Syndrome of inappropriate antidiuretic hormone

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Synonyms and Keywords: SIADH

Overview
The syndrome of inappropriate antidiuretic hormone (SIADH) is a condition commonly found in the hospital population, especially in patients being hospitalized for central nervous system (CNS) injury. This is a syndrome characterized by excessive release of antidiuretic hormone (ADH or vasopressin) from the posterior pituitary gland or another source. The result is hyponatremia, and sometimes fluid overload.

Historical Perspective
The condition was first described by researchers from Boston, Massachusetts and Bethesda, Maryland (including Dr Frederic Bartter) in two patients with lung cancer. Criteria were developed by Schwartz and Bartter in 1967, and have remained essentially unchanged since then. The condition is occasionally referred to by the names of the authors of the first report - Schwatz-Bartter syndrome.

Pathophysiology
The normal function of ADH on the kidneys is to control the amount of water reabsorbed by kidney nephrons. ADH acts in the distal portion of the renal tubule (Distal Convoluted Tubule) as well as on the collecting duct and causes the retention of water, but not solute. Hence, ADH activity effectively dilutes the blood (decreasing the concentrations of solutes such as sodium).

Developmentally, mammalian organisms have evolved in times of water scarcity and ADH is secreted to prevent water loss in the kidneys. When water is ingested, it is taken up into the circulation and results in a dilution of the plasma. This dilution, otherwise described as a reduction in plasma osmolality is detected by osmoreceptors in the hypothalamus of the brain and these then switch off the release of ADH. The decreasing concentration of ADH effectively inhibits the aquaporins in the collecting ducts and distal convoluted tubules in the nephrons of the kidney. Hence, less water is reabsorbed, thereby increasing urine output, decreasing urine osmolality, and increasing (normalization of) blood osmolality.

In SIADH the release of ADH is not inhibited by a reduction in plasma osmolality when the individual ingests water and the osmolality of the plasma drops. As the main solute of plasma is sodium, this hypoosmolar state is usually detected as a low sodium level on laboratory testing. SIADH is therefore primarily a condition that results in the abnormal handling of water loading and not a problem with excessive solute loss. This is why it is usually treated with fluid (in particular water) restriction. Diuretics may also be given to decrease reabsorption of water, but care must be taken not to correct water imbalances too rapidly.

This dilutional hyponatremia and all the consequences associated with that condition: headache, nausea, vomiting, and confusion may ensue. Severe hyponatremia may cause convulsions or coma.

Complete Differential Diagnosis of Causes of SIADH
(By organ system)

Complete Differential Diagnosis of Causes of SIADH
(In alphabetical order)
 * Agenesis corpus collosum
 * AIDS
 * Amyotropic lateral sclerosis
 * Asthma
 * Bacterial pneumonia
 * Brain abscess
 * Bronchial adenoma
 * Carbamazepine
 * Carcinoid
 * Cavernous sinus thrombosis
 * Chlorpropamide
 * Cyclophosphamide
 * Delirium tremens
 * Desmopressin
 * Duodenal carcinoma
 * Encephalitis
 * Ewing's sarcoma
 * Hydrocephalus
 * Lung abscess
 * Lung carcinoma
 * Lung cavitation
 * Meningitis
 * Mesothelioma
 * Midline defects
 * Mono Amine Oxidase Inhibitors
 * Multiple sclerosis
 * Nicotine
 * Ovarian cancer
 * Oxytocine
 * Pancreatic cancer
 * Peripheral neuropathy
 * Phenothiazines
 * Pneumothorax
 * Polyradiculitis
 * Positive pressure restoration
 * Psychosis
 * SSRI
 * Stroke
 * Thymoma
 * Tricyclic antidepressants
 * Tuberculosis
 * Vasopressin
 * Vinblastine
 * Vincristine

Causes
Some common causes of SIADH include:
 * Head injury
 * Subarachnoid hemorrhage
 * Cancers
 * Lung cancer (especially small cell lung cancer, as well as other small-cell malignancies of other organs)
 * Infections
 * Brain abscess
 * Pneumonia
 * Lung abscess
 * Drugs
 * Chlorpropamide
 * Cyclophosphamide
 * Carbamazepine
 * Selective serotonin reuptake inhibitors (SSRIs, a class of antidepressants)
 * Methylenedioxymethamphetamine (MDMA, commonly called Ecstasy. SIADH due to taking ecstasy was cited as a factor in the death of Leah Betts)

Treatment
Treatment of SIADH includes:
 * Fluid restriction
 * Intravenous saline
 * Drugs
 * Demeclocycline
 * Conivaptan - an approved antagonist of both V1A and V2 vasopressin receptors. Its indications are "treatment of euvolemic hyponatremia (e.g. the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.) in hospitalized patients."
 * Tolvaptan - an unapproved oral antagonist of the V2 vasopressin receptor. A randomized controlled trial showed conivaptan that can raise the serum sodium by 5 mmol/L.

Care must be taken when correcting hyponatremia. A rapid rise in the sodium level may cause central pontine myelinolysis.

Differential diagnosis
Cerebral salt wasting syndrome also presents with hyponatremia, but is treated differently.