Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

What is SIADH?

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterised by the excessive secretion of antidiuretic hormone (ADH) from the posterior pituitary gland, or another source. ADH controls water reabsorption via its action on the kidney nephrons, causing the retention of water (but not the retention of solutes). Therefore by increasing water retention, ADH causes dilution of the blood and in turn decreases the concentration of solutes, such as sodium. In fact, SIADH is one of the most common causes of hyponatraemia.

Physiology

Normal

1. ADH (also known as vasopressin) is produced by the hypothalamus in response to increased serum osmolality.

2. ADH transported from the hypothalamus to the posterior pituitary gland.

3. Next, ADH is released into the circulatory system via the posterior pituitary gland.

4. ADH travels to the kidneys, where it binds to ADH receptors on the distal convoluted tubule.

5. The binding of ADH to its receptors causes Aquaporin-2 channels to move from the cytoplasm and into the apical membrane of the tubules:

• These aquaporin-2 channels allow water to be reabsorbed out of the collecting ducts and back into the bloodstream.
• This results in both a decrease in volume and an increase in osmolality (concentration) of the urine excreted.

6. The extra water that has been reabsorbed re-enters the circulatory system, reducing the serum osmolality.

7. This reduction in serum osmolality is detected by the hypothalamus and results in decreased production of ADH.

Normal physiology: the negative feedback seen is not present in SIADH

Deranged physiology in SIADH

The important difference between normal physiology and what occurs in SIADH is the lack of any negative feedback mechanism. This results in an inability to reduce or stop ADH production – as a result, ADH is continually produced, regardless of what the serum osmolality is. This ultimately leads to abnormally low levels of serum sodium and relatively high levels of urinary sodium, giving rise to the characteristic symptoms and signs associated with SIADH.

What causes SIADH?

Causes of SIADH

• Brain damage – Meningitis / Subarachnoid haemorrhage (SAH)
• Malignancy – Small-cell lung cancer
• Drugs – Carbamazepine / SSRIs / Amitriptyline
• Infectious – Atypical pneumonia / Lung abscess /Cerebral abscess
• Hypothyroidism

Signs and Symptoms

Symptoms¹

Symptoms vary greatly depending on the time taken for the hyponatraemia to develop

Mild hyponatraemia may cause significant symptoms if the drop in sodium is acute, whereas chronically hyponatraemic patients may have very low serum sodium concentrations and yet be completely asymptomatic. This is thought to be due to a compensatory process known as cerebral adaptation, in which brain cells adapt their metabolism to cope with abnormal sodium levels. Cerebral adaptation can only take place if the change in sodium concentration is gradual, explaining the more severe symptoms seen in acute hyponatraemia and the potentially less severe symptoms seen in patients who are chronically hyponatraemic.

• Mild – Nausea / Vomiting / Headache / Anorexia / Lethargy
• Moderate – Muscle cramps / Weakness / Confusion / Ataxia
• Severe – Drowsiness / Seizures / Coma

Signs¹

The signs of SIADH also vary a great deal depending on the rate of serum sodium concentration change

• Decreased level of consciousness 
• Cognitive impairment (short-term memory loss / disorientation / confusion)
• Focal or generalised seizures
• Brain stem herniation – severe acute hyponatraemia (coma / respiratory arrest)
• Hypervolaemia -pulmonary oedema / peripheral oedema / raised JVP / ascites

Investigations³

Fluid status:

• Is the patient clinically or biochemically dehydrated?
  • In SIADH this will not be the case – the patient is either euvolemic or hypervolaemic
  • If dehydration is present, it suggests another cause for hyponatraemia – e.g. diuretics / renal failure

Serum sodium:

• Will be low in SIADH –  <135 mmol/L

Serum potassium:

• If serum potassium is raised in the presence of hyponatraemia Addison’s disease should be considered

Plasma osmolality

• Will be reduced (due to the low sodium concentration found in SIADH)

Urine osmolality:

• Normally if serum osmolality is low, urine osmolality should also be low – this is because the kidneys should be trying to retain solute.
• In SIADH, the excess ADH causes water retention, but not solute retention.
• As a result, concentrated urine relatively high in sodium is produced, despite low the low serum sodium.

Urine sodium :

• This will be seen to be relatively raised, in the context of the decreased serum sodium concentration

TFTs:

• Hypothyroidism is a cause of SIADH – ↓ T3 & ↑TSH would suggest this diagnosis

Serum cortisol:

• Addison’s disease causes ↓ Na – a low serum cortisol would suggest this diagnosis

Imaging:

• Useful in detecting causes of SIADH, for instance, small cell lung cancer

Algorithm to determine the cause of hyponatraemia²

Diagnosis

The following features must be present for a diagnosis of SIADH:³

• Hyponatraemia
• Low plasma osmolality
• Inappropriately elevated urine osmolality (>plasma osmolality)
• Urine [Na+] >40 mmol/L with normal salt intake
• Euvolaemia
• Normal thyroid and adrenal function

Management

It is difficult to give a generic step-by-step management strategy for SIADH as it can result from so many different causes. Therefore, the management strategy should be targeted to treat the underlying cause, in order to achieve long-term correction of sodium metabolism. Specialist endocrine input should be sought before commencing any of these management strategies:

Fluid restriction

This is a common management strategy used to increase serum sodium concentrations, at least temporarily, whilst the underlying cause is sought and treated. Usually, the fluid restriction is between 1-1.5 litres per day. However, this strategy is greatly dependent on patients co-operating with the treatment plan, which some patients may struggle to do.

Replacing sodium

Another general management strategy for treating hyponatraemia is to replace sodium either orally or via IV fluid. However, this must be done with great care – if the sodium concentration is corrected too rapidly, it can result in a devastating complication known as central pontine myelinolysis. Central pontine myelinolysis is characterised by permanent damage to the myelin sheath in the brain stem, causing acute paralysis, dysphagia, dysarthria, diplopia and decreased level of consciousness. As a result, this treatment strategy has to be carried out with extreme caution, and with the recommendation of not correcting serum sodium levels more than 10 mmol/L/24h.

Examples of treating the underlying cause

• Pneumonia – antibiotics
• Carbamazepine – consider switching to alternative anti-epileptic i.e. sodium valproate
• Hypothyroidism – levothyroxine replacement

References

1. Craig S; Hyponatremia in Emergency Medicine, Medscape, Apr 2010 (Symptoms & Signs)

2. Oxford handbook of clinical medicine 7th edition [p666-667]

3. Robert D. Zenenberg,Do, et. al (2010-04-27). “Hyponatremia: Evaluation and Management”. Hospital Practice. 38 (1): 89–96