INTRODUCTION — The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a disorder of impaired water excretion caused by the inability to suppress the secretion of antidiuretic hormone (ADH) . If water intake exceeds the reduced urine output, the ensuing water retention leads to the development of hyponatremia.
The SIADH should be suspected in any patient with hyponatremia, hypoosmolality, and a urine osmolality above 100 mosmol/kg. In SIADH, the urine sodium concentration is usually above 40 mEq/L, the serum potassium concentration is normal, there is no acid-base disturbance, and the serum uric acid concentration is frequently low . (See "Diagnostic evaluation of adults with hyponatremia".) (Related Pathway(s): Hyponatremia: Evaluation in adults.)
The pathophysiology and etiology of SIADH will be reviewed here. The treatment of this disorder is discussed separately. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat".)
Pathogenesis of hyponatremia — The plasma sodium concentration (PNa) is a function of the ratio of the body's content of exchangeable sodium and potassium (NaE and KE) and total body water (TBW) as described by Edelman's classic equation:
PNa ≈ (NaE + KE)/Total body water
Antidiuretic hormone (ADH, arginine vasopressin) secretion results in a concentrated urine and therefore a reduced urine volume. The higher the plasma ADH, the more concentrated the urine. In most patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), ingestion of water does not adequately suppress ADH, and the urine remains concentrated. This leads to water retention, which increases TBW. This increase in TBW lowers the plasma sodium concentration by dilution (see above equation) . In addition, the increase in TBW transiently expands the extracellular fluid volume and thereby triggers increased urinary sodium excretion, which both returns the extracellular fluid volume toward normal and further lowers the plasma sodium concentration.
Hyponatremia can occur in SIADH even if the only fluid given is isotonic saline . The mechanism by which this occurs and why isotonic saline administration can lower the plasma sodium concentration in patients with SIADH and a highly concentrated urine is discussed separately. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Intravenous hypertonic saline'.)
Patterns of ADH secretion — In normal individuals, plasma ADH levels are very low when the plasma osmolality is below 280 mosmol /kg, thereby permitting the excretion of ingested water, and ADH levels increase progressively as the plasma osmolality rises above 280 mosmol/kg (figure 1).
ADH regulation is impaired in SIADH; five different patterns have been described [3-5]. The prevalence of these patterns differs among series:
●Type A is characterized by grossly elevated levels of ADH unresponsive to osmotic deviations . Plasma ADH levels are often above that required for maximum antidiuresis, so the urine osmolality is typically very high. High hormone levels above the physiologic range suggest ectopic secretion of ADH, most commonly by bronchogenic carcinoma.
●Type B is characterized by an abnormally low osmotic threshold for ADH release (ie, a threshold that is below the level of plasma osmolality at which plasma ADH becomes detectable in normal individuals) and a linear increase in plasma ADH in response to a rising plasma osmolality. Such patients have been described as having a "reset osmostat." Establishing the presence of this condition is important because, unlike other forms of SIADH, there is no need to be concerned that the plasma sodium will continue to fall without therapy, because ADH secretion is suppressed when the plasma osmolality falls below the reset threshold level. This disorder is discussed in detail elsewhere. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Reset osmostat'.)
●Type C is characterized by ADH levels that are persistently in the physiologic range and are neither suppressed by a low plasma osmolality nor stimulated by a rising plasma osmolality. This pattern differs quantitatively from type A, in which superphysiologic levels of ADH are observed. However, like type A, it could occur in patients with ectopic ADH secretion.
●Type D is characterized by normal osmoregulation (ie, ADH secretion varies appropriately with the plasma osmolality), but the urine is concentrated even if ADH release is suppressed. At least one mechanism by which this occurs is a germ cell mutation in which the vasopressin-2 (V2) receptor is constituently activated . However, one study found that none of the six patients with a type D pattern had an activating mutation of the V2 receptor . Other potential mechanisms include production of an antidiuretic compound other than immunoreactive arginine vasopressin and a postreceptor defect in trafficking of aquaporin-2 water channels, which mediate ADH-induced antidiuresis. (See 'Hereditary SIADH' below.)
●Type E is characterized by a decline in plasma ADH as the serum sodium concentration increases during infusion of hypertonic saline. This pattern is hypothesized to be caused by altered baroreceptor signaling despite normovolemia so that a minor decrease in blood pressure or blood volume results in a large increase in ADH secretion. Similarly, a minor increase in blood pressure or blood volume caused by saline infusion results in a large decrease in ADH secretion .
