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

Primary Causes of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

The primary causes of SIADH include malignancies (especially small cell lung cancer), central nervous system disorders, pulmonary diseases, and medications, with small cell lung cancer accounting for 10-45% of cases. 1

Major Categories of SIADH Causes

1. Malignancies

• Small cell lung cancer: Most common malignancy causing SIADH (10-45% of SCLC cases) 2, 1
• SCLC cells produce polypeptide hormones including vasopressin (ADH) 2
• Other malignancies with reported SIADH association:
  • Head and neck cancers
  • Extrapulmonary small cell carcinomas (nasopharynx, gastrointestinal tract, genitourinary tract) 2

2. Central Nervous System Disorders

• Stroke
• Intracranial hemorrhage
• Brain trauma
• CNS infections (meningitis, encephalitis)
• Brain tumors and metastases 1
• Paraneoplastic encephalomyelitis 2

3. Pulmonary Diseases

• Pneumonia
• Tuberculosis
• Asthma
• COPD
• Positive pressure ventilation 1

4. Medications

• Antidepressants: SSRIs, SNRIs, MAOIs, mirtazapine
• Antipsychotics: Especially atypical antipsychotics
• Anticonvulsants: Carbamazepine, valproate
• Chemotherapeutic agents: Cisplatin 2
• Diuretics: Especially thiazides
• Pain medications: NSAIDs, opioids
• Other: Immunosuppressants 1

5. Other Causes

• Post-surgical states
• HIV infection
• Genetic mutations (rare activating mutations of V2 receptor) 3
• Idiopathic SIADH

Pathophysiology and Diagnostic Considerations

SIADH occurs when there is excessive release of ADH despite normal or low serum osmolality. This leads to:

• Water retention
• Dilutional hyponatremia
• Continued urinary sodium excretion
• Inappropriately concentrated urine 1

Diagnostic Criteria for SIADH

1. Hyponatremia (serum sodium <134 mEq/L)
2. Plasma hypoosmolality (<275 mOsm/kg)
3. Inappropriately high urine osmolality (>500 mOsm/kg)
4. High urinary sodium concentration (>20 mEq/L)
5. Normal adrenal and thyroid function
6. Euvolemic status 1

Clinical Pearls and Pitfalls

Important Clinical Considerations

• In patients with cancer, especially SCLC, SIADH occurs more frequently than other paraneoplastic syndromes like Cushing syndrome 2
• Hyponatremia in cancer patients may be multifactorial - consider both SIADH and treatment-related causes (e.g., cisplatin, opiates) 2
• In patients with neurological symptoms and SIADH, consider paraneoplastic syndromes and obtain comprehensive paraneoplastic antibody panel 2

Common Pitfalls

• Misdiagnosis: Failing to distinguish between SIADH and cerebral salt wasting (CSW), which require opposite treatments 1
• Incomplete evaluation: Not performing necessary diagnostic tests to confirm SIADH (less than 50% of patients receive complete diagnostic workup) 4
• Ineffective treatment selection: Using therapies with limited efficacy like fluid restriction alone, which fails to increase serum sodium by ≥5 mEq/L in 55% of cases 4
• Overly rapid correction: Correcting sodium too quickly (>8 mmol/L/24h) can lead to osmotic demyelination syndrome 1

Treatment Considerations

• First-line treatment for SIADH is treating the underlying cause when possible 3
• Fluid restriction (1,000-1,500 mL/day) is the mainstay of therapy for chronic SIADH 1
• For refractory cases, options include:
  • Vasopressin receptor antagonists (tolvaptan)
  • Demeclocycline
  • Urea
  • Loop diuretics with salt tablets 1, 3

By identifying and addressing the underlying cause of SIADH, clinicians can more effectively manage this condition and improve patient outcomes.