Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). The inappropriate secretion of ADH can be due to various causes, including increased production by the pituitary gland due to trauma, disease, or certain medications; the ectopic secretion of ADH by cancer; or hereditary causes (nephrogenic SIADH). Syndrome of inappropriate antidiuretic hormone secretion is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. Syndrome of inappropriate antidiuretic hormone secretion should be suspected in any patient with hyponatremia, hypo-osmolality, and high urine osmolality.

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Antidiuretic Hormone (ADH)

Source

  • Synthesized in the hypothalamus:
    • Supraoptic nuclei
    • Paraventricular nuclei
  • Stored and secreted by the posterior pituitary 

Secreted in response to

  • Increased serum osmolarity: 
    • Detected by osmoreceptors (hypothalamus)
    • ADH is very sensitive to osmolality, responding to as little as a 1% increase.
  • Hypovolemia: 
    • Detected by baroreceptors (left atrium, carotid artery, aortic arch) 
    • Caused by low blood volume or blood pressure
    • ADH is less sensitive to blood pressure and volume, requiring a change of 10%–15% to stimulate its release. 

Function

  • Increases free water absorption (via V2 receptors)
    • ↓ Serum osmolarity
    • ↑ Urine osmolarity 
    • ↑ Intravascular volume 
  • Vasoconstriction (via V1 receptors)
  • Release of von Willebrand’s factor from endothelial cells

Antidiuretic hormone regulation

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Etiology and Pathophysiology

  • Acquired SIADH: continuous production of ADH without a proper feedback mechanism control
  • Hereditary SIADH: 
    • A mutation affects the gene for the renal V2 receptor
    • Also called nephrogenic syndrome of inappropriate antidiuresis
  • Both types cause free-water absorption → dilutional hyponatremia → cerebral edema and neurologic symptoms
Table: Causes of acquired SIADH
Major causesExamples
Central nervous system causes
  • Stroke
  • Subarachnoid hemorrhage
  • Infection:
    • Meningitis
    • Encephalitis
  • Trauma
Neoplasms
  • Small cell lung cancer
  • Head and neck cancers
Pulmonary causes
  • Pneumonia
  • Tuberculosis
  • Atelectasis
Medications
  • Chlorpropamide
  • Carbamazepine, oxcarbazepine
  • SSRIs
  • Vincristine, vinblastine, vinorelbine, cisplatin
  • MOAIs
  • Haloperidol
Surgery
  • Occurs in surgeries of the abdominal and thoracic regions
  • Mechanism of release is mediated through pain afferents.
SSRI: selective serotonin uptake inhibitor
MOAI: monoamine oxidase inhibitor

Clinical Presentation

  • Patients are usually euvolemic.
  • Patient presentation depends on:
    • The rate and severity of hyponatremia (acute and chronic)
    • The degree of cerebral edema
  • Acute hyponatremia:
    • Cerebral edema is the main problem.
    • Symptoms are mostly neurologic and include:
      • Nausea 
      • Vomiting
      • Seizures
      • Brainstem herniation
      • Coma
      • Death 
    • Movement of water into cells will stimulate additional ADH secretion.
    • A major complication is hypoxemic respiratory failure.
  • Chronic hyponatremia:
    • The cells adapt to the osmotic shift/dilutional hyponatremia by losing organic osmolytes (inositol, betaine, glutamate); therefore, the cerebral edema will be reduced.
    • Symptoms are subtle, including:
      • Abnormal gait
      • Confusion
      • Cognitive defects

Diagnosis

  • Laboratory results: 
    • Serum sodium < 135 mEq/L
    • Serum osmolality < 280 mOsm/kg
    • Urine sodium > 20–40 mEq/L (unless on a low-sodium diet)
    • Reduced anion gap
    • Urine osmolality > 100 mOsm/kg
  • Further tests should be performed to find the underlying cause according to the history:
    • Patients with long-standing smoking history and weight loss require a chest X-ray and/or computed tomography (CT) scan to rule out possible lung cancer.
    • Creatinine levels to assess renal function

Diagnostic algorithm for volemic and sodium alterations

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Management

  • The underlying cause should be treated if feasible.
  • The low levels of sodium (hyponatremia) should be corrected:
    • Correction should be done gradually (< 8 mEq/L per 24 hours) to prevent osmotic demyelination syndrome.
    • Fast correction will cause osmotic demyelination syndrome (dysphagia, dysarthria, diplopia, ataxia, ataxia, mutism, locked-in syndrome).
    • Acute and severe symptoms (e.g., seizure):
      • Hypertonic saline
    • Mild symptoms:
      • Fluid restriction
      • Salt tablets
  • Adjunctive medications may be used:
    • Furosemide 
    • Vasopressin antagonists (conivaptan, tolvaptan)
    • Demeclocycline 

Differential Diagnosis

The differential diagnosis of SIADH includes other hyponatremic conditions:

  • Hyponatremia: a low sodium concentration in the blood. Generally defined as sodium concentration < 135 mEq/L, with severe hyponatremia being < 120 mEq/L. The disorders that cause hyponatremia can be divided into:
    • Disorders that cause impairment in urinary water excretion: 
      • Gastrointestinal (GI) losses (vomiting, diarrhea) 
      • Renal losses (diuretic therapy, adrenal insufficiency)
      • Disorders with edema (chronic heart failure, cirrhosis, nephrotic syndrome)
      • Renal failure (acute kidney injury and chronic kidney disease)
      • Other causes of excess ADH (cortisol deficiency, hypothyroidism, administration of ADH derivatives)
    • Disorders in which renal handling of water is normal:
      • Primary polydipsia
      • Cerebral salt wasting
  • Cerebral salt wasting: renal loss of Na+ with an intracranial disease, which leads to hyponatremia and a decrease in extracellular fluid volume. Presents with volume contraction and SIADH patients will be euvolemic. The treatment is salt and volume replacement.
  • Adrenal insufficiency (Addison’s disease): glucocorticoid and mineralocorticoid insufficiency due to the destruction or dysfunction of the entire adrenal cortex. Cortisol has a negative feedback effect on ADH and adrenocorticotropic hormone (ACTH). The absence of cortisol thus removes this inhibitory effect, increasing the release of ADH.
  • Psychogenic polydipsia: increase in water intake attributed to a defect in the thirst mechanism, mostly in patients with psychosis.
  • Hypervolemic hyponatremia: a deficit of free water excretion that leads to inappropriate water retention in relation to the sodium concentration. This osmotic imbalance results in an expanded extracellular volume and dilutional hyponatremia. It can be seen in cases of chronic heart failure, cirrhosis, and nephrotic syndrome. Easy to diagnose based on the significant symptoms and laboratory values of the underlying disease.

References

  1. Jameson, J.L., et al. (Ed.). (2015). Harrison’s Principles of Internal Medicine (20th ed., pp. 299–303, 610, & 2281).
  2. Sterns, R.H., Emmett, M., & Forman, J.P. (2019). Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). UpToDate. Retrieved Jan 11, 2021, from https://www.uptodate.com/contents/pathophysiology-and-etiology-of-the-syndrome-of-inappropriate-antidiuretic-hormone-secretion-siadh
  3. Thomas, C.P., Lederer, E., Batuman, V., & Fraer, M. (2019) Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH). https://emedicine.medscape.com/article/246650-overview
  4. Verbalis, J.G., et al. (Ed.) (2013). Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 126(10 Suppl 1), S1-42. https://doi.org/10.1016/j.amjmed.2013.07.006

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