Causes of Syndrome of Inappropriate Antidiuretic Hormone (SIADH)
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) has numerous causes, including malignancies, pulmonary disorders, central nervous system diseases, and medications.
Malignancies
- Small cell lung cancer is the most common malignancy associated with SIADH, occurring in approximately 15% of cases 1
- Other malignancies that can cause SIADH include head and neck cancer (3% of cases), non-small-cell lung cancer (0.7% of cases), and various other tumors 1
- Primary brain tumors, hematologic malignancies, gastrointestinal cancers, gynecological cancers, breast cancer, and prostate cancer have all been reported to cause SIADH 1
Central Nervous System Disorders
- Stroke can induce SIADH through inappropriate ADH secretion resulting in concentrated urine and decreased free water excretion 2
- Subarachnoid hemorrhage is associated with SIADH and higher rates of cerebral ischemia and worse outcomes 3
- Other neurological conditions including brain trauma can trigger SIADH 4
Pulmonary Disorders
- Various pulmonary diseases beyond lung cancer can cause SIADH 5
- Positive pressure ventilation has been shown to produce SIADH 1
- Pulmonary infections can trigger inappropriate ADH secretion 1
Medications
- Multiple medications can induce SIADH, including: 6, 7
- Chemotherapeutic agents such as cisplatin, vinca alkaloids (vincristine, vinblastine)
- Cyclophosphamide and melphalan
- Antidepressants
- Antiepileptic drugs like carbamazepine
- Chlorpropamide
- NSAIDs
- Opioids
Other Causes
- Conditions with decreased left atrial pressure can lead to SIADH 1
- Surgery can trigger inappropriate ADH secretion 5
- Rare activating mutations of the vasopressin type 2 (V2) receptor can cause SIADH 8
Diagnostic Considerations
- SIADH is characterized by hyponatremia (serum sodium <135 mmol/L), hypoosmolality (plasma osmolality <275 mosm/kg), inappropriately high urine osmolality (>500 mosm/kg), and high urinary sodium concentration (>20 mEq/L) 3
- Diagnosis requires exclusion of other conditions that can increase vasopressin or impair urinary dilution 5
- Assessment of extracellular fluid volume status is crucial to distinguish SIADH (euvolemic) from other causes of hyponatremia 3
- Serum uric acid <4 mg/dL has a positive predictive value of 73-100% for SIADH 4
Clinical Implications
- SIADH is the most common cause of hyponatremia among hospitalized patients 5
- Hyponatremia in SIADH is dilutional in nature due to excessive fluid retention 9
- Symptoms generally occur when hyponatremia is severe (≤125 mEq/L) and may include anorexia, vomiting, confusion, seizures, and in severe cases, coma and death 7
- Determination of the etiology of SIADH is important because removal of the stimulus for inappropriate ADH secretion offers the most effective therapy 8
Treatment Principles
- The optimal therapy for SIADH is to treat the underlying cause 1
- Fluid restriction to 1 L/day is the cornerstone of treatment for SIADH when the underlying cause cannot be immediately addressed 3, 2
- For severe symptomatic hyponatremia, 3% hypertonic saline may be required with careful monitoring 3
- The rate of sodium correction should not exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 3, 2