What is the pathophysiology of Syndrome of Inappropriate Antidiuretic Hormone (SIADH)?

Pathophysiology of SIADH

SIADH is characterized by excessive release of antidiuretic hormone (ADH), leading to water retention and hyponatremia, commonly associated with malignancies, CNS disorders, pulmonary diseases, medications, and post-surgical states. 1

Core Mechanism of ADH Action

The pathophysiology of SIADH centers around the inappropriate secretion of ADH (also called vasopressin) despite normal or low serum osmolarity. Under normal circumstances:

1. ADH acts on the collecting ducts of the kidney by binding to vasopressin V2 receptors (V2R) on the basolateral membrane of collecting duct cells
2. This binding initiates a signaling cascade:
   • G protein activation
   • Adenylyl cyclase stimulation
   • cAMP production
   • Protein kinase A (PKA) activation
3. The cascade results in the insertion of aquaporin-2 (AQP2) water channels into the apical membrane of collecting duct cells
4. These water channels enable water reabsorption from the tubular lumen into the hypertonic medullary interstitium, allowing for concentrated urine formation 1

Pathophysiological Changes in SIADH

In SIADH, this normal regulatory mechanism becomes dysfunctional:

• ADH is secreted despite low serum osmolarity (normally, low osmolarity would inhibit ADH release)
• The persistent ADH action leads to:
  • Excessive water reabsorption in the collecting ducts
  • Dilutional hyponatremia
  • Continued urinary sodium excretion
  • Inappropriately concentrated urine despite hyponatremia 1, 2

Volume Status in SIADH

A key distinguishing feature of SIADH is euvolemia:

• Despite water retention, patients maintain euvolemia due to:

  • Intact volume regulatory mechanisms
  • Pressure natriuresis from slight volume expansion
  • Continued sodium excretion in the urine (typically >20 mEq/L) 1

• This contrasts with Cerebral Salt Wasting (CSW), which presents with hypovolemia despite similar laboratory findings 1

Diagnostic Criteria Reflecting Pathophysiology

The diagnostic criteria for SIADH directly reflect its underlying pathophysiology:

• Hyponatremia (serum sodium <134 mEq/L)
• Plasma hypoosmolality (<275 mOsm/kg)
• Inappropriately concentrated urine (>500 mOsm/kg) despite hyponatremia
• Elevated urinary sodium (>20 mEq/L) despite hyponatremia
• Euvolemic state
• Normal adrenal and thyroid function 1

Common Etiologies and Their Mechanisms

SIADH can result from various underlying conditions:

1. Malignancies: Especially small cell lung cancer (10-45% of cases), which can produce ectopic ADH 1

2. CNS disorders: Conditions like stroke, hemorrhage, trauma, and infections can disrupt the normal hypothalamic regulation of ADH release 1

3. Pulmonary diseases: Pneumonia, tuberculosis, asthma, and COPD can trigger non-osmotic ADH release through various mechanisms including hypoxia and inflammation 1

4. Medications: Many drugs can induce SIADH by:

   • Enhancing ADH release (e.g., SSRIs, carbamazepine)
   • Potentiating ADH effects at the kidney (e.g., NSAIDs)
   • Direct stimulation of V2 receptors (e.g., desmopressin) 1

Clinical Manifestations Related to Pathophysiology

The symptoms of SIADH are primarily neurological and result from:

• Water movement into brain cells causing cerebral edema
• Severity depends on both the absolute sodium level and the rate of decline
• Symptoms range from mild (headache, irritability) to severe (seizures, coma) 1, 3

Pitfalls in Understanding SIADH Pathophysiology

• Misdiagnosis: Confusing SIADH with cerebral salt wasting can lead to inappropriate treatment, as CSW requires volume repletion while SIADH requires fluid restriction 1

• Competing Stimuli: In scenarios with competing stimuli (e.g., hypovolemia with hyponatremia), volume stimuli may override osmotic inhibition, resulting in continued ADH secretion despite hyponatremia 1

• Rapid Correction Risks: Understanding the pathophysiology is crucial for treatment, as overly rapid correction of sodium can lead to osmotic demyelination syndrome 1, 4

SIADH represents a classic example of a hormone regulatory system gone awry, where the normal feedback mechanisms that should suppress ADH in the face of hyponatremia fail to function properly, leading to a predictable constellation of clinical and laboratory findings.