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

Causes of Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

SIADH is most commonly caused by malignancies (particularly small cell lung cancer), central nervous system disorders, pulmonary diseases, and medications that stimulate inappropriate release of antidiuretic hormone. 1

Major Categories of SIADH Causes

1. Malignancies

• Small cell lung cancer (most common malignant cause, occurring in approximately 15% of cases) 1, 2
• Other lung cancers (less common, approximately 0.7% in non-small cell lung cancer) 2
• Head and neck cancers (3% of cases) 2
• Hematologic malignancies 2
• Brain tumors 2
• Various other carcinomas (gastrointestinal, gynecological, breast, prostate) 2

2. Central Nervous System Disorders

• Traumatic brain injury 3
• Encephalitis (including HHV-6B encephalitis) 1
• Meningitis 1
• Stroke 1
• Brain tumors (primary or metastatic) 2

3. Pulmonary Diseases

• Pneumonia 1
• Positive pressure ventilation 2
• Respiratory infections 2
• Decreased left atrial pressure conditions 2

4. Medications

• Chemotherapeutic agents:
  • Platinum-based chemotherapy (cisplatin) 1, 2
  • Vinca alkaloids (vincristine, vinblastine) 1, 2
  • Cyclophosphamide 2
  • Melphalan 2
• Other medications:
  • Opioids 1
  • NSAIDs 1
  • Anticonvulsants 1
  • Antidepressants 1

Clinical Presentation and Diagnostic Features

SIADH is characterized by:

• Hyponatremia (serum sodium < 135 mEq/L) 1
• Hypoosmolality of plasma (< 275 mOsm/kg) 1
• Inappropriately high urine osmolality (> 500 mOsm/kg) relative to plasma osmolality 1
• Elevated urinary sodium concentration (> 20-40 mEq/L) 1
• Clinical euvolemia (absence of edema or volume depletion) 1
• Normal renal, adrenal, and thyroid function 4

Clinical Manifestations

Symptoms depend on the severity and rapidity of sodium decline:

• Mild (Na 125-135 mEq/L): Headache, confusion, nausea, weakness 1
• Moderate to severe (Na < 125 mEq/L): Vomiting, lethargy, seizures, coma 1

Management Considerations

For confirmed SIADH:

1. Treat the underlying cause when possible (e.g., cancer therapy for malignancy-related SIADH) 2
2. Fluid restriction (first-line for chronic, mild-moderate cases) 1, 5
3. Discontinuation of implicated medications 1
4. For severe or symptomatic cases:
   • Hypertonic saline 6
   • Pharmacologic options:
     • Vasopressin receptor antagonists (conivaptan, tolvaptan) 6, 5
     • Demeclocycline 1, 3
     • Urea 5

Important Clinical Pitfalls

• SIADH must be distinguished from other causes of hyponatremia, particularly adrenal insufficiency 1
• Overly rapid correction of hyponatremia can lead to neurologic damage through osmotic demyelination syndrome 6
• SIADH following traumatic brain injury is usually transient but can become chronic in rare cases 3
• In cancer patients, hyponatremia may be multifactorial (SIADH plus effects of chemotherapy, opioids, or other medications) 1
• SIADH in small cell lung cancer is associated with shorter survival 1

When evaluating a patient with suspected SIADH, always exclude other causes of hyponatremia including hypothyroidism, adrenal insufficiency, heart failure, cirrhosis, and renal salt wasting before confirming the diagnosis.