Determinants of urine output — In addition to the persistent secretion of ADH, there are two other potentially important determinants of the urine output in patients with SIADH: the rate of solute excretion and partial escape from the effect of ADH.
Solute excretion — In normal subjects, the urine output is primarily determined by water intake. Changes in water intake lead to alterations in the plasma osmolality that are sensed by the osmoreceptors in the hypothalamus that regulate both ADH release and thirst. As an example, an increase in water intake sequentially lowers the plasma osmolality, decreases ADH secretion, and reduces collecting tubule permeability to water; the net effect is the rapid excretion of the excess water in a dilute urine.
In SIADH, however, an increase in water intake does not produce an increase in water excretion because ADH release is relatively fixed. Suppose that a patient has moderately severe SIADH with a urine osmolality that cannot be reduced below 750 mosmol/kg (the normal minimum urine osmolality is 40 to 100 mosmol/kg). In this patient, the urine output is determined by the rate of excretion of solutes (primarily sodium and potassium salts and urea). Now suppose this patient consumes a typical Western diet containing approximately 750 mosmol of solute, all of which are excreted in the urine each day. With a fixed urine osmolarity of 750 mosmol/kg, the daily urine output will be only one liter (750 ÷ 750 = 1), and it will not increase in response to increased water intake.
One way to increase water excretion in this hypothetical patient with SIADH is to prescribe a high-salt and -protein diet while restricting water ingestion. If, for example, the solute intake and therefore solute excretion rose to 1200 mosmol/day, the urine output would increase to 1.6 L/day (1200 ÷ 750 = 1.6). The increase in water excretion would then tend to raise the plasma sodium concentration toward normal.
Similar considerations concerning the role of solute intake apply when ADH effect is relatively fixed at a low level in central or nephrogenic diabetes insipidus. (See "Urine output in diabetes insipidus".)
Escape from the effect of ADH — Studies in experimental animals given ADH and water have shown an initial phase of water retention and hyponatremia followed by partial escape from the antidiuresis so that, despite persistently high levels of ADH, urine osmolality decreases. When the urine osmolality falls, water excretion increases, matching water intake, and the plasma sodium concentration tends to stabilize [6,7]. A similar response appears to occur in humans [8,9].
This escape from ADH-induced antidiuresis appears to be mediated by decreased expression of aquaporin-2, the ADH-sensitive water channel in the collecting tubules . The regulation of aquaporin-2 in this setting appears to be unrelated to plasma or tissue osmolality [11,12].
ETIOLOGY — One of the following causes of persistent antidiuretic hormone (ADH) release is likely to be present in patients who fulfill the clinical criteria for the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) [1,13].
CNS disturbances — Any CNS disorder, including stroke, hemorrhage, infection, trauma, and psychosis, can enhance ADH release. A discussion of the disturbances in water balance that may occur in patients with mental illness and a brief review of the antidiuretic action of carbamazepine, a drug that can cause an SIADH picture, are found elsewhere. (See "Causes of hypotonic hyponatremia in adults".)
As in other causes of SIADH, hyponatremia associated with intracranial bleeding, as well as other severe neurologic events, is due to ADH-mediated water retention and to urinary sodium losses. However, with these severe neurologic conditions, there is uncertainty as to whether the sodium losses are a result of SIADH-induced expansion of the extracellular volume or whether they are caused by salt wasting (ie, cerebral salt wasting), with release of ADH that is secondary to a reduction in extracellular fluid volume. (See 'Cerebral salt wasting' below.)
Because of this uncertainty, therapy of hyponatremia in patients with CNS disorders usually requires the administration of hypertonic saline, rather than fluid restriction or isotonic saline. (See 'Cerebral salt wasting' below.)
Malignancies — Ectopic production of ADH by a tumor is most often due to a small cell carcinoma of the lung and is rarely seen with other lung tumors [1,14]. Less common causes of malignancy-associated SIADH include head and neck cancer, olfactory neuroblastoma (esthesioneuroblastoma), and extrapulmonary small cell carcinomas [15-17].
Ectopic ADH secretion by tumor cells has been documented in vitro. In addition, some small cell lung cancer cells increase ADH secretion in response to high osmolality, suggesting a degree of regulation of the ectopic secretion . This in vitro finding is compatible with the clinical observation that some patients with tumor-induced SIADH show evidence of osmoregulation of ADH release . (See "Pathobiology and staging of small cell carcinoma of the lung".)
