Syndrome of Inappropriate Antidiuretic Hormone Secretion 

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of euvolemic hyponatremia in hospitalized patients. The syndrome is defined by the hyponatremia and hypo-osmolality that results from inappropriate, continued secretion and/or action of antidiuretic hormone (ADH) despite normal or increased plasma volume, which results in impaired water excretion. The antidiuretic hormone (ADH) promotes the reabsorption of water from the tubular fluid in the collecting duct, the hydro-osmotic effect, and it does not exert a significant effect on the rate of Na⁺ reabsorption. A second action of ADH is to cause arteriolar vasoconstriction and a rise in arterial blood pressure, the pressor effect.

Physiology of ADH

Arginine vasopressin (AVP), the naturally occurring ADH in humans, is an octapeptide similar in structure to oxytocin. AVP is synthesized in the cell bodies of neurons in the supraoptic and paraventricular nuclei of the anterior hypothalamus and travels along the supraopticohypophyseal tract into the posterior pituitary. Here, it is stored in secretory granules in association with a carrier protein, neurophysin, in the terminal dilatations of secretory neurons that rest against blood vessels.

The major stimuli for AVP secretion are hyperosmolality and effective circulating volume depletion, which are sensed by osmoreceptors and baroreceptors, respectively. Osmoreceptors are specialized cells in the hypothalamus that perceive changes in the extracellular fluid (ECF) osmolality. Baroreceptors are located in the carotid sinus, aortic arch, and left atrium; these receptors participate in the nonosmolar control of AVP release by responding to a change in effective circulating volume.

Three known receptors bind AVP at the cell membrane of target tissues: V1a, V1b (also known as V3), and V2; these mediate AVP’s various effects.

V1a receptor is the vascular smooth muscle cell receptor but is also found on a number of other cells, such as hepatocytes, cardiac myocytes, platelets, brain, and testis. The V1a receptors signal by activation of phospholipase C and elevation in intracellular calcium, which, in turn, stimulates vasoconstriction. V1b (V3) receptors are found predominantly in the anterior pituitary, where they stimulate ACTH secretion.

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 on the basolateral membrane of the principal cells of the connecting tubule and collecting duct of the distal nephron.^[1] Activation of the V2 receptor results in insertion of the water channel aquaporin-2 in the luminal membrane of the collecting duct, thus making it more permeable to water. Activation of the V2 receptors also increases urea and Na⁺ chloride reabsorption by the ascending limb of loop of Henle, thus increasing medullary tonicity and providing the osmotic gradient for maximal water absorption.^[1] V2 receptors are also found in vascular endothelial cells and stimulate the release of von Willebrand factor.^[1]

Normally, AVP secretion ceases when plasma osmolality falls below 275 mOsm/kg. This decrease causes increased water excretion, which leads to a dilute urine with an osmolality of 40-100 mOsm/kg. When plasma osmolality rises, AVP is secreted, which results in an increase in water reabsorption and an increase in urine osmolality to as much as 1400 mOsm/kg. An 8-10% reduction in circulating volume also significantly increases AVP release. In most physiologic states, the volume receptors and osmoreceptors act in concert to increase or decrease AVP release. However, a reduction in actual or effective circulating volume is an overriding stimulus for secretion of AVP and takes precedence over extracellular osmolality when osmolality is normal or reduced. Finally, AVP is also released in response to stressful stimuli, such as pain or anxiety, and by various drugs. The released AVP is rapidly metabolized in the liver and kidneys and has a half-life of 15-20 minutes.

The key to understanding the pathophysiology, signs, symptoms, and treatment of SIADH is the awareness that the hyponatremia in this syndrome is a result of an excess of water and not a deficiency of Na⁺.

SIADH consists of hyponatremia, inappropriately elevated urine osmolality (>100 mOsm/kg), and decreased serum osmolality in a euvolemic patient. SIADH should be diagnosed when these findings occur in the setting of otherwise normal cardiac, renal, adrenal, hepatic, and thyroid function; in the absence of diuretic therapy; and in absence of other factors known to stimulate ADH secretion, such as hypotension, severe pain, nausea, and stress.

In general, the plasma Na⁺ concentration is the primary osmotic determinant of AVP release. In persons with SIADH, the nonphysiological secretion of AVP results in enhanced water reabsorption, leading to dilutional hyponatremia. While a large fraction of this water is intracellular, the extracellular fraction causes volume expansion. Volume receptors are activated and natriuretic peptides are secreted, which causes natriuresis and some degree of accompanying potassium excretion (kaliuresis). Eventually, a steady state is reached and the amount of Na⁺ excreted in the urine matches Na intake. Ingestion of water is an essential prerequisite to the development of the syndrome; regardless of cause, hyponatremia does not occur if water intake is severely restricted.

In addition to the inappropriate AVP secretion, persons with this syndrome may also have an inappropriate thirst sensation, which leads to an intake of water that is in excess of free water excreted. This increase in water ingested may contribute to the maintenance of hyponatremia.

