Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Background
Water balance is an important regulatory function involving the hypothalamus and the kidneys (among other organs). Various hormones are also involved, of which the antidiuretic hormone (ADH) arginine vasopressin is most important.
The syndrome of inappropriate secretion of ADH (SIADH) is characterized by the nonphysiologic release of ADH, resulting in impaired water excretion with normal sodium excretion.
SIADH was first described by Schwartz and associates in 2 patients with bronchogenic carcinoma and was later further characterized by Bartter and Schwartz.
Pathophysiology
ADH is a polypeptide synthesized in the supraoptic and paraventricular nuclei in the hypothalamus and is released in response to a number of stimuli. ADH is rapidly metabolized in the liver and kidneys and has a half-life of 15-20 minutes.
In the kidneys, ADH acts on the principal cells of the cortical and medullary collecting tubules to increase water permeability. Other renal actions include local production of prostaglandins in a variety of renal cells, including the glomerulus and the thick ascending limb of the loop of Henle. Elsewhere, ADH causes vasoconstriction in a number of vascular beds and releases factor VIII and von Willebrand factor from vascular endothelium.
Three known receptors bind ADH at the cell membrane: V1a, V1b (also known as V3), and V2. The vasopressin (AVP, ADH) receptor subtypes belong to the G protein–coupled receptor superfamily. The V1a and V1b receptors signal by activation of phospholipase C and elevation in intracellular calcium, which, in turn, stimulates protein kinase C.
V1a subtype is ubiquitous and found on cells, such as vascular smooth muscle cells, hepatocytes, platelets, brain cells, and uterus cells. V1b receptors are found predominantly in the anterior pituitary.
V2 receptors are coupled to adenylate cyclase, causing a rise in intracellular cyclic adenosine monophosphate (cAMP), which serves as the second messenger. V2 receptors are found predominantly in the principal cells of the renal collecting duct, where they mediate antidiuretic response. V2 receptors are also found in endothelial cells and induce the secretion of von Willebrand factor.
ADH activates the V2 receptor on the basolateral membrane of the principal cells of the renal collecting duct. This activates cyclic adenosine monophosphate through heterotrimeric G proteins, which results in insertion of aquaporin-2 water channels in the luminal membrane, thus making it more permeable to water.
The major stimuli to ADH are hyperosmolality and effective circulating volume depletion. Normally, ADH secretion ceases when plasma osmolality falls below 275 mOsm/kg. This fall causes increased water excretion, which leads to a dilute urine with an osmolality of 40-100 mOsm/kg. In addition to the hypothalamic osmoreceptors, hypothalamic neurons secreting ADH also receive input from baroreceptors in the great vessels and the atria. This results in nonosmotic release of ADH. Other stimuli for ADH secretion include pain and nausea.
In general, the plasma sodium concentration is the primary osmotic determinant of ADH release. However, in persons with SIADH, a nonphysiologic secretion of ADH results in enhanced water reabsorption, leading to dilutional hyponatremia. Sodium excretion is intact, and the amount of sodium excreted in the urine varies with diet. Ingestion of water is an essential prerequisite to the development of dilutional hyponatremia; regardless of cause, hyponatremia does not occur if water is restricted.
The continued presence of ADH with water intake causes retention of ingested water. While a large fraction of this water is intracellular, the extracellular fraction causes volume expansion. Volume receptors are activated and peptides (eg, atrial natriuretic peptide) are secreted, which causes natriuresis with some degree of accompanying kaliuresis and diuresis. Thus, these patients are euvolemic or are slightly volume-expanded.
If water and sodium intake remain constant, a steady state is reached and sodium excretion equals sodium intake. Experimental evidence indicates that several days after ADH-induced water retention, escape from its effect occurs. This results in the establishment of a water balance and a newer, stable (although lower) sodium concentration. This is thought to be mediated via pressure-induced natriuresis and diuresis. Other authorities attribute this escape phenomenon to a decrease in the aquaporin-2 channel expression in the renal collecting duct.
In addition to the inappropriate ADH secretion, persons with this syndrome also may have an inappropriate thirst sensation, which leads to an intake of water that is in excess of the free water excreted. This increase in water ingested may then contribute to the maintenance of hyponatremia.
Before the diagnosis of SIADH is made, other causes for a decreased diluting capacity (eg, renal, pituitary, adrenal, thyroid, cardiac, or hepatic disease) must be excluded. In addition, nonosmotic stimuli for arginine vasopressin release, particularly hemodynamic derangements (eg, due to hypotension, nausea, uncontrolled pain, or drugs) must be excluded.
Frequency
United States
SIADH is usually observed in patients in hospital settings, and the frequency may be as high as 35%.
Mortality/Morbidity
The mortality rate for acute symptomatic hyponatremia has been noted to be as high as 55% and as low as 5%, depending on the reference source. The mortality rate associated with chronic hyponatremia has been reported to be 14-27%.
In a retrospective case note review by Clayton and colleagues, patients with a multifactorial cause for hyponatremia in an inpatient setting had a significantly higher mortality rate. The outcome was least favorable in patients who were normonatremic at admission and became hyponatremic during the course of their hospitalization. The etiology of hyponatremia was a more important prognostic indicator than the level of absolute serum sodium in the patients.