Syndrome of Inappropriate ADH Secretion (SIADH)

See general article on Hyponatraemia.

Hyponatraemia is the commonest electrolyte disorder in inpatients. The commonest underlying causes are

• Volume depletion of the extracellular fluid or
• SIADH - a syndrome of non-osmotic secretion of vasopressin (initially termed antidiuretic hormone)

In SIADH there is "inappropriate" secretion of vasopressin from either

1. The posterior pituitary gland or from
2. Ectopic sources e.g. small-cell lung cancer

(See table below for full list)

Total body sodium content is normal, but water is retained because of elevated vasopressin.⁷ Patients with SIADH continue to drink normal amounts of fluids despite low plasma osmolalities, due to a downward resetting of their osmotic threshold for thirst.⁸ The vasopressin leads to water absorption from renal collecting ducts despite continued fluid intake. However, in two-thirds of patients with SIADH secretion is fully suppressed despite hyponatraemia.¹

This largely depends upon the rate of fall in serum sodium:

• Slow fall in serum sodium - asymptomatic or non-specific features e.g. impaired memory, difficulty concentrating and possibly even falls.¹
• Rapid fall in serum sodium (i.e. rate of fall greater than 0.5 mmol/l/h) - this is potentially fatal. Features may include:
  • Confusion
  • Hallucinations
  • Drowsiness
  • Convulsions
  • Coma
  • Respiratory arrest leading to death
• Symptoms are uncommon until the serum sodium falls below 120 mol/l, or the plasma osmolality drops below 268 mOsmol/kg.
• The cerebral oedema resulting from water intoxication causes the drowsiness, lethargy, irritability, mental confusion and disorientation, with fits and coma being the most profound features.

SIADH can only be diagnosed when there is normal adrenal and thyroid function. There should be no recent use of diuretics. The following features are essential for the diagnosis:

• Hyponatraemia (serum sodium < 135 mmol/l)
• Decreased plasma osmolality (<275 mOsm/kg) and increased urine osmolality (>100 mOsm/kg)
• Euvolaemic on clinical examination
• Increased urinary sodium ( > 40mmol/l)

Other supporting features may include the correction of hyponatraemia with fluid restriction and failure of hyponatraemia to correct with 0.9% saline.

• Renal disease - in chronic kidney disease there is hyponatraemia due to an inability to dilute the urine.
• Adrenal disease (i.e. Addison's disease) - can also cause high urinary sodium with low plasma osmolality.
• Hypothyroidism - hyponatraemia occurs with normal extracellular fluid volume.
• Hyponatraemia with a high plasma osmolality is also caused by hyperglycaemia.
• Hypervolaemic hyponatraemia may be caused by oedema-forming states such as congestive heart failure, liver cirrhosis, renal disease.
• Hyponatraemia in CNS disorders may be due to cerebral salt wasting (CSW) which causes a contracted blood volume, whereas SIADH is a volume-expanded state. In CSW there is excessive release of brain naturietic peptide.¹⁰ Accurate diagnosis is important because vigorous saline replacement and resuscitation is required for CSW, whereas fluid restriction is the treatment of choice for SIADH.

• U & Es and creatinine
• Paired plasma and urine osmolality
• Urinary sodium
• Thyroid function tests
• Adrenal function i.e. 9am cortisol
• Looking for the underlying cause - this should be guided by the history and clinical examination e.g.
  CXR, blood cultures, imaging of the CNS

Acute development of hyponatraemia

• The condition can be fatal when hyponatraemia rapidly develops.
• Severe and symptomatic hyponatraemia which has developed within 48 hours should be treated rapidly.
• Patients may need to be intubated and ventilated if experiencing multiple seizures.
• Endocrinologists should be involved from the outset.
• Serum sodium should be corrected by 3% saline aiming to increase it by 1-2 mmol/L per hour (maximum 8-10 mmol/l in first 24 hours).This needs to be performed under close supervision.
• Some advocate the use of furosemide but this may enhance the rise in serum sodium.

Chronic development of hyponatraemia

• If sodium is corrected too quickly patients may develop central pontine myelinolysis (osmotic demyelination). Patients develop spastic quadriplegia and pseudobulbar palsy.
• Thus the priority here is to find the underlying cause.
• Best effects are with treatment of the underlying cause e.g. withdraw offending drugs, treat neoplasia or infection.
• Fluid restriction to 500-1000 ml/day usually reverses any adverse clinical features and restores the circulating sodium level and osmolality to normal.
• Demethylchlortetracycline (demeclocycline) 600 to 1200 mg daily which induces nephrogenic diabetes insipidus is often highly effective, making water restriction unnecessary (nausea, photosensitivity and diabetes insipidus can occur). It should only be used under specialist guidance.
• Vasopressin receptor antagonists are now licensed for the treatment of chronic hyponatraemia secondary to SIADH in hospitals.^11,12

The prognosis of patients with hyponatraemia is poor and this usually relates to the underlying cause. Mild hyponatraemia is also associated with a poorer outcome especially when there are other co-morbidities present e.g. cardiac failure.¹³

1. Ellison DH, Berl T; Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007 May 17;356(20):2064-72.
2. McDade G; Disorders of sodium balance: hyponatraemia and drug use (and abuse). BMJ. 2006 Apr 8;332(7545):853.
3. OMIM - X-linked Nephrogenic Syndrome of Inappropriate Antidiuresis (NSAID)
4. Feldman BJ, Rosenthal SM, Vargas GA, et al; Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med. 2005 May 5;352(18):1884-90. [abstract]
5. Siegel AJ, Verbalis JG, Clement S, et al; Hyponatremia in marathon runners due to inappropriate arginine vasopressin secretion. Am J Med. 2007 May;120(5):461.e11-7. [abstract]
6. Dhawan SS; Herpes zoster ophthalmicus and syndrome of inappropriate antidiuretic hormone secretion. Am J Med Sci. 2007 Jan;333(1):56-7. [abstract]
7. Warrell DA, et al. Syndrome of Inappropriate ADH Secretion. Oxford Textbook of Medicine, 4th Edition, Parts 12.3 and 12.12. Oxford University Press: 2003.
8. Smith D, Moore K, Tormey W, et al; Downward resetting of the osmotic threshold for thirst in patients with SIADH. Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E1019-23. Epub 2004 Jun 22. [abstract]
9. Baylis PH; The syndrome of inappropriate antidiuretic hormone secretion. Int J Biochem Cell Biol. 2003 Nov;35(11):1495-9. [abstract]
10. Lien YH, Shapiro JI; Hyponatremia: clinical diagnosis and management. Am J Med. 2007 Aug;120(8):653-8. [abstract]
11. Summary of Product Characteristics - Samsca® 15 mg tablets (tolvaptan), Otsuka Pharmaceuticals (UK) Ltd electronic Medicines Compendium, updated 3 August 2009; accessed 29 jan 2010
12. Schrier RW, Gross P, Gheorghiade M, et al; Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006 Nov 16;355(20):2099-112. Epub 2006 Nov 14. [abstract]
13. Reynolds RM, Padfield PL, Seckl JR; Disorders of sodium balance. BMJ. 2006 Mar 25;332(7543):702-5.

• SIADH (GPN)