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Syndrome of Inappropriate Antidiuretic Hormone Secretion
Updated: May 28, 2009
Introduction
Background
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) consists of hyponatremia, inappropriately elevated urine osmolality (>200 mOsm/kg), excessive urine sodium excretion (UNa >30 mEq/L), and decreased serum osmolality. These findings occur in the absence of diuretic therapy; in the presence of euvolemia without edema; and in the setting of otherwise normal cardiac, renal, adrenal, hepatic, and thyroid function. The key to the pathophysiology, signs, symptoms, and eventual treatment of SIADH is an understanding that the hyponatremia is a result of excess water and not a sodium deficiency.
Inappropriate secretion of the antidiuretic hormone (ADH), also known as vasopressin, due to any cause interferes with renal excretion of water and results in production of concentrated urine and hyponatremia.
Pathophysiology
The serum sodium concentration is normally regulated by the balance of water intake, renal excretion of sodium, and ADH-mediated water conservation by the distal renal tubule. These processes are mediated by stimulation of thirst, secretion of ADH, feedback mechanisms of the renin-angiotensin-aldosterone system, and variation of renal handling of filtered sodium. Disorders in any one of these components of sodium balance can result in hyponatremia.1
ADH is secreted by the posterior pituitary gland. Its effect in the kidney is mediated via the vasopressin V2 receptor on the basolateral surface of the principal cells of the collecting duct, cyclic AMP, protein kinase A, and a molecular dynein motor. The key action of ADH in the kidney is the insertion of water channels into the principal cells of the collecting duct, thus increasing the permeability of water. These channels include aquaporin-2, which is located at the apical membrane, and aquaporin-3, which is located at the basolateral membrane. These channels allow free water to be reabsorbed from the collecting duct within the hypertonic renal medulla. In SIADH, the inappropriately elevated level of vasopressin enhances the reabsorption of water, thereby leading to production of concentrated urine, inability to excrete water, and consequently hyponatremia.
Two scenarios exist in which vasopressin secretion will be sustained or increased despite hypoosmolality. An appropriate increase in ADH secretion occurs when the vascular baroreceptors sense a decrease in the effective circulatory volume associated with cirrhosis, nephrotic syndrome, congestive heart failure, and plasma volume depletion. In these cases, the stimulus brought about by hypovolemia for ADH secretion overrides osmotic signals and results in hyponatremia.2 Inappropriate ADH secretion occurs when there is dysregulation of cells secreting vasopressin. The posterior pituitary is not always the source of ADH secretion. A variety of ADH-secreting tumors has been associated with SIADH, as well as various CNS disorders, pulmonary disorders, and drugs.
Frequency
United States
Hyponatremia is the most common electrolyte derangement occurring in hospitalized patients. When defined as plasma sodium concentration of less than 135 mEq/L, the prevalence of hyponatremia in hospitalized patients may be as high as 15-30%.3 In one study, the prevalence of hyponatremia in hospitalized patients, defined as plasma sodium concentration of less than 130 mEq/L, was 2.5%. Two thirds of these patients had hospital-acquired hyponatremia. Remarkably, non-osmotic secretion of vasopressin was found in 97% of all patients with hyponatremia.4 In another study among emergency department patients, the prevalence of hyponatremia, defined as serum sodium concentration of less than 130 mEq/L, was 2.9%. Additionally, the prevalence of acute hyponatremia was 0.8%.5 Although a number of potential causes of hyponatremia exist, ADH dysregulation is the most common.4
Mortality/Morbidity
The fatality rate of patients with hyponatremia (when defined by a sodium concentration of <130 mEq/L) is 60-fold compared to that of patients without documented hyponatremia. Morbidity and mortality rates are higher in hospitalized patients and those with acute onset or severe hyponatremia.4
Race
No evidence for race predilection was found in studies of SIADH.
