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Causes of the SIADH

Burton D Rose, MD

UpToDate performs a continuous review of over 350 journals and other resources.
Updates are added as important new information is published. The literature review
for version 14.2 is current through April 2006; this topic was last changed on
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INTRODUCTION The syndrome of inappropriate antidiuretic hormone secretion
(SIADH) should be suspected in any patient with hyponatremia, hypoosmolality, a
urine osmolality above 100 mosmol/kg, a urine sodium concentration that is usually
above 40 meq/L, normal acid-base and potassium balance, and frequently a low
plasma uric acid concentration [1]. (See "Diagnosis of hyponatremia").
An inappropriate elevation in ADH release of any cause produces hyponatremia by
interfering with urinary dilution, thereby preventing the excretion of ingested water.
An interesting observation in the SIADH is the development of partial escape from
ADH which tends to protect against progressive water retention. (See "Urine output in
the SIADH").
Although ADH secretion or effect is inappropriately increased in the SIADH, up to
one-third of patients have a downward resetting of the osmostat in which the plasma
sodium concentration is normally regulated (and is therefore stable) at a new lower
level, typically between 125 and 135 meq/L [1]. Establishing the presence of this
condition is important clinically because correcting the hyponatremia is both
unnecessary and likely to be ineffective, since raising the plasma osmolality will
stimulate both ADH release and thirst. (See "Treatment of hyponatremia: SIADH and
reset osmostat").
ETIOLOGY In the absence of adrenal insufficiency or hypothyroidism, one of the
following causes of persistent ADH release is likely to be present in a patient who
fulfills the clinical criteria for the SIADH [1]:
CNS disturbances Any CNS disorder, including stroke, hemorrhage, infection,
trauma, and psychosis can enhance ADH release. (See "Polydipsia and hyponatremia
in patients with mental illness" for a review of disturbances in water balance that may

occur in this setting and for a brief review of the antidiuretic action of carbamazepine,
a drug that can cause an SIADH picture). The hyponatremia associated with
intracranial bleeding and other severe neurologic events may be only partly due to
excess ADH, as there may also be renal salt-wasting. In this setting, therapy may
require the administration of saline as well as fluid restriction (see "Cerebral saltwasting" below).
Tumors Ectopic production of ADH by a tumor is most often due to a small cell
carcinoma of the lung, but is also occasionally seen with other lung tumors [1,2]. Less
common causes of ectopic ADH secretion include cancer of the duodenum or
pancreas, and an olfactory neuroblastoma (esthesioneuroblastoma).
Proof of ectopic secretion has come from the ability of tumor cells to secrete ADH 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
[3]. 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, particularly the
infrequently used oral hypoglycemic agent chlorpropamide, carbamazepine,
oxcarbazepine (a derivative of carbamazepine), and high-dose intravenous
cyclophosphamide [1,5-13]. 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 [6]. 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 [7,8,11].
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 [12,13]. As a result, marked water retention and potentially fatal hyponatremia
may ensue in selected cases [12]. 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 [13]. 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. (See "Chapter 6B: Antidiuretic hormone and water balance",
section on Other factors affecting ADH secretion). 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 may be more commonly associated with the selective serotonin reuptake
inhibitors (eg, fluoxetine, sertraline) than has been commonly thought. While only a
few case reports have appeared in the literature [14], there are several hundred other
instances reported to various monitoring bodies such as the Food and Drug
Administration [15]. The exact prevalence is unknown; patients above age 65 may be
more susceptible to complication [16].

Other drugs that have been associated with the SIADH include vincristine,
vinblastine, cisplatin, thiothixene, thioridazine, haloperidol, amitriptyline, monoamine
oxidase inhibitors, bromocriptine, lorcainide, amiodarone, ciprofloxacin, and
'"ecstasy" (methylenedioxymethamphetamine), a drug of abuse that may also be
associated with excessive water intake [1,14,17-19]. (See "Designer drugs in adults").
Hyponatremia can also be induced by the administration of exogenous ADH, as with
intravenous vasopressin to control gastrointestinal bleeding or dDAVP to treat central
diabetes insipidus, platelet dysfunction, or nocturia [20,21].
Major surgery Major abdominal or thoracic surgery is commonly associated with
hypersecretion of ADH, a response that is probably mediated by pain afferents [2225]. Hyponatremia is also a common late complication of transsphenoidal pituitary
surgery, occurring in 21 to 35 percent of cases [26,27]. 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 "Causes of
central diabetes insipidus", section on Neurosurgery or trauma). Rarely, the
hyponatremia after pituitary surgery is due to cerebral salt wasting (see "Cerebral saltwasting" 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 [23]. A similar response may infrequently be seen with asthma, atelectasis,
acute respiratory failure, and pneumothorax [1,23].
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) [28-31].
HIV infection A common cause of hyponatremia is symptomatic HIV infection,
either the acquired immune deficiency syndrome (AIDS) or early symptomatic HIV
infection [32]. 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 [32]. (See
"Electrolyte disturbances with HIV infection").
Hereditary SIADH Two infants have been described with hyponatremia, urinary
findings consistent with SIADH, and no detectable circulating ADH [33]. Genetic
analysis revealed gain-of-function mutations in the vasopressin-2 receptor that
mediates the antidiuretic response to ADH, resulting in persistent activation of the
receptor. This is the reverse of hereditary nephrogenic diabetes insipidus in which
most patients have a loss-of-function mutation in this receptor. (See "Causes of
nephrogenic diabetes insipidus", section on Hereditary nephrogenic DI).

Idiopathic Some patients appear to have idiopathic SIADH. The most likely causes
of this problem are an occult tumor (most often oat cell carcinoma or olfactory
neuroblastoma) and, in older patients, giant cell (temporal) arteritis [1,34,35].
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 SIADH, except that salt-wasting is the primary defect with the ensuing
volume depletion leading to a secondary rise in ADH release. This distinction is not
always easy to make since the true volume status of the patient is sometimes difficult
to ascertain. The pathogenesis, manifestations, and treatment of cerebral salt-wasting
are discussed separately. (See "Cerebral salt-wasting").
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