Neurologic manifestations

Neurologic complications in SIADH occur as a result of the brain's response to changes in osmolality. Hyponatremia and hypo-osmolality lead to acute edema of the brain cells. The rigid calvaria prevent expansion of brain volume beyond a certain point, after which the brain cells must adapt to persistent hypo-osmolality. However, a rapid increase in brain water content of more than 5-10% leads to severe cerebral edema and herniation and is fatal.

In response to a decrease in osmolality, brain ECF fluid moves into the CSF. The brain cells then lose potassium and intracellular organic osmolytes (amino acids, such as glutamate, glutamine, taurine, polyhydric alcohol, myoinositol, methylamine, and creatinine). This occurs concurrently to prevent excessive brain swelling.^[2]

Following correction of hyponatremia, the adaptive process does not match the extrusion kinetics. Electrolytes rapidly reaccumulate in the brain ECF 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 Na⁺ exceeds 0.5 mEq/L/h for patients with severe hyponatremia. At this rate of correction, osmolytes that have been lost in defense against brain edema during the development of hyponatremia cannot be restored as rapidly when hyponatremia is rapidly corrected. The brain cells are thus subject to osmotic injury, a condition termed osmotic demyelination. Certain factors such as hypokalemia, severe malnutrition, and advanced liver disease predispose patients to this devastating complication.^[2]

SIADH is most often caused by either inappropriate hypersecretion of ADH from its normal hypothalamic source or by ectopic production. The causes of SIADH can be divided into 4 broad categories: nervous system disorders, neoplasia, pulmonary diseases, and drug induced (which include those that [1] stimulate AVP release, [2] potentiate effects of AVP action, or [3] have an uncertain mechanism).

Nervous system disorders are as follows:

• Acute psychosis
• Acute intermittent porphyria
• Brain abscess
• Cavernous sinus thrombosis
• Cerebellar and cerebral atrophy
• Cerebrovascular accident
• CNS lupus
• Delirium tremens
• Encephalitis (viral or bacterial)
• Epilepsy
• Guillain-Barré syndrome
• Head trauma
• Herpes zoster (chest wall)
• Hydrocephalus
• Hypoxic ischemic encephalopathy
• Meningitis (viral, bacterial, tuberculous, and fungal)
• Midfacial hypoplasia
• Multiple sclerosis
• Perinatal hypoxia
• Rocky Mountain spotted fever
• Schizophrenia
• Shy-Drager syndrome
• Subarachnoid hemorrhage
• Subdural hematoma
• Ventriculoatrial shunt obstruction
• Wernicke encephalopathy

Neoplasia disorders are as follows:

• Pulmonary - Lung carcinoma and mesothelioma
• Gastrointestinal - Carcinomas of the duodenum, pancreas, and colon
• Genitourinary - Adrenocortical carcinoma; carcinomas of cervix, ureter/bladder, and prostate; and ovarian tumors
• Other - Brain tumors, carcinoid tumors, Ewing sarcoma, leukemia, lymphoma, nasopharyngeal carcinoma, neuroblastoma (olfactory), and thymoma

Pulmonary disorders are as follows:

• Acute bronchitis/bronchiolitis
• Acute respiratory failure
• Aspergillosis (cavitary lesions)
• Asthma
• Atelectasis
• Bacterial pneumonia
• Chronic obstructive lung disease
• Cystic fibrosis
• Emphysema
• Empyema
• Pneumonia (viral, bacterial [mycoplasmal], fungal)
• Pneumothorax
• Positive pressure ventilation
• Pulmonary abscess
• Pulmonary fibrosis
• Sarcoidosis
• Tuberculosis
• Viral pneumonia

Drugs that stimulate AVP release are as follows:

• Acetylcholine
• Antineoplastic agents - Adenine arabinoside, cyclophosphamide, ifosfamide, vincristine, vinblastine
• Barbiturates
• Bromocriptine
• Carbachol
• Chlorpropamide
• Clofibrate
• Cyclopropane
• Dibenzazepines (eg, carbamazepine, oxcarbazepine
• Halothane
• Haloperidol
• Histamine
• Isoproterenol
• Lorcainide
• Opiates e.g. Morphine
• Nicotine (inhaled tobacco)
• Nitrous oxide
• Phenothiazines (eg, thioridazine)
• Thiopental
• MAOIs (eg, tranylcypromine)
• Tricyclic antidepressants (eg, amitriptyline, desipramine)

Drugs that potentiate the effects of AVP action (primarily facilitates peripheral action of ADH) are as follows:

• Clofibrate
• Griseofulvin
• Hypoglycemic agents – Metformin, phenformin, tolbutamide
• Oxytocin (large doses)
• Prostaglandin synthetase inhibitors (inhibit renal PGE₂ synthesis) – Indomethacin, aspirin, nonsteroidal anti-inflammatory drugs
• Theophylline
• Triiodothyronine
• Vasopressin analogs (eg, AVP, DDAVP)

