eMedicine Specialties > Pediatrics: General Medicine > Endocrinology
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Updated: Jul 11, 2008
Introduction
Background
The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is the most common cause of euvolemic hyponatremia in pediatrics. 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.
Arginine vasopressin (AVP), the naturally occurring ADH in humans, is an octapeptide similar in structure to oxytocin. It 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, where it is stored in secretory granules in association with a carrier protein, neurophysin. Neurophysins are peptides composed of 2 proteins, each capable of binding 2 molecules of ADH. The neurophysin-vasopressin combination is stored in the posterior pituitary in the terminal dilatations of secretory neurons that rest against blood vessels. ADH is released from the neuron onto the capillary basement membrane in the posterior pituitary and thus directly into the circulation.
Two types of receptors participate in the release of ADH from the posterior pituitary. Osmoreceptors are a group of specialized cells that perceive changes in the extracellular fluid (ECF) osmolality. A 2% increase in the serum osmolality perfusing the supraoptic nuclei can cause release of ADH, while a 1.2% decrease in the serum osmolality causes a decrease in plasma ADH levels. Secretion of ADH is suppressed at plasma osmolalities below 280 mOsm/kg.
Baroreceptors (which are located in the carotid sinus, aortic arch, and left atrium) participate in the nonosmolar control of ADH release by responding to a change of plasma volume. An 8-10% reduction in plasma volume causes a significant increase in ADH release. In most physiological states, the volume receptors and osmoreceptors act in concert to increase or decrease ADH release. However, the overriding stimulus for secretion of ADH may be the effective intravascular volume, not the state of extracellular osmolality. ADH is also released in response to several drugs and various stressful stimuli such as pain or anxiety.
The primary role of ADH is to promote the reabsorption of water from the tubular fluid along the course of the distal tubule and collecting duct, the hydroosmotic effect. A second action of ADH is to cause arteriolar vasoconstriction and a rise in arterial blood pressure, the pressor effect. ADH has no significant effect on the rate of sodium reabsorption.
Pathophysiology
The fundamental problem in SIADH is a failure to maximally suppress vasopressin secretion. ADH excess results in water retention and volume expansion, leading to weight gain and natriuresis. Serum osmolality falls below the reference range. Hyponatremia does not develop unless the patient is ingesting or receiving some source of free water. The natriuresis, which occurs in SIADH despite hyponatremia and further contributes to hyponatremia, is produced by a decrease in proximal tubular sodium reabsorption secondary to the expansion of the extracellular fluid volume.
Hypervolemia suppresses the renin-angiotensin-aldosterone system during the water retention phase, but later, levels of renin and aldosterone rise again, perhaps in response to hyponatremia. The main mediator of the natriuresis in SIADH is probably the atrial natriuretic peptide (ANP), which may suppress proximal tubular reabsorption of sodium in response to expanded ECF volume. Sodium balance is maintained in SIADH, and the sodium output equals the intake.
Four distinct types of osmoregulatory defects have been defined on the basis of plasma AVP determinations during the infusion of hypertonic sodium chloride solution.
In type A (random), observed in approximately 20% of patients, large and unrelated fluctuations in AVP occur unrelated to the rise in plasma osmolality. This pattern usually occurs in association with tumors.
In type B (reset osmostat), observed in about 35% of patients, a prompt and parallel rise in AVP and in plasma osmolality occurs, but a significant lowering of the threshold for release is noted. This pattern is consistent with an osmoreceptor reset at a lower-than-normal level.
In type C (leak), observed in approximately 35% of patients, AVP is persistently elevated at low and normal plasma osmolality; however, above the threshold for AVP release, plasma AVP increases normally. This pattern is observed with meningitis or head injuries.
In type D (normal), observed in approximately 10% of patients, plasma AVP is appropriately suppressed under hypotonic conditions and does not rise until plasma osmolality reaches the normal threshold level; it does not result in maximal urinary dilution. This pattern is consistent with an increased renal sensitivity to vasopressin and is observed in patients with bronchogenic carcinoma and diabetes mellitus.
Frequency
United States
Although SIADH is not unusual in adults, it is rare in the pediatric population, and other causes of hyponatremia are more common. It is the most common cause of hypotonic normovolemic hyponatremia in children. Exact incidence figures are not available.
Mortality/Morbidity
The presence of hyponatremia, its severity, and delay in initiating adequate treatment appear to be the main indicators for both morbidity and mortality.
- The mortality rate in patients with hyponatremia is 50-fold higher than in patients who do not develop hyponatremia. Moreover, the mortality rate in patients with serum sodium concentrations less than 120 mmol/L is 25%, or twice that, of patients with mild hyponatremia.
- Acute decreases in serum sodium in adults are associated with a cited mortality rate of 5-50%, depending on the severity and rate of development; in children, the mortality rate is only about 8%. Infants probably tolerate cerebral edema with fewer untoward effects because of their expandable cranium.
- Symptomatic postoperative hyponatremia can result in high morbidity and mortality rates in children of both sexes, which is due in large part to inadequate brain adaptation and lack of timely treatment.
Sex
- Controlled studies in adults have shown that women and men are equally likely to develop hyponatremia and hyponatremic encephalopathy after surgery.
- Menstruating women who develop hyponatremic encephalopathy are 25 times more likely to die or have permanent brain damage than either men or postmenopausal women.
Age
The syndrome has been described in newborns, children, adults, and elderly people.
