What are the common causes of Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion?

Common Causes of SIADH

SIADH is most commonly caused by malignancies (particularly small cell lung cancer), medications (especially chemotherapeutic agents, antidepressants, and anticonvulsants), pulmonary disorders, and central nervous system pathology.

Malignancy-Related Causes

Small cell lung cancer (SCLC) is the most frequent malignant cause of SIADH, occurring in approximately 10-45% of SCLC cases, though only 1-5% develop symptomatic SIADH 1. The tumor cells directly produce arginine vasopressin (ADH), creating a paraneoplastic syndrome 1. Other malignancies can also cause SIADH, including:

• Non-small cell lung cancer: Occurs in approximately 0.7% of cases, with squamous cell carcinoma and adenocarcinoma both capable of producing ADH 1, 2
• Head and neck cancers: SIADH develops in approximately 3% of patients 2
• Other malignancies: Brain tumors, hematologic malignancies, gastrointestinal cancers, and genitourinary cancers have been reported, though less commonly 2

Hyponatremia in SCLC patients is associated with shortened survival, making early detection critical 1.

Medication-Induced SIADH

Multiple drug classes are well-established causes of SIADH through stimulation of inappropriate ADH release 3:

Chemotherapeutic Agents

• Platinum-based chemotherapy (cisplatin) 1, 2
• Vinca alkaloids (vincristine, vinblastine) 1, 2
• Cyclophosphamide and melphalan 2

Psychotropic Medications

• SSRIs and SNRIs: These antidepressants stimulate inappropriate ADH release despite low serum osmolality 3
• Carbamazepine and oxcarbazepine: Have moderate to high level evidence for causing SIADH 3
• Certain antipsychotics 3

Other Medications

• NSAIDs 1, 3
• Opioids 1
• Tramadol: Added to high-risk medications in 2019 guidelines 3

The concurrent use of multiple CNS agents or combining thiazide diuretics with SIADH-inducing medications substantially increases risk 3.

Pulmonary Disorders

Non-malignant pulmonary conditions are important causes of SIADH 1, 4:

• Pulmonary infections (pneumonia, tuberculosis)
• Positive pressure ventilation 2
• Other intrathoracic disorders 2

Central Nervous System Pathology

CNS disorders cause SIADH through disruption of normal hypothalamic-pituitary function and ADH regulation 5:

• CNS infections: Including abscesses and encephalitis (HHV-6B encephalitis commonly presents with SIADH as a cardinal feature) 5
• Space-occupying lesions: Brain tumors and abscesses 5
• Subarachnoid hemorrhage: Associated with higher rates of cerebral ischemia when hyponatremia develops 3
• Other neurological diseases 4

Neuroimaging with CT or MRI is essential to identify structural lesions such as ring-enhancing abscesses with surrounding edema 5.

Post-Operative SIADH

Inappropriate infusion of hypotonic fluids in the post-operative state remains a common iatrogenic cause 4. This is particularly relevant as hypotonic fluids like D5W worsen hyponatremia by providing free water that cannot be properly excreted 3.

Critical Diagnostic Pitfall

SIADH must be distinguished from cerebral salt wasting (CSW), particularly in neurosurgical patients, as they require opposite management approaches 3, 5. SIADH is characterized by euvolemia (CVP 6-10 cm H₂O), while CSW presents with hypovolemia (CVP <6 cm H₂O) 3. Using fluid restriction in CSW instead of SIADH can be hazardous and worsen outcomes 3, 6.

Additional Considerations

• Adrenal insufficiency and hypothyroidism must be excluded before diagnosing SIADH, as these conditions can mimic the syndrome 1
• A serum uric acid level <4 mg/dL in the presence of hyponatremia has a positive predictive value for SIADH of 73-100% 3
• The etiology is frequently multifactorial in clinical practice, requiring regular reassessment of clinical status and biochemistry during treatment 7