Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

A 70-year-old woman with a history of small cell lung cancer presents with increasing confusion and lethargy over the past few days. She is clinically euvolaemic on examination. Blood tests reveal hyponatraemia with a serum sodium of 120 mmol/L, and serum osmolality is low. Her urine osmolality is found to be inappropriately high. What is the most likely diagnosis?

Pathophysiology

Syndrome of Inappropriate Antidiuretic Hormone (SIADH) is characterised by the unregulated release of antidiuretic hormone (ADH), also known as vasopressin, leading to water retention and dilutional hyponatraemia. Physiologically, ADH release from the posterior pituitary is tightly regulated by plasma osmolality via hypothalamic osmoreceptors. When plasma osmolality rises, ADH is released, increasing water permeability in the renal collecting ducts, concentrating urine and diluting plasma.

In SIADH, ADH is secreted despite low plasma osmolality, resulting in continued water reabsorption, leading to:

• Dilutional hyponatraemia: The increased water reabsorption expands the intravascular and intracellular fluid compartments, diluting serum sodium concentration.
• Inappropriately concentrated urine: Despite the hyponatraemia and low serum osmolality, urine osmolality remains high because the kidneys continue to reabsorb water under the influence of inappropriately elevated ADH levels.

Aetiology

SIADH has a wide variety of causes, which can be broadly categorised as follows:

• Malignancy:  Small cell lung cancer (SCLC) is the most common malignancy associated with SIADH, often due to ectopic ADH production by the tumour. Other malignancies that can cause SIADH include head and neck cancers, pancreatic cancer, and lymphoma.
• Central Nervous System (CNS) disorders: SIADH can be caused by a range of CNS disturbances affecting ADH regulation, including:
  • Trauma: Head injury can disrupt hypothalamic-pituitary pathways, leading to dysregulation of ADH release.
  • Infection: Meningitis and encephalitis can cause inflammation and damage within the CNS, affecting ADH secretion.
  • Stroke: Both ischaemic and haemorrhagic.
  • Space-occupying lesions: Tumors or abscesses compressing the hypothalamus or pituitary can lead to SIADH.
• Pulmonary disease: Various pulmonary conditions can trigger SIADH, potentially through the release of inflammatory mediators or direct stimulation of ADH secretion:
  • Pneumonia
  • Tuberculosis (TB)
  • Chronic obstructive pulmonary disease (COPD)
  • Sarcoidosis
• Drugs: Certain medications can interfere with ADH regulation or enhance its effects:
  • Antidepressants: Particularly selective serotonin reuptake inhibitors (SSRIs)
  • Antiepileptics: Such as carbamazepine
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Cytotoxic agents: Like cyclophosphamide
  • Proton Pump Inhibitors
  • Narcotics: Such as morphine
  • Thiazide diuretics
• Other causes:
  • HIV infection
  • Post-operative state
  • Porphyria
  • Idiopathic

Epidemiology & Risk Factors

SIADH is a relatively common cause of euvolemic hyponatraemia. The following factors may increase the risk of developing SIADH:

• Age: Older adults are more susceptible to SIADH due to age-related changes in ADH regulation.
• Underlying medical conditions: The presence of any of the aetiologies listed above, particularly malignancies, CNS disorders, and pulmonary disease, significantly increases the risk.
• Medications: Use of certain medications, as outlined in the aetiology section, is a significant risk factor.
• Hospitalisation: SIADH is more common in hospitalised patients, potentially due to factors such as fluid shifts, medications, and underlying illnesses.

Clinical Features

The clinical manifestations of SIADH are primarily due to hyponatraemia. The severity of symptoms correlates with the degree and rate of decline in serum sodium concentration.

• Mild hyponatraemia (sodium 130-135 mmol/L): Often asymptomatic
• Moderate hyponatraemia (sodium 120-129 mmol/L): May be asymptomatic, especially if developing slowly. Symptoms may include:
  • Nausea
  • Vomiting
  • Headache
  • Lethargy
  • Confusion
• Severe hyponatraemia (sodium <120 mmol/L): Symptoms may be more pronounced and can include:
  • Muscle weakness
  • Seizures
  • Altered mental status
  • Coma

It is important to note that patients with SIADH are clinically euvolemic, meaning they do not show signs of fluid overload (oedema) or dehydration.