Clinical
History
Overt clinical manifestations of syndrome of inappropriate antidiuretic hormone (SIADH) are largely related to the cellular swelling and cerebral edema associated with hyponatremia. Most patients with SIADH are asymptomatic if the serum osmolality remains above 240 mOsm/kg of water. The clinical manifestations of SIADH are those of water intoxication. Symptoms are more likely to develop in elderly patients and young children with hyponatremia.
- SIADH is most common in children with CNS infections, intrathoracic disease, and in postoperative patients.
- Among premature neonates, the syndrome most often accompanies brain injury and is closely associated with intracranial hemorrhage.
- Signs and symptoms of SIADH, as a rule, are those of hyponatremia and are often vague and nonspecific.
- The clinical manifestations of SIADH are usually related to the degree of the hyponatremia and to the rate at which hyponatremia develops.
- GI tract symptoms occur early in the disease and include the following:
- Anorexia
- Nausea
- Vomiting
- Most of the symptoms are neuropsychiatric in nature and include the following:
- Headaches
- Blurred vision
- Lethargy
- Apathy
- Disorientation
- Agitation
- Irritability
- Muscular symptoms include the following:
- Muscle cramps
- Muscle weakness
- Vasopressin-resistant polyuria with hyponatremia, particularly in the setting of cerebral injury or cerebral disease or when accompanied by dehydration, should prompt consideration of salt wasting in the differential diagnoses. Cerebral salt wasting must be distinguished from SIADH because management of these 2 conditions significantly differs.
Physical
- SIADH is often first recognized upon finding hypotonic hyponatremia in a child without other major symptoms and in the absence of dehydration.
- Edema is clinically undetectable, although patients with SIADH have a modest increase in ECF volume because of water retention but have normal sodium excretion.
- Usually, these patients have volume expansion short of edema and a maximum weight gain of 8%.
- Although the patient appears clinically euvolemic without signs of edema, most adult patients with normovolemic ADH excess have retained 4-5 liters of water.
- Two thirds of total body water resides in the intracellular space (2.7-3.3 L).
- The remaining one third (1.3-1.7 L) is found in the ECF, of which 75% (1-1.3 L) goes into the interstitial space and only 25% (300-400 mL) goes into the intravascular space.
- The absence of a decreased blood volume is one of the criteria for the diagnosis of SIADH because hypovolemia would result in appropriate ADH secretion by stimulating the baroreceptors (volume receptors).
- Skin turgor and blood pressure are usually normal.
- Hypovolemia, hypotension, and overt signs of hypervolemia are absent.
- Deep tendon reflexes are depressed.
- Pathologic reflexes, such as positive Babinski reflexes, may be present.
- Asymmetric pupils may be present.
- Abnormal sensorium may occur.
- Pseudobulbar palsy may occur.
- Cheyne-Stoke respirations may be present.
- Seizures may occur.
Causes
SIADH is most often caused by either inappropriate hypersecretion of ADH from its normal hypothalamic source or, less often, by an ADH-like substance produced by neoplastic tissues. In general, the etiology of SIADH can be classified into 3 categories including nervous system disorders, neoplasia, and pulmonary diseases. Media file 1 lists the various disorders in which SIADH may occur.
- Nervous system disorders
- SIADH in children is most often observed in association with intracranial disease or injury (ie, infection, brain abscesses, encephalitis) and in postoperative patients.
- Laboratory evidence of SIADH has been reported in as many as 90% of patients with meningitis in some older studies. Some studies show that although hyponatremia may frequently be observed in patients with bacterial meningitis, the degree of hyponatremia is most often clinically insignificant and usually responds to minimal fluid restriction.1
- Neoplasms: Malignancies producing excessive ADH secretion are uncommon in children.
- Pulmonary disorders: Intrathoracic disturbances are less common causes in children than in adults.
- Acquired immunodeficiency syndrome (AIDS)
- Hyponatremia has been reported in as many as 40% of adult patients with human immunodeficiency virus (HIV) infection.
- Patients with AIDS can have many potential causes for increased ADH secretion, including volume depletion and infection of the lungs and the CNS.
- Although one third of the hyponatremic patients with AIDS are clinically hypovolemic, the remaining hyponatremic patients fulfill most of the criteria for SIADH.
- Drugs
- Many drugs that impair renal water excretion (see Media file 2), either by stimulating ADH release or by enhancing the peripheral action of ADH, have been associated with a biochemical and clinical syndrome indistinguishable from SIADH.
- The list of drugs associated with SIADH continues to grow as new drugs are described.
- Be aware that many chemotherapeutic drugs cause nausea, which is a powerful stimulus of vasopressin secretion.
- Miscellaneous causes: SIADH has been associated with an array of other disorders, including temporal arteritis, polyarteritis nodosa, sarcoidosis, Rocky Mountain spotted fever, carcinoma of the cervix, olfactory neuroblastoma, and herpes zoster infection of the chest wall.
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Further Reading
Keywords
syndrome of inappropriate antidiuretic hormone secretion, SIADH, euvolemic hyponatremia, arginine vasopressin, vasopressin secretion, osmoregulatory defect, hypervolemia, hypotonic normovolemic hyponatremia, cerebral edema, hyponatremic encephalopathy, brain injury, skin turgor, seizures, neoplasia, brain abscesses, encephalitis, meningitis, temporal arteritis, polyarteritis nodosa, sarcoidosis, Rocky Mountain spotted fever, carcinoma of the cervix, olfactory neuroblastoma, herpes zoster, hypothyroidism, mineralocorticoid deficiency, glucocorticoid deficiency, pituitary insufficiency, hepatic disease
