Syndrome of inappropriate antidiuretic hormone

The syndrome of inappropriate antidiuretic hormone (SIADH) is a condition commonly found in the hospital population, especially in patients being hospitalized for central nervous system (CNS) injury. This is a syndrome characterized by excessive release of antidiuretic hormone (ADH or vasopressin) from the posterior pituitary gland or another source. The result is hyponatremia, and sometimes fluid overload. It should be noted that vasopressin has other important functions, addressed in the appropriate articles.

Pathophysiology

The normal function of ADH on the kidneys is to control the amount of water reabsorbed by kidney nephrons. ADH acts in the distal portion of the renal tubule (Distal Convoluted Tubule) as well as on the collecting duct and causes the retention of water, but not solute. Hence, ADH activity effectively dilutes the blood (decreasing the concentrations of solutes such as sodium).

ADH is secreted to prevent water loss in the kidneys. When water is ingested, it is taken up into the circulation and results in a dilution of the plasma. This dilution, otherwise described as a reduction in plasma osmolality is detected by osmoreceptors in the hypothalamus of the brain and these then switch off the release of ADH. The decreasing concentration of ADH effectively inhibits the aquaporins in the collecting ducts and distal convoluted tubules in the nephrons of the kidney. Hence, less water is reabsorbed, thereby increasing urine output, decreasing urine osmolality, and increasing (normalization of) blood osmolality.

In SIADH the release of ADH is not inhibited by a reduction in plasma osmolality when the individual ingests water and the osmolality of the plasma drops. As the main solute of plasma is sodium, this hypoosmolar state is usually detected as a low sodium level on laboratory testing. SIADH is therefore primarily a condition that results in the abnormal handling of water loading and not a problem with excessive solute loss. This is why it is usually treated with fluid (in particular water) restriction. Diuretics may also be given to decrease reabsorption of water, but care must be taken not to correct water imbalances too rapidly.

This causes dilutional hyponatremia and all the consequences associated with that condition: headache, nausea, vomiting, and confusion may ensue. Severe hyponatremia may cause convulsions or coma.

Clinical Findings

In general, increased ADH causes water retention and extracellular fluid volume expansion without edema or hypertension, owing to natriuresis (retention of water and passing of sodium in urine). The water retention and sodium loss both cause hyponatremia, which is a key feature in SIADH. Hyponatremia and concentrated urine (U_Osm >300 mOsm) are seen, as well as no signs of edema or dehydration. When hyponatremia is severe (sodium <120 mOsm), or acute in onset, symptoms of cerebral edema become prominent (irritability, confusion, seizures, and coma).

Diagnosis

Laboratory findings in diagnosis of SIADH include-

• Hyponatremia <130 mEq/L, and P_Osm <270 mOsm/kg.

Other findings include-

• Urine sodium concentration >20 mEqlL (inappropriate natriuresis)
• Maintained hypervolemia
• Suppression of renin-angiotensin system
• No equal concentration of atrial natriuretic peptide
• Low blood urea nitrogen (BUN)
• Low creatinine
• Low uric acid
• Low albumin

Causes

Some common causes of SIADH include:

• Head injury
  • Subarachnoid hemorrhage
• Cancers
  • Lung cancer (especially small cell lung cancer, as well as other small-cell malignancies of other organs)
• Infections
  • Brain abscess
  • Pneumonia
  • Lung abscess
• Drugs
  • Chlorpropamide
  • Clofibrate
  • Phenothiazine
  • Cyclophosphamide
  • Carbamazepine
  • Selective serotonin reuptake inhibitors (SSRIs, a class of antidepressants)
  • Methylenedioxymethamphetamine (MDMA, commonly called Ecstasy. SIADH due to taking ecstasy was cited as a factor in the death of Leah Betts)

Management

Management of SIADH includes:

• Treating underlying causes when possible.
• Fluid restriction to 800-1,000 ml/d should be obtained to increase serum sodium.
• Intravenous saline - For very symptomatic patients (severe confusion, convulsions, or coma) hypertonic saline (5%) 200-300 ml IV in 3-4 h should be given.
• Drugs
  • Demeclocycline can be used in chronic situations when fluid restrictions are difficult to maintain; demeclocycline is the most potent inhibitor of AVP action.
  • Conivaptan - an approved antagonist of both V_1A and V₂ vasopressin receptors. Its indications are "treatment of euvolemic hyponatremia (e.g. the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.) in hospitalized patients."^[1]
  • Tolvaptan - an unapproved oral antagonist of the V₂ vasopressin receptor. A randomized controlled trial showed conivaptan that can raise the serum sodium by 5 mmol/L. ^[2]

Care must be taken when correcting hyponatremia. A rapid rise in the sodium level may cause central pontine myelinolysis.^[3]

Differential diagnosis

Cerebral salt wasting syndrome also presents with hyponatremia, but is treated differently.

History

The condition was first described by researchers from Boston, Massachusetts and Bethesda, Maryland (including Dr Frederic Bartter) in two patients with lung cancer.^[4] Criteria were developed by Schwartz and Bartter in 1967,^[5] and have remained essentially unchanged since then.^[6] The condition is occasionally referred to by the names of the authors of the first report - Schwatz-Bartter syndrome.^[7]

References