Investigations

Diagnosing SIADH requires a combination of clinical assessment, laboratory tests, and exclusion of other causes of hyponatraemia.

• Serum osmolality:  Low serum osmolality (<280 mOsm/kg) is a key feature of SIADH, reflecting the hypotonicity of plasma due to water retention.
• Urine osmolality:  High urine osmolality (>100 mOsm/kg) in the setting of serum hypo-osmolality is considered inappropriate and supports the diagnosis of SIADH. This indicates that the kidneys continue to concentrate urine despite low plasma osmolality, suggesting unregulated ADH activity.
• Urine sodium: Urinary sodium is often elevated (≥ 20 mEq/L) in SIADH. This is because the kidneys continue to excrete sodium despite hyponatraemia, reflecting the ongoing water reabsorption and dilution of serum sodium.
• Assessment of volume status: Careful clinical examination to confirm euvolaemia is crucial in distinguishing SIADH from other causes of hyponatraemia.
• Exclusion of other causes: Important to rule out other conditions that can cause hyponatraemia, such as hypothyroidism or adrenal insufficiency.

Management

The management of SIADH aims to:

• Identify and address the underlying cause: If SIADH is secondary to a treatable cause, such as medication use or an infection, addressing that cause is paramount.
• Correct hyponatraemia: The rate and method of correction depend on the severity of hyponatraemia and the presence of symptoms.
• Prevent complications: Careful monitoring and management are needed to avoid complications associated with hyponatraemia and its correction.

Treatment Options:

• Fluid restriction:  The cornerstone of SIADH treatment is fluid restriction. Limiting fluid intake reduces the amount of water available for reabsorption, helping to increase serum sodium concentration. Typical fluid restriction targets range from 500 to 1000 mL per day.
• Hypertonic saline:  Intravenous hypertonic saline (3%) is used for severe or symptomatic hyponatraemia (<120 mEq/L), particularly when rapid correction is necessary. Hypertonic saline directly increases serum sodium concentration, but it must be administered cautiously to avoid complications such as osmotic demyelination syndrome.
• ADH antagonists (vaptans):  Tolvaptan and conivaptan are selective vasopressin receptor antagonists that block the action of ADH in the renal collecting ducts, promoting free water excretion and increasing serum sodium. They are typically used for severe SIADH or when fluid restriction is ineffective.
• Demeclocycline:  Demeclocycline is a tetracycline antibiotic that has the off-label use of treating chronic SIADH. It impairs the renal response to ADH, promoting water excretion. However, demeclocycline can cause renal toxicity and photosensitivity, limiting its use.

Complications & Prognosis

The prognosis of SIADH depends largely on the underlying cause and the severity and duration of hyponatraemia. Prompt recognition and management are essential to minimise complications.

Potential Complications:

• Neurological complications: Severe or rapidly developing hyponatraemia can lead to cerebral oedema, seizures, coma, and even death.
• Osmotic demyelination syndrome: This serious neurological condition can occur if chronic hyponatraemia is corrected too rapidly. It is characterised by demyelination in the pons and other areas of the brain, leading to neurological deficits such as paralysis, dysarthria, and cognitive impairment.
• Falls: Hyponatraemia increases the risk of falls, particularly in older adults.
• Complications related to underlying cause: The underlying condition causing SIADH can often have its own set of complications, influencing the overall prognosis.

Prognosis:

• SIADH caused by transient factors (e.g. medications, post-operative state) typically resolves with correction of the underlying cause and appropriate management.
• SIADH due to chronic conditions (e.g. malignancies, CNS disorders) may require long-term management and monitoring to control hyponatraemia and prevent complications. The overall prognosis in these cases is influenced by the course of the underlying disease.