Syndrome of Inappropriate Antidiuretic Hormone Secretion

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatraemia, typically euvolaemic and sometimes hypervolaemic. It results from inappropriate, non-physiological antidiuretic hormone secretion or action in the absence of an appropriate osmotic or volume related stimulus. This produces water retention and dilutional hyponatraemia.

There is a broad range of underlying causes, including:

• malignancy (particularly small cell lung cancer, given its recognised capacity for ectopic antidiuretic hormone production)
• central nervous system pathology (stroke, haemorrhage, infection, trauma)
• pulmonary pathology (pneumonia, and other significant respiratory pathology)
• medications (particularly certain antidepressants, antiepileptics and antipsychotics)

Diagnosis combines biochemical criteria with careful exclusion of the alternative causes of euvolaemic hyponatraemia and confirmation of a plausible underlying cause.

Pathophysiology

• Inappropriate antidiuretic hormone secretion (or, less commonly, receptor activation independent of the hormone itself) produces excessive renal free water reabsorption at the collecting duct. This dilutes circulating sodium and produces hyponatraemia despite normal or even mildly expanded total body water.
• Severity of hyponatraemia and symptoms reflects the degree of biochemical derangement and, critically, the speed of its development.
• Rapid onset hyponatraemia produces substantially more severe symptoms at any given sodium concentration than gradual, chronic hyponatraemia, which allows a degree of cerebral osmotic adaptation.

• Symptoms of hyponatraemia range from absent or mild, non-specific features (nausea, headache, mild confusion) in chronic, mild to moderate hyponatraemia, to severe, potentially life threatening manifestations (seizure, significantly reduced consciousness, coma) in more severe or rapidly developing hyponatraemia.
• Symptom severity reflects both the absolute sodium level and the rate of its development.
• Clinical assessment characteristically shows euvolaemia: normal skin turgor, absence of oedema or significant postural blood pressure change, and normal jugular venous pressure.
• This is essential to the diagnostic evaluation. SIADH must be distinguished from the causes of hyponatraemia with clear hypervolaemia (heart failure, cirrhosis, nephrotic syndrome) or hypovolaemia (diuretic use, gastrointestinal or renal salt and water losses), which need an entirely different management approach.
• The underlying cause frequently brings its own symptoms or clinical context: respiratory symptoms with a pulmonary cause, neurological symptoms with a central nervous system cause, a malignancy history or new symptoms suggesting malignancy, and a relevant medication history.
• Seek these actively, as they bear directly on the diagnosis and on targeted treatment of the cause.

• Diagnostic criteria are hyponatraemia with reduced plasma osmolality, inappropriately concentrated urine, elevated urinary sodium, clinical euvolaemia, and normal renal, adrenal and thyroid function.
• Urine osmolality above 100 mOsm per kg reflects ongoing renal water retention despite plasma hypo-osmolality, which would normally maximally suppress antidiuretic hormone and produce maximally dilute urine.
• Urinary sodium is generally above 30 mmol per litre, reflecting normal renal sodium handling in euvolaemia. This contrasts with the sodium retention expected in genuine volume depletion.
• Adrenal insufficiency and hypothyroidism can produce a biochemically similar picture and must be specifically excluded.
• Once the diagnosis is biochemically supported, search fully for the underlying cause. This includes a thorough medication review and chest imaging, given the relevance to pulmonary causes and to underlying malignancy, particularly small cell lung cancer.
• Where the presentation indicates, add further imaging or investigation directed at a suspected central nervous system or other underlying cause.
• Establish the rate of onset of hyponatraemia where possible from the history and any prior biochemistry. It bears directly on the safe rate of correction.

• Fluid restriction, typically to approximately 1 to 1.5 litres per day, is standard first line management for chronic, mild to moderate, asymptomatic or minimally symptomatic hyponatraemia due to SIADH. Guide the degree of restriction and expected response by regular biochemical monitoring.
• Severe, symptomatic hyponatraemia (significant confusion, seizure, or reduced consciousness) needs more active treatment, typically hypertonic (3 percent) sodium chloride as a carefully calculated, controlled infusion.
• The critical principle is strict avoidance of overly rapid correction. Rapid correction risks osmotic demyelination syndrome, a severe, potentially permanent neurological injury. The risk is particularly relevant in chronic, longstanding hyponatraemia, where cerebral osmotic adaptation has occurred.
• The generally recommended maximum rate of sodium correction is 8 to 10 mmol per litre in any 24 hour period. Some protocols recommend a more conservative limit in patients at higher risk of osmotic demyelination, such as those with chronic alcohol use, malnutrition, or advanced liver disease.
• Monitor biochemistry frequently throughout active correction to ensure the limit is not inadvertently exceeded.
• Have a proactive plan available. Where correction is faster than intended, consider deliberate re-lowering of sodium using desmopressin combined with free water administration.
• Vasopressin receptor antagonists (tolvaptan) directly block the antidiuretic hormone receptor and are an effective, targeted option for SIADH.
• They need structured initiation protocols, including close sodium monitoring in the initial days, because of the same risk of overly rapid correction as with hypertonic saline. Use should generally be guided by specialist nephrology or endocrinology input, given this safety consideration and the relatively high cost of the class.
• Where a specific cause is identified, such as a causative medication, infection or malignancy, definitive treatment of the cause is the most effective long term approach. Use symptomatic treatment (fluid restriction or, where indicated, active correction) in parallel to manage the consequences of the hyponatraemia.
• Demeclocycline, an older agent that induces a degree of nephrogenic diabetes insipidus, is a further, less commonly used option for chronic SIADH not adequately managed with fluid restriction alone.
• Its use has declined with the availability of the more targeted vasopressin receptor antagonists and because of concerns about nephrotoxicity.