Sex
In one study,5 acute symptomatic hyponatremia was found more often in female emergency department patients than in male emergency department patients. Another study reported a higher prevalence of symptomatic hyponatremia among female geriatric patients than among male geriatric patients (4.6% vs 2.6%).6
Age
Studies suggest that the very old and very young develop symptoms with lesser decreases in serum sodium levels than adults.7
Clinical
History
Signs and symptoms of hyponatremia are primarily related to the dysfunction of the central nervous system and correlate with severity and rapidity of development of hyponatremia. Anorexia, nausea, and malaise are the earliest findings, followed by headache, irritability, confusion, muscle cramps, weakness, obtundation, seizures, and coma. These occur as osmotic fluid shifts result in cerebral edema and increased intracranial pressure. Whereas most patients with serum sodium concentration above 125 mEq/L are asymptomatic, those with lower levels typically have symptoms, especially in the setting of a rapid decrease. When sodium concentration drops below 105 mEq/L, life-threatening complications are likely to occur.8
Helpful historical details in identifying the responsible mechanism for hyponatremia include diet, fluid intake, gastrointestinal losses, amount of urinary output, and medications. Historical information can give important clues in deciding whether the hyponatremia is from an acute or chronic condition. This may help the physician in correlating the degree of hyponatremia with the patient’s neurologic condition and influence the rate of sodium correction.
Prior to establishing a diagnosis of SIADH, a detailed history should be obtained in order to exclude the numerous disorders capable of causing hyponatremia. These include congestive heart failure, hepatic dysfunction, adrenal insufficiency, renal failure, and thyroid diseases.
Physical
On physical examination, evaluation of volume status is important. SIADH is characterized by euvolemic hyponatremia. Edema in a hyponatremic patient should lead to the consideration of conditions other than SIADH, such as the hypervolemic hyponatremic states (CHF, cirrhosis, and nephrotic syndrome). Other findings consistent with euvolemia include normal blood pressure, absence of orthostatic instability, moist mucous membranes, and normal skin turgor. Prominent physical examination findings may be seen only in severe or rapid-onset hyponatremia and include confusion, lethargy, weakness, myoclonus, asterixis, depressed reflexes, generalized seizures, and coma.
Causes
Some of the causes of SIADH are listed below:
- Central nervous system disease - Tumor, trauma, infection, cerebrovascular accident, subarachnoid hemorrhage, Guillain-Barré syndrome, delirium tremens, multiple sclerosis
- Pulmonary disease - Tumor, pneumonia, chronic obstructive pulmonary disease, lung abscess, tuberculosis, cystis fibrosis, positive-pressure ventilation
- Carcinoma - Lung, pancreas, thymoma, ovary, lymphoma
- Drugs - Exogenous vasopressin, nonsteroidal anti-inflammatory drugs, nicotine, diuretics, chlorpropamide, carbamazepine, tricyclic antidepressants, SSRIs, vincristine, thioridazine, cyclophosphamide, clofibrate
- Surgery - Postoperative
- Idiopathic (most common)
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References
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Brenner BM. Pathophysiology of water metabolism. In: Brenner & Rector's The Kidney. 7th ed. Saunders; 2004:chap 19.
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Soupart A, Decaux G. Therapeutic recommendations for management of severe hyponatremia: current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol. Sep 1996;46(3):149-69. [Medline].
[Best Evidence] Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. Nov 16 2006;355(20):2099-112. [Medline].
Yeates KE, Morton AR. Vasopressin antagonists: role in the management of hyponatremia. Am J Nephrol. 2006;26(4):348-55. [Medline].
Verbalis JG. AVP receptor antagonists as aquaretics: review and assessment of clinical data. Cleve Clin J Med. Sep 2006;73 Suppl 3:S24-33. [Medline].
Further Reading
Keywords
SIADH, antidiuretic hormone, ADH, vasopressin, syndrome of inappropriate antidiuretic hormone secretion, hyponatremia, elevated urine osmolality, excessive sodium excretion, excess water, renal excretion of water, concentrated urine, ADH dysregulation
