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Literature review current through: Oct 2020. | This topic last updated: Oct 22, 2019.
INTRODUCTION
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 [1]. (See
"Diagnostic evaluation of adults with hyponatremia".)
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".)
PATHOPHYSIOLOGY
Hyponatremia can occur in SIADH even if the only fluid given is isotonic saline [2]. 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 [5]. 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 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.
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].
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]:
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 [18]. This in vitro finding is
compatible with the clinical observation that some patients with tumor-induced SIADH
show evidence of osmoregulation of ADH release [4]. (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 [20]. 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 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 [33].
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 [1,29,34-38].
Rarely, hyponatremia after pituitary surgery is due to cerebral salt wasting. (See
'Cerebral salt wasting' below.)
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 [51,52]. 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 [53]. 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 [54]. 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.
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 [57]. 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 [58].
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 [58]. 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
[59-62]. 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 [1,60,63,64].
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".)
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SUMMARY
• The clinical picture of SIADH may result from genetic disorders that result in
antidiuresis. (See 'Hereditary SIADH' above.)
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REFERENCES
1. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th e
d, McGraw-Hill, New York 2001. p.703.
4. Robertson GL, Shelton RL, Athar S. The osmoregulation of vasopressin. Kidney Int
1976; 10:25.
7. Gross PA, Anderson RJ. Effects of DDAVP and AVP on sodium and water balance in
conscious rat. Am J Physiol 1982; 243:R512.
8. LEAF A, BARTTER FC, SANTOS RF, WRONG O. Evidence in man that urinary
electrolyte loss induced by pitressin is a function of water retention. J Clin Invest
1953; 32:868.
10. Ecelbarger CA, Nielsen S, Olson BR, et al. Role of renal aquaporins in escape from
vasopressin-induced antidiuresis in rat. J Clin Invest 1997; 99:1852.
11. Murase T, Ecelbarger CA, Baker EA, et al. Kidney aquaporin-2 expression during
escape from antidiuresis is not related to plasma or tissue osmolality. J Am Soc
Nephrol 1999; 10:2067.
13. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N
Engl J Med 2007; 356:2064.
14. Johnson BE, Chute JP, Rushin J, et al. A prospective study of patients with lung
cancer and hyponatremia of malignancy. Am J Respir Crit Care Med 1997;
156:1669.
16. Talmi YP, Wolf GT, Hoffman HT, Krause CJ. Elevated arginine vasopressin levels in
squamous cell cancer of the head and neck. Laryngoscope 1996; 106:317.
17. Sørensen JB, Andersen MK, Hansen HH. Syndrome of inappropriate secretion of
antidiuretic hormone (SIADH) in malignant disease. J Intern Med 1995; 238:97.
18. Kim JK, Summer SN, Wood WM, Schrier RW. Osmotic and non-osmotic regulation
of arginine vasopressin (AVP) release, mRNA, and promoter activity in small cell
lung carcinoma (SCLC) cells. Mol Cell Endocrinol 1996; 123:179.
21. Gold PW, Robertson GL, Ballenger JC, et al. Carbamazepine diminishes the
sensitivity of the plasma arginine vasopressin response to osmotic stimulation. J
Clin Endocrinol Metab 1983; 57:952.
26. Bressler RB, Huston DP. Water intoxication following moderate-dose intravenous
cyclophosphamide. Arch Intern Med 1985; 145:548.
29. ten Holt WL, van Iperen CE, Schrijver G, Bartelink AK. Severe hyponatremia during
therapy with fluoxetine. Arch Intern Med 1996; 156:681.
30. Liu BA, Mittmann N, Knowles SR, Shear NH. Hyponatremia and the syndrome of
inappropriate secretion of antidiuretic hormone associated with the use of
selective serotonin reuptake inhibitors: a review of spontaneous reports. CMAJ
1996; 155:519.
31. Covyeou JA, Jackson CW. Hyponatremia associated with escitalopram. N Engl J
Med 2007; 356:94.
33. Fabian TJ, Amico JA, Kroboth PD, et al. Paroxetine-induced hyponatremia in older
adults: a 12-week prospective study. Arch Intern Med 2004; 164:327.
