SIADH

• The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterised by excessive secretion of antidiuretic hormone (ADH) from the posterior pituitary gland or another source.
• ADH controls water reabsorption via its effect on kidney nephrons, causing the retention of water (but not the retention of solutes). By increasing water retention, ADH assists in the dilution of the blood, decreasing the concentration of solutes such as sodium.
• Normal physiology of ADH secretion: 

  1. ADH is produced by the hypothalamus in response to increased serum osmolality.
  2. Released into the circulatory system by posterior pituitary.
  3. At kidneys, binds to ADH receptors on the distal convoluted tubules.
  4. Aquaporin-2 channels move from cytoplasm, into the apical membrane of the tubules. Water is reabsorbed into blood. Decreasing volume and increasing urine osmolality.
  5. Water reabsorbed reduces serum osmolality.
  6. This is detected by the hypothalamus and causes decreased production of ADH.
• The difference between normal physiology and what occurs in SIADH is the lack of an effective negative feedback mechanism. This results in continual ADH production, independent of serum osmolality. This leads to abnormally low serum sodium levels and relatively high urinary sodium levels.
• There are lots of potential causes of SIADH, including:

  • Primary brain injury (e.g. meningitis, subarachnoid haemorrhage)
  • Malignancy (e.g. small-cell lung cancer)
  • Drugs  (e.g. carbamazepine, SSRIs, amitriptyline)
  • Infectious (e.g. atypical pneumonia, cerebral abscess)
  • Hypothyroidism
• The symptoms of SIADH vary depending upon both the severity of the hyponatraemia and the rate at which it develops:

  • Mild hyponatraemia: nausea, vomiting, headache, anorexia and lethargy.
  • Moderate hyponatraemia: muscle cramps, weakness, confusion and ataxia.
  • Severe hyponatraemia: drowsiness, seizures and coma.
• 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 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 occur if the change in sodium concentration is gradual, explaining the more severe symptoms associated with acute hyponatraemia and the potentially less severe symptoms associated with chronic hyponatraemia.
• Clinical signs of SIADH can include:

  • Decreased level of consciousness
  • Cognitive impairment: short-term memory loss, disorientation and confusion
  • Focal or generalised seizures
  • Brain stem herniation (severe acute hyponatraemia) results in coma and respiratory arrest
  • Hypervolaemia: pulmonary oedema, peripheral oedema, raised jugular venous pressure and ascites
• A fluid/hydration status assessment is vital in any patient with hyponatraemia
• • Patients with SIADH are typically euvolemic or hypervolaemic (i.e. not dehydrated)
  • If dehydration is present, it may suggest an alternative cause for the hyponatraemia (e.g. diuretic-related renal failure)
• Relevant bloods for diagnosing SIADH include:

  • Urea & electrolytes: serum sodium is low in SIADH (<130 mmol/L).
  • Plasma osmolality: reduced in SIADH (due to low serum sodium).
  • Thyroid function tests (TFTs): hypothyroidism is a potential cause of SIADH.
  • Serum cortisol: should be checked to rule out Addison’s disease as a cause of hyponatraemia (cortisol is reduced in Addison’s disease).
• Relevant urine tests for diagnosing SIADH include:

  Urine osmolality: in healthy individuals, if serum osmolality is low, urine osmolality should also be low, as the kidneys should be working hard to retain solute. In SIADH, excess ADH results in water retention but not solute retention. As a result, concentrated urine (which is relatively high in sodium) is produced despite low serum sodium.

  Urine sodium: raised in SIADH despite low serum sodium concentration.
• Relevant imaging for diagnosing SIADH include:

  Chest X-ray and/or CT-chest: used to rule out causes of SIADH (e.g. small cell lung cancer, atypical pneumonia).
• The following features must be present for a diagnosis of SIADH to be established: ³

  • Hyponatraemia
  • Low plasma osmolality
  • Inappropriately elevated urine osmolality (i.e. greater than plasma osmolality)
  • Urine [Na+] >40 mmol/L despite normal salt intake
  • Euvolaemia
  • Normal thyroid and adrenal function
• Management of SIADH varies depending on the underlying cause. Definitive management involves treating the underlying cause of SIADH. Fluid restriction is a common management strategy used to increase serum sodium concentrations, at least temporarily, whilst the underlying cause is sought and treated. 
• In the management of SIADH, electrolyte free water clearance should be calculated using the Furst formula which is urine sodium plus urine potassium divided by serum sodium. If the value is less than 0.5 then the patient should be commenced on 1L fluid restriction, if between 0.5-1.0 the patient should be on 0.5L fluid restriction, if the value is 1.0 then fluid restriction is not advised.
• Once fluid restriction is commenced, the response should be assessed after 24-48 hours, if response is poor then consult with the endocrinologist and consider Tolvaptan or Demeclocycline and monitor sodium 6 hourly and aim for a target of 130mmol/L.