Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH)

Pathophysiology

Anti-diuretic hormone (ADH) is produced in the hypothalamus and secreted by the posterior pituitary gland. It is also known as “vasopressin”. ADH stimulates water reabsorption from the collecting ducts in the kidneys. SIADH is a condition where there is inappropriately large amounts of ADH.

This may be the result of the posterior pituitary secreting too much ADH or the ADH may be coming from somewhere else, for example a small cell lung cancer.

The excessive ADH results in excessive water reabsorption in the collecting ducts. This water dilutes the sodium in the blood so you end up with a low sodium concentration (hyponatraemia). The excessive water reabsorption is not usually significant enough to cause a fluid overload, therefore you end up with a “euvolaemic hyponatraemia”. The urine becomes more concentrated as less water is excreted by the kidneys therefore patients with SIADH have a “high urine osmolality” and “high urine sodium”.

      

Symptoms are Non-Specific

  • Headache
  • Fatigue
  • Muscle aches and cramps
  • Confusion
  • Severe hyponatraemia can cause seizures and reduced consciousness

        

SIADH has countless causes:

  • Post-operative from major surgery
  • Infection, particularly atypical pneumonia and lung abscesses
  • Head injury
  • Medications (thiazide diuretics, carbamazepine, vincristine, cyclophosphamide, antipsychotics, SSRIs, NSAIDSs,)
  • Malignancy, particularly small cell lung cancer
  • Meningitis

      

Initial Diagnosis

In a way, SIADH is a diagnosis of exclusion as we do not have a reliable test to directly measure ADH activity. Clinical examination will show euvolaemia. U+Es will show a hyponatraemia. Urine sodium and osmolality will be high.

Other causes of hyponatraemia need to be excluded:

  • Negative short synacthen test to exclude adrenal insufficiency
  • No history of diuretic use
  • No diarrhoea, vomiting, burns, fistula or excessive sweating
  • No excessive water intake
  • No chronic kidney disease or acute kidney injury

      

Establish the Cause

Sometimes the cause will be clear, for example a new medication, a chest infection or recent major surgery. This can be confirmed by treating the underlying cause and assessing whether the hyponatraemia resolves.

Perform a chest xray as a first line investigation for pneumonia, lung abscess and lung cancer.

We have to suspect malignancy in someone with persistent hyponatraemia with no clear cause, particularly in someone with a history of smoking, weight loss or other features of malignancy. If malignancy is suspected the NICE CKS (March 2015) recommend a CT thorax/abodmen/pelvis and MRI brain to find the malignancy.

      

Management

The aim is to establish and treat the cause of the SIADH. It is most common for medications to be the cause so if possible it is best to stop the causative medication. It is essential correct the sodium slowly to prevent central pontine myelinolysis. Aim for a change in sodium of less than 10 mmol/l per 24 hours.

Fluid restriction involves restricting their fluid intake to 500mls – 1litre. This may be enough to correct the hyponatraemia without the need for medications.

Tolvaptan. “Vaptans” are ADH receptor blockers. They are very powerful and can cause a rapid increase in sodium. Therefore they are usually initiated by a specialist endocrinologist and require close monitoring, for example 6 hourly sodium levels.

Demeclocycline is a tetracycline antibiotic that inhibits ADH. It was used prior to the development of vaptans and is now rarely used for this purpose.

      

Central Pontine Myelinolysis

Central pontine myelinolysis (CPM) is also (and more accurately) known as “osmotic demyelination syndrome”. It is usually a complication of long term severe hyponatraemia (< 120 mmols/l) being treated too quickly (> 10 mmol/l increase over 24 hours).

As blood sodium level falls water will move by osmosis across the blood-brain barrier into the cells of the brain from the area of low concentration of solutes (the blood) to the area of high concentration of solutes (the brain). This causes the brain to swell. The brain adapts to this by reducing the solutes in the brain cells so that water is balanced across the blood-brain barrier and the brain does not become oedematous. This adaptation takes a few days. Therefore, if the hyponatraemia has been present and severe for a long time the brain cells will also have a low osmolality. This is not a problem until the blood sodium levels rapidly rise. When this happens water will rapidly shift out of the brain cells and into the blood. This causes two phases of symptoms:

First phase: this is due to the electrolyte imbalance and the patient presents as encephalopathic and confused. They may have a headache or nausea and vomiting. These symptoms often resolve prior to the onset of the second phase.

Second phase: this is due to the demyelination of the neurones, particularly in the pons. This occurs a few days after the rapid correction of sodium. This may present as spastic quadriparesis, pseudobulbar palsy and cognitive and behavioural changes. There is a significant risk of death.

Prevention is essential as treatment is only supportive once CPM occurs. A proportion of patients make a clinical improvement but most are left with some neurological deficit.

 

Last updated December 2018
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