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Syndrome of inappropriate antidiuretic hormone secretion

Syndrome of inappropriate antidiuretic hormone secretion
Classification and external resources
ICD-10 E22.2
ICD-9 253.6
DiseasesDB 12050
MedlinePlus 003702
eMedicine emerg/784 med/3541 ped/2190
NCI Syndrome of inappropriate antidiuretic hormone secretion
Patient UK Syndrome of inappropriate antidiuretic hormone secretion
MeSH D007177

The syndrome of inappropriate antidiuretic hormone secretion or SIADH (other names: Schwartz-Bartter syndrome, SIAD—syndrome of inappropriate antidiuresis) is characterized by excessive release of antidiuretic hormone from the posterior pituitary gland or another source. The result is often dilutional hyponatremia in which the plasma sodium levels are lowered and total body fluid is increased. It was originally described in people with small-cell carcinoma of the lung, but it can be caused by a number of underlying medical conditions. The treatment may consist of fluid intake restriction, various medicines, and management of the underlying cause. SIADH was first described in 1957.

Signs and symptoms



  • Muscle aches
  • Generalized muscle weakness




It should be noted that prominent physical findings may be seen only in severe or rapid-onset hyponatraemia.[1]


Some common causes of SIADH include:[citation needed]


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), causing hyponatremia; this is compounded by the fact that the body responds to water retention by decreasing aldosterone, thus allowing even more sodium wasting. For this reason, a high urinary sodium excretion will be seen. [3]

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 normalizing blood osmolality.[citation needed]

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 restriction. Diuretics (furosemide specifically) may also be given to decrease reabsorption of water, but care must be taken not to correct water imbalances too rapidly.[2]

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.[2]

The abnormalities underlying type D syndrome of inappropriate antidiuretic hormone hypersecretion concern individuals where vasopressin release and response are normal but where abnormal renal expression and translocation of aquaporin 2, or both are found.[4] It has been suggested that this is due to abnormalities in the secretion of secretin in the brain and that "Secretin as a neurosecretory hormone from the posterior pituitary, therefore, could be the long-sought vasopressin independent mechanism to solve the riddle that has puzzled clinicians and physiologists for decades."[4]

In general, increased ADH causes water retention without interstitial fluid volume expansion and without edema or hypertension. The water retention causes hyponatremia, which is a key feature in SIADH. This is purely a problem of water metabolism with no abnormalities in total body sodium metabolism.[5] Hyponatremia and inappropriately concentrated urine (UOsm >100 mOsm/L)[6] are seen, as well as no signs of edema or hypovolemia. When hyponatremia is severe (sodium <120 mOsm), or acute in onset, symptoms of cerebral edema become prominent (irritability, confusion, seizures, and coma).


Laboratory findings in diagnosis of SIADH include:

  • Euvolemic hyponatremia <134 mEq/L, and POsm <275 mOsm/kg OR ( POsm - Serum [Urea]mmol/l < 280 mOsm/kg )
  • Urine osmolality >100mOsm/kg of water during hypotonicity[2]
  • Urine sodium concentration >40 mEq/L with normal dietary salt intake

Other findings:

Differential diagnosis

Antidiuretic hormone (ADH) is released from the posterior pituitary for a number of physiologic reasons. The majority of patients with hyponatremia, other than those with excessive water intake (polydipsia) or renal salt wasting will have elevated ADH as the cause of their hyponatremia. However, not every patient with hyponatremia and elevated ADH has SIADH. One approach to a patient with hyponatremia is to divide ADH release into appropriate (not SIADH) or inappropriate (SIADH).[7]

Appropriate ADH release can be a result of hypovolemia, a so-called osmotic trigger of ADH release. This may be true hypovolemia, as a result of dehydration with fluid losses replaced by free water (seen sometimes in Marathon runners[8] as well as in acutely ill patients). It can also be perceived hypovolemia, as in the conditions of congestive heart failure (CHF) and cirrhosis in which the kidneys perceive a lack of intravascular volume. The hyponatremia caused by appropriate ADH release (from the kidneys' perspective) in both CHF and cirrhosis have been shown to be an independent poor prognostic indicator of mortality.[9][10]

Appropriate ADH release can also be a result of non-osmotic triggers. Symptoms such as nausea/vomiting and pain are significant causes of ADH release.[11] The combination of osmotic and non-osmotic triggers of ADH release can adequately explain the hyponatremia in the majority of patients who are hospitalized with acute illness and are found to have mild to moderate hyponatremia. SIADH is less common than appropriate release of ADH. While it should be considered in a differential, other causes should be considered as well.

Cerebral salt wasting syndrome also presents with hyponatremia, there are signs of dehydration.

Most cases of hyponatremia in adults[citation needed] and children[12] are caused by appropriate secretion of antidiuretic hormone rather than SIADH or another cause.


Management of SIADH includes:

  • Treating underlying causes when possible.
  • Long-term fluid restriction of 1,200–1,800 mL/day[13] will increase serum sodium through decreasing total body water.
  • For very symptomatic patients (severe confusion, convulsions, or coma) hypertonic saline (3%) 1–2 ml/kg 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 Vasopressin (ADH/AVP) action. However, demeclocycline has a 2–3 day delay in onset with extensive side effect profile, including skin photosensitivity, and nephrotoxicity.[14]
    • Urea: oral daily ingestion has shown favorable long-term results with protective effects in myelinosis and brain damage.[14] Limitations noted to be undesirable taste and is contraindicated in patients with cirrhosis to avoid initiation or potentiation of hepatic encephalopathy.
    • Conivaptan – an antagonist of both V1A 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."[15] Conivaptan, however, is only available as a parenteral preparation.[14]
    • Tolvaptan – an antagonist of the V2 vasopressin receptor. A randomized controlled trial showed tolvaptan is able to raise serum sodium in patients with euvolemic or hypervolemic hyponatremia in 2 different tests. Combined analysis of the 2 trials showed an improvement in hyponatremia in both the short term (primary sodium change in average AUC: 3.62+/- 2.68 and 4.35 +/-2.87) and long term with long term maintenance (primary sodium change in average AUC: 6.22 +/- 4.22 and 6.20 +/- 4.92), at 4 days and 30 days, respectively. Tolvaptan's side effect profile is minimal. Discontinuation of the Tolvaptan showed return of hyponatremia to control values at their respective time frames.[16]

No head-to-head study is currently available to quantify and compare the relative efficacies of V2 vasopressin receptor antagonists with demeclocycline or other treatment options.[citation needed]

Care must be taken when correcting hyponatremia. A rapid rise in the sodium level may cause central pontine myelinolysis.[17] Avoid correction by more than 12 mEq/L/day. Initial treatment with hypertonic saline may abruptly lead to a rapid dilute diuresis and fall in ADH. Rapid diuresis may lead to over-rapid rise in serum sodium, and should be managed with extreme care.[citation needed]


The condition was first described by researchers from Boston, Massachusetts and Bethesda, Maryland (including Dr Frederic Bartter) in two patients with lung cancer.[18] Criteria were developed by Schwartz and Bartter in 1967[19] and have remained essentially unchanged since then.[20] The condition is occasionally referred to by the names of the authors of the first report - Schwartz-Bartter syndrome.[21]


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  21. ^ Schwartz-Bartter syndrome at Who Named It?