What is the Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), its diagnosis, treatment, and differential diagnoses?

From the Guidelines

Syndrome of Inappropriate Antidiuretic Hormone (SIADH) is a condition characterized by excessive release of antidiuretic hormone (ADH) from the posterior pituitary gland, leading to water retention and hyponatremia, and should be treated with vasopressin receptor antagonists such as tolvaptan starting at 15 mg daily, as recommended by the most recent and highest quality study 1.

Diagnosis of SIADH

Diagnosis requires the presence of:

• Hyponatremia (serum sodium <135 mEq/L)
• Decreased serum osmolality (<275 mOsm/kg)
• Inappropriately concentrated urine (urine osmolality >100 mOsm/kg)
• Elevated urine sodium (>20 mEq/L)
• Normal volume status (no edema or dehydration)
• Normal renal, adrenal, and thyroid function

Treatment of SIADH

Treatment depends on symptom severity and sodium levels.

• For mild cases (sodium >125 mEq/L), fluid restriction to 800-1000 mL/day is the first-line approach.
• For moderate to severe cases, especially with neurological symptoms, 3% hypertonic saline may be administered at 1-2 mL/kg/hr with careful monitoring to avoid rapid correction (limit to 8-10 mEq/L in 24 hours to prevent osmotic demyelination syndrome).
• Pharmacological options include oral salt tablets, loop diuretics like furosemide 20-40 mg daily with salt supplementation, and vasopressin receptor antagonists such as tolvaptan starting at 15 mg daily.
• Underlying causes must be addressed simultaneously.

Differential Diagnoses

Important differential diagnoses include:

• Cerebral salt wasting syndrome
• Hypothyroidism
• Adrenal insufficiency
• Heart failure
• Cirrhosis
• Nephrotic syndrome
• Renal failure
• Psychogenic polydipsia
• Medication-induced hyponatremia (particularly thiazide diuretics, SSRIs, and certain antiepileptics)

The use of vaptans, such as tolvaptan, has been shown to be effective in improving serum sodium concentration in patients with SIADH, heart failure, and liver cirrhosis, without affecting renal function, urinary sodium excretion, cardiovascular function, or the renin-angiotensin-aldosterone system 1.

From the FDA Drug Label

Tolvaptan tablets are indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Definition of SIADH: The FDA drug label does not provide a definition of SIADH.

Diagnosis of SIADH:

• The FDA drug label does not provide information on how to diagnose SIADH.
• However, it is mentioned that tolvaptan is indicated for the treatment of SIADH.

Treatment of SIADH:

• Tolvaptan is indicated for the treatment of SIADH.
• The usual starting dose for tolvaptan tablets is 15 mg administered once daily without regard to meals.
• The dose of tolvaptan can be increased at 24-hour intervals to 30 mg once daily, then to 60 mg once daily, until either the maximum dose of 60 mg or normonatremia (serum sodium >135 mEq/L) is reached.

Differential Diagnoses:

• The FDA drug label does not provide information on differential diagnoses for SIADH.
• However, it is mentioned that tolvaptan is contraindicated in patients with hypovolemic hyponatremia, and that patients with acute and transient hyponatremia associated with head trauma or postoperative state, and patients with hyponatremia due to primary polydipsia, uncontrolled adrenal insufficiency, or uncontrolled hypothyroidism were excluded from clinical trials. 2, 2, 2

From the Research

Definition and Diagnosis of SIADH

• The Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) is a condition characterized by the excessive secretion of antidiuretic hormone (ADH), leading to water retention and hyponatremia 3, 4, 5, 6, 7.
• Diagnosis of SIADH involves ascertaining the euvolemic state of extracellular fluid volume, both clinically and by laboratory measurements 4.
• Laboratory tests, such as serum sodium levels, osmolality, and urine osmolality, are used to confirm the diagnosis of SIADH 4, 5, 6, 7.

Treatment of SIADH

• Treatment of SIADH aims to correct hyponatremia and alleviate symptoms 4, 5, 6, 7.
• Therapeutic modalities include:
  • Fluid restriction: a common treatment approach, but may be limited by patient compliance 4, 6.
  • Hypertonic saline: used to rapidly correct severe hyponatremia 4, 6.
  • Demeclocycline: a tetracycline antibiotic that can be used to treat SIADH, but may have adverse effects 4, 6.
  • Vasopressin receptor antagonists (vaptans): a class of medications that specifically target the vasopressin receptor, including tolvaptan, which has been shown to be effective in treating SIADH-associated hyponatremia 3, 4, 5, 6, 7.
• Tolvaptan, in particular, has been found to be effective in increasing serum sodium levels in patients with SIADH, with a recommended starting dose of 7.5mg or 3.75mg in high-risk patients, and close monitoring of sodium levels to prevent overcorrection 3, 5.

Differential Diagnoses

• Other causes of hyponatremia, such as:
  • Heart failure 7.
  • Liver disease 7.
  • Nephrotic syndrome 7.
  • Hypothyroidism 7.
• Other conditions that may mimic SIADH, such as:
  • Cerebral salt wasting 7.
  • Adrenal insufficiency 7.
• A thorough diagnostic evaluation is necessary to distinguish SIADH from other causes of hyponatremia and to guide appropriate treatment 4, 7.