Drugs — Certain drugs can enhance ADH release or effect, including chlorpropamide, carbamazepine, oxcarbazepine (a derivative of carbamazepine), high-dose intravenous cyclophosphamide, and selective serotonin reuptake inhibitors (table 1) [1,19-27]. Experimental studies suggest that chlorpropamide may increase concentrating ability both by increasing sodium chloride reabsorption in the loop of Henle (thereby enhancing the efficiency of countercurrent exchange) and by augmenting collecting tubule permeability to water . The latter effect may be mediated by an increased number of ADH receptors in the collecting tubule cells. Carbamazepine and oxcarbazepine also act at least in part by increasing the sensitivity to ADH [21,22,25].
SIADH due to high-dose intravenous cyclophosphamide may be a particular problem since patients receiving this regimen are often fluid loaded to prevent hemorrhagic cystitis [26,27]. As a result, marked water retention and potentially fatal hyponatremia may ensue in selected cases . This complication has been primarily described with doses in the range of 30 to 50 mg/kg used to treat malignancy, or 6 g/m2 as given in the STAMP protocol in preparation for bone marrow rescue . Although less common, hyponatremia can also occur with the lower doses (10 to 15 mg/kg) that are given as pulse therapy in autoimmune diseases such as lupus nephritis. Chemotherapy-induced nausea may play a contributory role since nausea is a potent stimulus to ADH release . The fall in the plasma sodium concentration in this setting can be minimized by using isotonic saline rather than free water to maintain a high urine output.
SIADH is also associated with the selective serotonin reuptake inhibitors (eg, fluoxetine, sertraline) [29-33]. The exact prevalence is unknown; patients above age 65 years may be more susceptible to the complication . The risk of developing severe hyponatremia requiring hospitalization is greatest in the first few weeks after initiating treatment with these agents .
Many other drugs have been associated with the SIADH. These include vincristine, vinblastine, vinorelbine, cisplatin, thiothixene, thioridazine, haloperidol, amitriptyline, monoamine oxidase inhibitors, melphalan, ifosfamide, methotrexate, opiates, nonsteroidal antiinflammatory agents, interferon-alpha, interferon-gamma, sodium valproate, bromocriptine, lorcainide, amiodarone, ciprofloxacin, high-dose imatinib, and "ecstasy" (methylenedioxymethamphetamine), a drug of abuse that may also be associated with excessive water intake [1,29,35-39].
Surgery — Surgical procedures are often associated with hypersecretion of ADH, a response that is probably mediated by pain afferents [40-42]. In addition, hyponatremia may develop after other types of interventional procedures, such as cardiac catheterization .
Hyponatremia is also a common late complication of transsphenoidal pituitary surgery, occurring in 21 to 35 percent of cases [44,45]. Although relative cortisol deficiency may contribute, the major cause is inappropriate ADH release from the injured posterior pituitary gland. The fall in the plasma sodium concentration is most severe on the sixth to seventh postoperative day. This form of isolated hyponatremia (or isolated second phase) appears to be a subset of the classic triphasic cycle in which initial polyuria is followed by transient SIADH and then either recovery or, in severe cases, a third phase of permanent central diabetes insipidus. (See "Clinical manifestations and causes of central diabetes insipidus", section on 'Neurosurgery or trauma'.)
Rarely, hyponatremia after pituitary surgery is due to cerebral salt wasting. (See 'Cerebral salt wasting' below.)
Pulmonary disease — Pulmonary diseases, particularly pneumonia (viral, bacterial, tuberculous), can lead to the SIADH, although the mechanism by which this occurs is not clear . A similar response may infrequently be seen with asthma, atelectasis, acute respiratory failure, and pneumothorax [1,41].
Hormone deficiency — Both hypopituitarism and hypothyroidism may be associated with hyponatremia and an SIADH picture that can be corrected by hormone replacement. (See "Hyponatremia and hyperkalemia in adrenal insufficiency" and "Causes of hypotonic hyponatremia in adults", section on 'Hypothyroidism'.)