34. Holden R, Jackson MA. Near-fatal hyponatraemic coma due to vasopressin over-
secretion after "ecstasy" (3,4-MDMA). Lancet 1996; 347:1052.
35. Wilkins B. Cerebral oedema after MDMA ("ecstasy") and unrestricted water intake.
Hyponatraemia must be treated with low water input. BMJ 1996; 313:689.
39. Fieldman NR, Forsling ML, Le Quesne LP. The effect of vasopressin on solute and
water excretion during and after surgical operations. Ann Surg 1985; 201:383.
41. Gowrishankar M, Lin SH, Mallie JP, et al. Acute hyponatremia in the perioperative
period: insights into its pathophysiology and recommendations for management.
Clin Nephrol 1998; 50:352.
44. Olson BR, Rubino D, Gumowski J, Oldfield EH. Isolated hyponatremia after
transsphenoidal pituitary surgery. J Clin Endocrinol Metab 1995; 80:85.
45. Dunn AL, Powers JR, Ribeiro MJ, et al. Adverse events during use of intranasal
desmopressin acetate for haemophilia A and von Willebrand disease: a case
report and review of 40 patients. Haemophilia 2000; 6:11.
46. Shepherd LL, Hutchinson RJ, Worden EK, et al. Hyponatremia and seizures after
intravenous administration of desmopressin acetate for surgical hemostasis. J
Pediatr 1989; 114:470.
48. Feeney JG. Water intoxication and oxytocin. Br Med J (Clin Res Ed) 1982; 285:243.
50. Vitting KE, Gardenswartz MH, Zabetakis PM, et al. Frequency of hyponatremia and
nonosmolar vasopressin release in the acquired immunodeficiency syndrome.
JAMA 1990; 263:973.
51. Gitelman SE, Feldman BJ, Rosenthal SM. Nephrogenic syndrome of inappropriate
antidiuresis: a novel disorder in water balance in pediatric patients. Am J Med
2006; 119:S54.
52. Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of
inappropriate antidiuresis. N Engl J Med 2005; 352:1884.
55. Powlson AS, Challis BG, Halsall DJ, et al. Nephrogenic syndrome of inappropriate
antidiuresis secondary to an activating mutation in the arginine vasopressin
receptor AVPR2. Clin Endocrinol (Oxf) 2016; 85:306.
56. Erdélyi LS, Mann WA, Morris-Rosendahl DJ, et al. Mutation in the V2 vasopressin
receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
Kidney Int 2015; 88:1070.
61. Miller M, Hecker MS, Friedlander DA, Carter JM. Apparent idiopathic
hyponatremia in an ambulatory geriatric population. J Am Geriatr Soc 1996;
44:404.
63. Inappropriate antidiuretic hormone secretion of unknown origin. Kidney Int 1980;
17:554.
Relation between plasma ADH concentration and plasma osmolality in normal humans in
whom the plasma osmolality was changed by varying the state of hydration. The osmotic
threshold for thirst is a few mosmol/kg higher than that for ADH.
Data from Robertson GL, Aycinena P, Zerbe RL. Neurogenic disorders of osmoregulation. Am J Med 1982;
72:339.
Antidepressants
SSRIs
Tricyclic
MAOI
Venlafaxine
Anticonvulsants
Carbamazepine
Sodium valproate
Lamotrigine
Antipsychotics
Phenothiazines
Butyrophenones
Anticancer drugs
Vinca alkaloids
Platinum compounds
Ifosfamide
Melphalan
Cyclophosphamide
Methotrexate
Pentostatin
Antidiabetic drugs
Chlorpropamide
Tolbutamide
Vasopressin analogues
Desmopressin
Oxytocin
Terlipressin
Vasopressin
Miscellaneous
Opiates
MDMA (ecstasy)
Levamisole
Interferon
NSAIDs
Clofibrate
Nicotine
Amiodarone
Monoclonal antibodies
SSRIs: selective serotonin reuptake inhibitors; MAOI: monoamine oxidase inhibitor; MDMA: 3,4-
methylenedioxymethamphetamine; NSAIDs: nonsteroidal antiinflammatory drugs.
Adapted from:
1. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia.
Neprhol Dial Transplant 2014; 29 Suppl 2:i1.
2. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis 2008; 52:144.
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