Drugs with an uncertain mechanism are as follows:

• Antineoplastic agents – Cisplatin, melphalan, methotrexate, imatinib
• Ciprofloxacin
• Clomipramine
• Ecstasy
• Phenoxybenzamine
• Na⁺ valproate
• SSRIs (eg, sertraline, fluoxetine, paroxetine)
• Thiothixene

The list of drugs that can induce SIADH is long. SIADH has been reported as an adverse effect of multiple psychotropic medications.^[3] Many chemotherapeutic drugs cause nausea, which is a powerful stimulus of vasopressin secretion. SIADH is also a leading cause of hyponatremia in children following chemotherapy or stem cell transplantation.

Miscellaneous causes are as follows:

• Exercise-induced hyponatremia
• Giant cell arteritis
• HIV infection - Hyponatremia has been reported in as many as 40% of adult patients with HIV infection. Patients with acquired immunodeficiency syndrome (AIDS) can have many potential causes for increased ADH secretion, including volume depletion and infection of the lungs and the CNS.^[4] Although one third of the hyponatremic patients with AIDS are clinically hypovolemic, the remaining hyponatremic patients fulfill most of the criteria for SIADH.
• Idiopathic

Occurrence in the United States

Hyponatremia is the most common electrolyte derangement occurring in hospitalized patients. When defined as plasma Na⁺ concentration of less than 135 mEq/L, the prevalence of hyponatremia in hospitalized patients has been reported in different studies as being between 2.5% and 30%.^{[5, 6, 7, 8]} In the majority of cases, the hyponatremia was hospital acquired or aggravated by the hospitalization and may be secondary to the administration of hypotonic intravenous (IV) fluids.^[5] SIADH can also arise postoperatively from stress, pain, and medications used. However, not all hospital-acquired hyponatremia is SIADH and SIADH should be differentiated from the hyponatremia that occurs in patients with limited capacity to excrete free water, such as in patients with chronic kidney disease.

Sex- and age-related demographics

Increasing age (>30 y) is a risk factor for hyponatremia in hospitalized patients.^[8] Men appear to be more likely to develop mild or moderate, but not severe, hyponatremia.^[8] Low body weight is also a risk factor for hyponatremia. Women appear to be more prone to drug-induced hyponatremia and to exercise-induced hyponatremia (marathon runners), although this may be an association with low body weight rather than sex.^[1]

The prognosis of SIADH correlates with the underlying cause and to the effects of severe hyponatremia and its overzealous correction. Rapid and complete recovery tends to be the rule with drug-induced SIADH when the offending agent is withdrawn. Successful treatment of pulmonary or CNS infection also can lead to correction of SIADH. However, patients who present with neurologic symptoms or have severe hyponatremia even without symptoms may develop permanent neurologic impairment. Patients whose serum Na⁺ is rapidly corrected, especially those who are asymptomatic, can also develop permanent neurologic impairment from central pontine myelinolysis (CPM).

Complications

The following complications are noted in SIADH:

• Cerebral edema may be observed when plasma osmolality decreases faster than 10 mOsm/kg/h. This can lead to cerebral herniation.
• Noncardiogenic pulmonary edema may develop, especially in marathon runners.^[9]
• CPM is the feared complication of excessive, overly rapid correction of hyponatremia. Typical features are disorders of upper motor neurons, including spastic quadriparesis and pseudobulbar palsy, as well as mental disorders ranging from confusion to coma.^[10] The risk is increased in persons with hepatic failure, potassium depletion, large burns, and malnutrition.^[11] Premenopausal patients undergoing surgery, especially gynecologic or related procedures, and those with serum Na of less than 105 may also have an increased risk. Once CPM occurs as a complication, there is no proven treatment.

Morbidity and mortality

Previously, mild hyponatremia was considered relatively asymptomatic. However, evidence suggests that even mild hyponatremia can cause significant impairment, such as unsteady gait, and lead to frequent falls. This effect may be greater in elderly persons, who are more sensitive to changes in serum Na⁺.^[12]

The mortality of patients with hyponatremia (Na⁺ < 130 mEq/L) is increased 60-fold compared with that of patients without documented hyponatremia, although this may be partly related to their comorbid conditions rather than to the hyponatremia itself. Predictors for higher morbidity and mortality rates include being hospitalized, acute onset, and severity of hyponatremia.^[7] When the Na⁺ concentration drops below 105 mEq/L, life-threatening complications are much more likely to occur.^[11]

In a retrospective case note review by Clayton and colleagues, patients with a multifactorial cause for hyponatremia in an inpatient setting had significantly higher mortality rates.^[13] The etiology of hyponatremia was a more important prognostic indicator than the level of absolute serum Na⁺ in the patients. The outcome was least favorable in patients who were normonatremic at admission and became hyponatremic during the course of their hospitalization.