Hormone administration — The SIADH can by induced by exogenous hormone administration, as with vasopressin (to control gastrointestinal bleeding), desmopressin (dDAVP; to treat von Willebrand disease or hemophilia or platelet dysfunction), or oxytocin (to induce labor) [46-49]. As with vasopressin and desmopressin, oxytocin acts by increasing the activity of the vasopressin-2 (V2; antidiuretic) receptor .
HIV infection — A common cause of hyponatremia is symptomatic HIV infection, either the acquired immune deficiency syndrome (AIDS) or early symptomatic HIV infection . Although volume depletion (due, for example, to gastrointestinal losses) or adrenal insufficiency may be responsible, many patients have the SIADH. Pneumonia, due to Pneumocystis carinii or other organisms, central nervous system infections, and malignant disease, are most often responsible in this setting . (See "Electrolyte disturbances with HIV infection".)
Hereditary SIADH — The clinical picture of SIADH may result from genetic disorders that result in antidiuresis. A mutation affecting the gene for the renal V2 receptor, which some investigators have named nephrogenic syndrome of inappropriate antidiuresis, has been found to cause clinically significant hyponatremia.
In the initial description of the nephrogenic syndrome, two male infants were described who presented with hyponatremia, hypoosmolality, increased urine osmolality, and a high urine sodium concentration consistent with SIADH, but with no detectable circulating ADH [52,53]. Gain-of-function mutations were found in the gene encoding the V2 receptor that mediates the antidiuretic response to ADH; persistent activation of the receptor was responsible for the persistent antidiuretic state . The gene for the V2 receptor is located on the X chromosome, and loss-of-function mutations of the gene are responsible for X-linked nephrogenic diabetes insipidus. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus", section on 'Hereditary nephrogenic DI'.)
The nephrogenic syndrome of inappropriate antidiuresis has also been found in adult men and women. In one study, a 74-year-old man with an initial diagnosis of SIADH was unresponsive to oral inhibitors of the V2 receptor; he was subsequently discovered to have a gain-of-function mutation of the gene for this receptor . After screening of family members, two additional hemizygous males and four heterozygous females were identified. Spontaneous episodes of hyponatremia and/or an abnormal water load test were observed in all but one woman with the genetic defect, who had preferential inactivation of the X chromosome harboring the mutated allele.
Most patients with the nephrogenic syndrome of inappropriate antidiuresis harbor a mutation that "locks" the V2 receptor in the open position and thereby makes it unresponsive to vasopressin antagonists . Gain-of-function mutations involving other regions of the gene have been reported in which response to vasopressin antagonists is preserved .
An activating mutation affecting the signaling pathway between the V2 receptor and cyclic adenosine monophosphate has been identified as another cause of the nephrogenic syndrome of antidiuresis in children with hyponatremia . The mutation is located in the gene encoding the guanine-nucleotide alpha subunit (GNAS), which is involved in transmitting signals via the G protein-coupled V2 receptor.
Polymorphisms in the genes encoding the hypothalamic osmoreceptor, transient receptor potential vanilloid type 4 (TRPV4), may also cause mild hyponatremia . Population studies show that men but, for reasons unknown, not women with a proline to serine substitution at residue 19 are two to six times more likely to have a serum sodium ≤135 mEq/L than men with the wild-type allele . The mean serum sodium concentrations among men with one copy of the variant allele are lower by approximately 2 mEq/L. In vitro, TRPV4 channels with the variant allele are hyporesponsive to mild hypotonic stress but respond normally to severe osmotic stress. Thus, affected individuals would be expected to behave as if they have a reset osmostat, with a lower-than-normal serum sodium concentration that regulates normally around that value. Based upon what has been observed in genetically engineered mice that lack a functioning TRVPV4 channel, it has been postulated that humans with the variant hypofunctioning allele would exhibit unrestricted drinking, and therefore, more severe hyponatremia, if they were to develop SIADH for another reason. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Reset osmostat'.)
Idiopathic — Idiopathic SIADH has been described primarily in older adult patients [60-63]. However, some cases of apparently idiopathic disease were later found to be caused by an occult tumor (most often small cell carcinoma or olfactory neuroblastoma) and, in older patients, giant cell (temporal) arteritis [1,61,64,65].
CEREBRAL SALT WASTING — A rare syndrome has been described in patients with cerebral disease (particularly subarachnoid hemorrhage) that mimics all of the findings in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) except that salt wasting is thought to be the primary defect, with the ensuing volume depletion causing a secondary rise in antidiuretic hormone (ADH) release. This distinction is not easy to make since the true volume status of the patient is often difficult to ascertain. The pathogenesis, manifestations, and treatment of cerebral salt wasting are discussed separately. (See "Cerebral salt wasting".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyponatremia".)
