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Syndrome of Inappropriate Antidiuretic Hormone Secretion

Author: Keenan Bora, MD, Fellow, Medical Toxicology, Detroit Medical Center; Attending Physician, Medical Center Emergency Services, Detroit
Coauthor(s): Meher Chaudhry, MD, Chief Resident, Department of Emergency Medicine, Detroit Receiving Hospital, University Health Center
Contributor Information and Disclosures

Updated: Oct 20, 2009

Introduction

Background

The serum sodium concentration is regulated by the balance of water intake, renal filtration and reabsorption of sodium, and antidiuretic hormone (ADH) – mediated water conservation by the collecting duct. Water balance is normally mediated by thirst, the secretion of antidiuretic hormone (also known as vasopressin), the feedback mechanisms of the renin-angiotensin-aldosterone system, and renal handling of filtered sodium and water. Disorders in any one of these components of sodium balance can result in hyponatremia.¹

ADH is secreted by supraoptic and paraventricular nuclei in the hypothalamus and transmitted via the neuronal axons to the posterior pituitary where it is secreted.² It is released when a decrease in the effective circulatory volume is sensed by vascular baroreceptors primarily located in the large arterial vessels. The key action of ADH in the kidney is to trigger the insertion of aquaporin-2 into the principal cells of the collecting duct. Aquaporins' selective permeability allows water reabsorption and consequently urine concentration.²

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) was initially described by Leaf and Mamby. They demonstrated a direct relationship between excessive vasopressin and fall in serum sodium concentration without any change in urine osmolality or flow rate.³

Pathophysiology

The key to the pathophysiology, signs, symptoms, and treatment of SIADH is to understand that the hyponatremia is a result of excess water and not a serum sodium deficiency. SIADH consists of hyponatremia, inappropriately elevated urine osmolality (>200 mOsm/kg), excessive urine sodium (UNa >30 mEq/L), and decreased serum osmolality. These findings occur in the absence of diuretic therapy; in the presence of euvolemia without edema; in the setting of otherwise normal cardiac, renal, adrenal, hepatic, and thyroid function; and in absence of factors known to stimulate ADH secretion such as severe pain, hypotension, and stress.

In SIADH, the inappropriately elevated level of vasopressin enhances the reabsorption of water, thus concentrating the urine. It is the excess free water absorption that causes hyponatremia.

Two scenarios can occur in which vasopressin secretion will be not be correlated with the serum osmolality. First, a decrease in the effective circulatory volume may be falsely sensed by the large arterial baroreceptors in conditions such as cirrhosis, nephrotic syndrome, and congestive heart failure. In these cases, the stimulus for ADH secretion overrides osmotic signals, which are conveying a hypoosmotic state. ADH secretion ensues despite hypoosmolality resulting in hyponatremia.⁴ In contrast to patients with SIADH, these patients appear hypervolemic.

Second, inappropriate ADH secretion occurs when there is dysregulation of cells secreting vasopressin or in the feedback mechanisms responsible for its release. A variety of ADH-secreting tumors both inside and outside the pituitary have been associated with SIADH, as well as certain CNS disorders, pulmonary disorders, and medications (see Differentials).

A distinction should be made between the SIADH and the clinical syndrome of euvolemic hyponatremia. A mutation of the ADH receptor can make it more responsive to ADH and can result in the same clinical picture of hyponatremia, concentrated urine output, and decreased serum osmolality but with normal ADH secretion.⁵

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%.^6,7 The prevalence of hyponatremia in hospitalized patients has been reported in different studies as being between 2.5 and 16%.^8,6 In a majority of cases, the hyponatremia was found to be hospital acquired. 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%.⁹ Although a number of potential causes of hyponatremia exist, ADH dysregulation is the most common.⁸

Mortality/Morbidity

The fatality rate of patients with hyponatremia (sodium <130 mEq/L) is 60-fold compared to that of patients without documented hyponatremia, though the mortality is typically related to comorbid conditions rather than the hyponatremia itself. Predictors for higher morbidity and mortality rates include being hospitalized, acute onset, and severe hyponatremia.⁸

Previously, mild hyponatremia was considered relatively asymptomatic. However, recent 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 their sodium.¹⁰

Race

No evidence for race predilection was found in studies of SIADH.

Sex

Studies reveal variable evidence between gender and hyponatremia. Studies showing that females are at increased risk for hyponatremia failed to take body mass into account. Men appear to be more likely to get mild or moderate but not severe hyponatremia.¹¹

Age

Increasing age is a strong risk factor for hyponatremia; although, again, this may be confounded by body mass.¹¹ The very old and very young develop symptoms with smaller changes in serum sodium levels than adults.^12,2

Clinical

History

Signs and symptoms of hyponatremia are primarily related to the central nervous system dysfunction and correlate with severity and acuity of the 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 resulting in cerebral edema and increased intracranial pressure. Those with rapidly decreasing sodium levels manifest more pronounced symptoms. Patients with moderate chronic hyponatremia may have decreased reaction times, cognitive slowing, and ataxia resulting in frequent falls.¹⁰ When sodium concentration drops below 105 mEq/L, life-threatening complications are likely to occur.¹³

Helpful historical details in identifying the responsible mechanism for hyponatremia include diet, fluid intake, gastrointestinal losses, amount of urinary output, medications, and weight loss. 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 (see Causes).

Physical

On physical examination, evaluation of volume status is important. SIADH is characterized by euvolemic hyponatremia. Edema in a hyponatremic patient is inconsistent with SIADH and may represent another hyponatremic states such as CHF, cirrhosis, or nephrotic syndrome. 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, ataxia, nystagmus, tremor, dysarthria, dysphagia, and coma.

Causes

Causes of syndrome of inappropriate antidiuretic hormone secretion (SIADH) vary widely. The syndrome was first described in patients with bronchogenic carcinoma. SIADH may be a marker for occult malignancy such as head and neck cancers. SIADH may also be manifested in cases of hypothyroidism and is corrected when thyroid hormone is replaced.

Many therapeutic agents can induce SIADH. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin E₂, which modulates vasopressin action and can result in decreased water excretion.⁵ SIADH has been reported as an adverse effect of multiple psychotropic medications.^14,15 While the exact mechanism of action is unknown, it has been proposed that serotonin and serotonergic medications cause increased ADH secretion via the 5-HT_1C and 5-HT₂ receptors.¹⁵

SIADH should be differentiated from hospital-acquired hyponatremia often seen secondary to overzealous administration of hypotonic IV fluids.⁶

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, bromocriptine, haloperidol, thiothixene, exogenous oxytocin, MAOIs
• Surgery - Postoperative
• Idiopathic

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