls below the threshold that should inhibit it. The continuous action of AVP leads to hyponatremia through over-accumulation of water in the body.
SIAD is not the same as the SIADH. SIAD emphasises the antidiuretic effect itself, which may come either from over-secretion of ADH or from an abnormality at the level of the kidney, whereas in the SIADH the emphasis is on the over-production of ADH. The SIADH is therefore a subgroup of SIAD, and it is the most common cause of hyponatremia. The main causes of SIAD are:
| Causes of SIAD | Examples |
|---|---|
| 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; pancreatic, duodenal and head/neck cancers |
| Surgery | Abdominal, thoracic or pituitary surgery |
| Pulmonary disease | Pneumonia; pneumothorax |
| Idiopathic |
The diagnosis of SIAD rests on exclusion, because its laboratory picture is shared with conditions that reduce renal water loss for other reasons. Causes of volume depletion must be excluded, together with endocrine causes of reduced water loss from the kidney other than ADH — hypotension and hypovolemia, adrenal failure, non-osmotic stimuli for AVP, oedema and hypothyroidism.
Central salt wasting
Central salt wasting is a rare acquired cause in which the patient has natriuresis, leading 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, so these patients may over-produce AVP after only a small fall in blood flow rather than a true fall in blood volume. Under the broad definition of SIAD this places it in the antidiuresis group, but it is not SIADH, because the patient is genuinely hypovolemic. That combination is also what makes it diagnosable: central salt wasting produces hyponatremia concurrent with clinical and laboratory signs of hypovolemia, whereas the patient with SIADH is clinically euvolemic.
Nephrogenic SIAD
Vasopressin acts on the kidney through the V2 receptor. A loss-of-function mutation in the gene for this receptor causes X-linked diabetes insipidus, in which water is lost. A gain-of-function mutation has the opposite effect: the receptor becomes constitutively active, meaning active without needing vasopressin, and the result is chronic hyponatremia.
Whichever group is responsible, the plasma sodium ends up low; how the patient presents then depends on how low it falls and how quickly it developed.