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●Definition – The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a disorder of impaired water excretion caused by the inability to suppress the secretion of antidiuretic hormone (ADH). (See 'Introduction' above.)
SIADH should be suspected in any patient with hyponatremia, hypoosmolality, and a urine osmolality above 100 mosmol/kg (algorithm 1). In SIADH, the urine sodium concentration is usually above 40 mEq/L, the serum potassium concentration is normal, there is no acid-base disturbance, and the serum uric acid concentration is frequently low. (See 'Introduction' above.) (Related Pathway(s): Hyponatremia: Evaluation in adults.)
●Pathogenesis – ADH secretion results in a concentrated urine and therefore a reduced urine volume. In most patients with SIADH, ingestion of water does not adequately suppress ADH, and the urine remains concentrated. This leads to water retention, which increases total body water (TBW). This increase in TBW lowers the plasma sodium concentration by dilution. In addition, the increase in TBW transiently expands the extracellular fluid volume and thereby triggers increased urinary sodium excretion, which both returns the extracellular fluid volume toward normal and further lowers the plasma sodium concentration. (See 'Pathophysiology' above.)
●Etiology – One of the following causes of persistent ADH release is likely to be present in patients who fulfill the clinical criteria for the SIADH (see 'Etiology' above):
•Any CNS disorder, including stroke, hemorrhage, infection, trauma, and psychosis can enhance ADH release. There is uncertainty as to whether hyponatremia in patients with severe neurologic disorders (such as hemorrhage or trauma) is due to SIADH or salt wasting (ie, cerebral salt wasting). (See 'CNS disturbances' above and 'Cerebral salt wasting' above.)
•Ectopic production of ADH by a tumor is most often due to a small cell carcinoma of the lung and is rarely seen with other lung tumors. Less common causes of malignancy-associated SIADH include head and neck cancer, olfactory neuroblastoma (esthesioneuroblastoma), and extrapulmonary small cell carcinomas. (See 'Malignancies' above.)
•Certain drugs can enhance ADH release or effect, including chlorpropamide, carbamazepine, oxcarbazepine (a derivative of carbamazepine), high-dose intravenous cyclophosphamide, and selective serotonin reuptake inhibitors (table 1). Many other drugs have been associated with the SIADH. These include vincristine, vinblastine, vinorelbine, cisplatin, thiothixene, thioridazine, haloperidol, amitriptyline, monoamine oxidase inhibitors, melphalan, ifosfamide, methotrexate, opiates, nonsteroidal antiinflammatory agents, interferon-alpha, interferon-gamma, sodium valproate, bromocriptine, lorcainide, amiodarone, ciprofloxacin, and high-dose imatinib. "Ecstasy" (methylenedioxymethamphetamine) is a drug of abuse that may also be associated with both SIADH and excessive water intake. (See 'Drugs' above.)
•Surgical procedures are often associated with hypersecretion of ADH, a response that is probably mediated by pain afferents. In addition, hyponatremia may develop after other interventional medical procedures, such as cardiac catheterization. (See 'Surgery' above.)
•Pulmonary diseases, particularly pneumonia (viral, bacterial, tuberculous), can lead to the SIADH, although the mechanism by which this occurs is not clear. A similar response may infrequently be seen with asthma, atelectasis, acute respiratory failure, and pneumothorax. (See 'Pulmonary disease' above.)
•Both hypopituitarism and hypothyroidism may be associated with hyponatremia and clinical findings identical to SIADH, but these abnormalities are corrected by hormone replacement. (See 'Hormone deficiency' above.)
•SIADH can by induced by exogenous administration of hormones: vasopressin (to control gastrointestinal bleeding); ADH analogs, such as desmopressin (dDAVP; to treat von Willebrand disease, hemophilia, other forms of platelet dysfunction, or enuresis); or other hormones with antidiuretic effects, such as oxytocin (to induce labor). (See 'Hormone administration' above.)
•Symptomatic HIV infection is associated with SIADH. (See 'HIV infection' above.)
•The clinical picture of SIADH may result from genetic disorders that result in antidiuresis. (See 'Hereditary SIADH' above.)