eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders

Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Author: Sonali Deshmukh, MBBS, Consulting Staff, Omaha Nephrology, Nebraska
Coauthor(s): Christie P Thomas, MB, BS, FRCP, FASN, FAHA, Professor, Department of Internal Medicine, Division of Nephrology, University of Iowa Hospitals and Clinics; Director of Transplantation Services, Veterans Affairs Medical Center
Contributor Information and Disclosures

Updated: May 28, 2009

Introduction

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.¹

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.² 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.

Clinical

History

SIADH is usually detected based on the results of laboratory testing.

• Two important considerations related to the history include the following:
  • Note symptoms that may suggest increased secretion of ADH, such as chronic pain, CNS or pulmonary tumors (eg, hemoptysis, chronic headaches), head injury, and drug use.
  • Determine if the patient has had excessive fluid intake because of inappropriate thirst or psychogenic polydipsia or because intravenous fluids were administered by health care providers.
• Depending on the magnitude and rate of development, hyponatremia may or may not cause symptoms. In general, slowly progressive hyponatremia is associated with fewer symptoms than a rapid drop of serum sodium to the same value. A recent paper by Decaux evaluating mild chronic hyponatremia suggests that it contributes to an increased rate of falls.³
• When the serum sodium level is less than 125 mEq/L, mild CNS symptoms, such as lethargy, fatigue, anorexia, nausea, and muscle cramps, may develop. A further decrease in the serum sodium level can lead to drowsiness, confusion, seizures, and coma.

Physical

After the identification of hyponatremia, the approach to the patient depends on the clinically assessed volume status. In SIADH, the patient is typically euvolemic and hypertension, peripheral and pulmonary edema, dry mucous membranes, reduced skin turgor, and orthostatic hypotension are usually absent.

• Neurologic signs may be present if hyponatremia is severe or if it develops rapidly.
  • These signs include Cheyne-Stokes respiration, drowsiness, disorientation, delirium, seizures, and coma.
  • Neurologic complications occur as a result of the brain's adaptation to changes in osmolality. Hyponatremia and hypoosmolality lead to acute edema of the brain cells. An increase in brain water content of more than 5-10% is incompatible with life. The rigid calvarium prevents expansion of brain volume beyond a certain point, after which the brain cells must adapt to persistent hypoosmolality.
  • In response to a decrease in osmolality, the brain rapidly loses electrolytes (eg, sodium and chloride from interstitial fluid in minutes, potassium from intracellular space within 2-3 h) and intracellular organic osmolytes (eg, amino acids, such as glutamate, glutamine, taurine, polyhydric alcohol, myoinositol, methylamine, and creatinine). This occurs concurrently to prevent excessive brain swelling.
  • Quantitative brain osmolyte modifications have been studied in humans in vivo (by proton magnetic resonance spectroscopy), and results showed profound decreases in myoinositol.
• Following correction of hyponatremia, the adaptive process does not match the extrusion kinetics.
  • Electrolytes rapidly reaccumulate within 24 hours, resulting in a significant overshoot above normal brain contents within the first 48 hours after correction.
  • Organic osmolytes return to normal brain content very slowly over 5-7 days. Electrolyte brain content returns to normal levels by the fifth day after correction, when organic osmolytes return to normal.
• Irreversible neurologic damage and death may occur when the rate of correction of sodium exceeds 0.5 mEq/L/h for patients with severe hyponatremia. At this rate of correction, the osmolytes that have been lost in defense against brain edema during the development of hyponatremia cannot be restored as rapidly. The brain cells are thus subject to osmotic injury. This condition is called osmotic demyelination. Certain conditions, such as female sex (menstruating women), young age, and hypoxia, predispose patients to worse outcomes.

Causes

In most patients, the defect in urinary dilution is caused by ectopic production, exogenous administration, or osmotically inappropriate neurohypophyseal secretion of ADH. The causes of SIADH are as follows:

• Increased hypothalamic production
  • Neuropsychiatric
    • Infections - Meningitis, encephalitis, abscess
    • Vascular - Thrombosis, subarachnoid or subdural hemorrhage
    • Neoplasms
    • Other - HIV, Guillain-Barré syndrome, acute intermittent porphyria, autonomic neuropathy, post–pituitary surgery, multiple sclerosis, psychosis
  • Drugs
    • Chemotherapeutic - Cyclophosphamide, vincristine, vinblastine
    • Antipsychotic - Thiothixene, thioridazine, haloperidol
    • Antidepressants - Monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors
    • Miscellaneous – Bromocriptine
• Pulmonary diseases
  • Pneumonia
  • Tuberculosis
  • Acute respiratory failure
  • Positive pressure ventilation
  • Asthma
  • Atelectasis
• Postoperative complications
• Severe nausea, pain
• Ectopic production of ADH
  • Oat cell of lung
  • Bronchogenic carcinoma
  • Carcinoma of duodenum, pancreas, or thymus
  • Olfactory neuroblastoma
• Potentiation of ADH effect
  • Chlorpropamide
  • Tolbutamide
  • Carbamazepine
  • Intravenous cyclophosphamide
• Exogenous administration of ADH
• Idiopathic

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