Syndrome of inappropriate antidiuretic hormone secretion ( SIADH), also known as the syndrome of inappropriate antidiuresis ( SIAD), is characterized by a physiologically inappropriate release of Vasopressin (ADH) either from the posterior pituitary gland, or an ectopic non-pituitary source, such as an ADH-secreting tumor in the lung. Unsuppressed ADH causes a physiologically inappropriate increase in solute-free water being Reabsorption by the Nephron of the kidney to the venous circulation leading to hypotonic hyponatremia (a low plasma osmolality and low sodium levels).
The causes of SIADH are commonly grouped into categories including: central nervous system diseases that directly stimulate the hypothalamus to release ADH, various cancers that synthesize and secrete ectopic ADH, various lung diseases, numerous drugs (carbamazepine, cyclophosphamide, SSRIs) that may stimulate the release of ADH, vasopressin release, desmopressin release, oxytocin, or stimulation of vasopressin receptor 2 on the kidney (the site of ADH action). Inappropriate antidiuresis may also be due to acute stressors such as exercise, pain, severe nausea or during the post-operative state. In 17–60% of people, the cause of inappropriate antidiuresis is never found.
ADH is derived from a preprohormone precursor that is synthesized in cells in the hypothalamus and stored in vesicles in the posterior pituitary. Appropriate ADH secretion is regulated by osmoreceptors on the hypothalamic cells that synthesize and store ADH. In appropriate ADH secretion, plasma hypertonicity activates these osmoreceptors, ADH is released into the blood stream, the kidneys increase solute-free water reabsorption, and the hypertonicity is alleviated. A decrease in the effective circulating volume of blood (the volume of arterial blood effectively perfusing tissues) also stimulates an appropriate, physiologic release of ADH. Inappropriate ADH secretion causes physiologically high water reabsorption by the kidneys, causing elevated fluid retention. This causes the extracellular fluid (ECF) space to become hypoosmolar and hyponatremic (low sodium). In the intracellular space, cells swell as intracellular volume increases as water moves from an area of low solute concentration (extracellular space) to an area of high solute concentration (the cells' interior). In severe or acute hypoosmolar hyponatremia, swelling of causes various neurological abnormalities, which in severe or acute cases can result in convulsions, coma, and death. The symptoms of chronic syndrome of inappropriate antidiuresis are more vague, and may include cognitive impairment, gait abnormality, or osteoporosis.
The main treatment of inappropriate antidiuresis is to identify and treat the underlying cause, if possible. This usually causes plasma osmolality and sodium levels to return to normal in several days. In those in which an underlying cause cannot be found, or is untreatable, treatments are targeted to alleviating correcting the hypoosmolality and hyponatremia. These include restriction of fluid intake, using salt tablets (sometimes with diuretics), urea supplements, intravenous saline, or increasing protein intake. The vasopressin receptor 2 antagonists, tolvaptan or conivaptan, may also be used. The presence of cerebral edema, or other moderate to severe symptoms, may necessitate intravenous hypertonic saline administration with close monitoring of the serum sodium levels to avoid overcorrection.
SIADH was originally described in 1957 in two people with small-cell carcinoma of the lung. reproduced as a Milestone in Nephrology with author commentary in
Signs and symptoms
Gastro-intestinal
- Anorexia (loss of appetite)
- Nausea
Musculoskeletal
Neuro-muscular
Respiratory
Neurological
Causes
A list of common causes is below:
Pathophysiology
Excessive ADH causes an inappropriate increase in the reabsorption in the kidneys of solute-free water ("free water"): excess water moves from the distal convoluted tubules (DCTs) and collecting tubules of the – via activation of aquaporins, the site of the – back into the circulation. This has two consequences. First, in the extracellular fluid (ECF) space, there is a Concentration of blood solutes, causing hypoosmolality, including a low sodium concentration – hyponatremia. There Also, virtually simultaneously to these ECF events, the intracellular space (ICF) volume expands. This is because the osmolality of the ECF is (transiently) less than that of the ICF; and since water is readily permeable to cell membranes, solute-free water moves from the ECF to the ICF compartment by osmosis: all cells swell. Swelling of – cerebral edema – causes various neurological abnormalities which in acute and/or severe cases can result in convulsions, coma, and death.
The normal function of ADH on the 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.
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.
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." There are no abnormalities in total body sodium metabolism. Hyponatremia and inappropriately concentrated urine (UOsm >100 mOsm/L) are seen.
Diagnosis
Urinalysis reveals a highly concentrated urine with a high fractional excretion of sodium (high sodium urine content compared to the serum sodium). A suspected diagnosis is based on a serum sodium under 138. A confirmed diagnosis has seven elements: 1) a decreased effective serum osmolality – <275 mOsm/kg of water; 2) urinary sodium concentration high – over 40 mEq/L with adequate dietary salt intake; 3) no recent diuretic usage; 4) no signs of ECF volume depletion or excess; 5) no signs of decreased arterial blood volume – cirrhosis, nephrosis, or congestive heart failure; 6) normal adrenal and thyroid function; and 7) no evidence of hyperglycemia (diabetes mellitus), hypertriglyceridemia, or hyperproteinia (myeloma).
There are nine supplemental features: 1) a low BUN; 2) a low uric acid; 3) a normal creatinine; 4) failure to correct hyponatremia with IV normal saline; 5) successful correction of hyponatremia with fluid restriction; 6) a fractional sodium excretion >1%; 7) a fractional urea excretion >55%; 8) an abnormal water load test; and 9) an elevated plasma AVP.
Appropriate ADH release can be a result of hypovolemia, a so-called non-osmotic trigger of ADH release. This may be true hypovolemia, as a result of dehydration with fluid losses replaced by free water. 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.
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. The combination of osmotic and non-osmotic triggers of ADH release can adequately explain the hyponatremia in the majority of people 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 (CSWS) also presents with hyponatremia, there are signs of dehydration for which reason the management is diametrically opposed to SIADH. Importantly CSWS can be associated with subarachnoid hemorrhage (SAH) which may require fluid supplementation rather than restriction to prevent brain damage.
Most cases of hyponatremia in children are caused by appropriate secretion of antidiuretic hormone rather than SIADH or another cause.
William Schwartz (1922–2009) attended Duke University after serving in the US Army in World War II. He observed that sulfanilamide increased excretion of sodium in patients with heart failure. This observation was the basis for the discovery and development of modern diuretic drugs. Frederic Bartter (1914–1983) worked on hormones affecting the kidney that led to the discovery of syndrome of inappropriate antidiuretic hormone (SIADH) in 1957 and Bartter syndrome in 1963. Schwartz-Bartter syndrome is named after these two scientists. The first reports of hyponatremia and renal sodium loss corrected by fluid restriction in patients with bronchogenic carcinoma were published by Bartter. At that time, no direct measurement of vasopressin was done. In summary, the condition was first described at separate institutions by William Schwartz and Frederic Bartter in two people with lung cancer. Criteria were developed by Schwartz and Bartter in 1967 and have remained unchanged since then.
Differential diagnosis
Treatment
Medications
Epidemiology
History
Society and culture
External links
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