SIADH
   HOME

TheInfoList



OR:

Syndrome of inappropriate antidiuretic hormone secretion (SIADH), also known as the syndrome of inappropriate antidiuresis (SIAD), is characterized by a physiologically inappropriate release of
antidiuretic hormone Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...
(ADH) either from the
posterior pituitary The posterior pituitary (or neurohypophysis) is the posterior lobe of the pituitary gland which is part of the endocrine system. Unlike the anterior pituitary, the posterior pituitary is not glandular, but largely a collection of axonal projec ...
gland, or an ectopic non-pituitary source, such as an ADH-secreting tumor in the lung. Unsuppressed ADH causes a physiologically inappropriate increase in solute-free water being reabsorbed by the tubules of the
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
to the
venous Veins () are blood vessels in the circulatory system of humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are those of the pulmonary and fetal c ...
circulation leading to hypotonic hyponatremia (a low plasma osmolality and low sodium levels). The causes of SIADH are commonly grouped into categories including:
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
diseases that directly stimulate the
hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
to release ADH, various cancers that synthesize and secrete ectopic ADH, various lung diseases, numerous drugs (
carbamazepine Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...
,
cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
, SSRIs) that may stimulate the release of ADH, vasopressin release, desmopressin release, oxytocin, or stimulation of vasopressin receptor 2 on the kidney (the site of ADH action). Inappropriate antidiuresis may also be due to acute stressors such as exercise, pain, severe nausea or during the post-operative state. In 17–60% of people, the cause of inappropriate antidiuresis is never found. ADH is derived from a preprohormone precursor that is synthesized in cells in the hypothalamus and stored in vesicles in the posterior pituitary. ''Appropriate'' ADH secretion is regulated by osmoreceptors on the hypothalamic cells that synthesize and store ADH. In appropriate ADH secretion, plasma hypertonicity activates these osmoreceptors, ADH is released into the blood stream, the kidneys increase solute-free water reabsorption, and the hypertonicity is alleviated. A decrease in the effective circulating volume of blood (the volume of arterial blood effectively perfusing tissues) also stimulates an appropriate, physiologic release of ADH. ''Inappropriate'' ADH secretion causes physiologically high water reabsorption by the kidneys, causing elevated fluid retention. This causes the
extracellular fluid In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 50–60% (range 45 to 75%) of total body weight; women and the obese typically ha ...
(ECF) space to become hypoosmolar and hyponatremic (low
sodium Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
). In the
intracellular space Intracellular space is the interior space of the plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and prote ...
, cells swell as intracellular volume increases as water moves from an area of low solute concentration (extracellular space) to an area of high solute concentration (the cells' interior). In severe or acute hypoosmolar hyponatremia, swelling of
brain cell Brain cells make up the functional tissue of the brain. The rest of the brain tissue is the structural stroma that includes connective tissue such as the meninges, blood vessels, and ducts. The two main types of cells in the brain are neurons, ...
s causes various
neurological Neurology (from , "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the nervous system, which comprises the brain, the s ...
abnormalities, which in severe or acute cases can result in
convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is often used as a synony ...
,
coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...
, and
death Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...
. The symptoms of chronic syndrome of inappropriate antidiuresis are more vague, and may include cognitive impairment, gait abnormalities, or
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
. The main treatment of inappropriate antidiuresis is to identify and treat the underlying cause, if possible. This usually causes plasma osmolality and sodium levels to return to normal in several days. In those in which an underlying cause cannot be found, or is untreatable, treatments are targeted to alleviating correcting the hypoosmolality and hyponatremia. These include restriction of fluid intake, using salt tablets (sometimes with
diuretics A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...
), urea supplements, intravenous saline, or increasing protein intake. The vasopressin receptor 2 antagonists, tolvaptan or
conivaptan Conivaptan, sold under the brand name Vaprisol, is a non-peptide inhibitor of the receptor for anti-diuretic hormone, also called vasopressin. It was approved in 2004 for hyponatremia (low blood sodium levels). Additionally, Conivaptan is used ...
, may also be used. The presence of
cerebral edema Cerebral edema is excess accumulation of fluid ( edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compres ...
, or other moderate to severe symptoms, may necessitate intravenous hypertonic saline administration with close monitoring of the serum sodium levels to avoid overcorrection. SIADH was originally described in 1957 in two people with
small-cell carcinoma Small-cell carcinoma, also known as oat cell carcinoma, is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tr ...
of the lung. reproduced as a Milestone in Nephrology with author commentary in


Signs and symptoms


Gastro-intestinal

*
Anorexia Anorexia nervosa (AN), often referred to simply as anorexia, is an eating disorder characterized by Calorie restriction, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. Individuals wit ...
(loss of appetite) *
Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...


Musculoskeletal

* Muscle aches * Generalized muscle weakness


Neuro-muscular

* Myoclonus * Decreased reflexes *
Ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
* Pathological
reflexes In biology, a reflex, or reflex action, is an involuntary, unplanned sequence or action and nearly instantaneous response to a Stimulus (physiology), stimulus. Reflexes are found with varying levels of complexity in organisms with a nervous s ...
*
Tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...
*
Asterixis Asterixis (more colloquially referred to as flapping tremor) is not actually a tremor, but rather a negative myoclonus. This movement disorder is characterized by an inability to maintain a position, which is demonstrated by jerking movements of t ...


Respiratory

* Cheyne-Stokes respiration


Neurological

*
Dysarthria Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. It is a condition in which problems effectively occur with the ...
*
Lethargy Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness, or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overw ...
*
Confusion In psychology, confusion is the quality or emotional state of being bewildered or unclear. The term "acute mental confusion"
*
Delirium Delirium (formerly acute confusional state, an ambiguous term that is now discouraged) is a specific state of acute confusion attributable to the direct physiological consequence of a medical condition, effects of a psychoactive substance, or ...
*
Seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
*
Coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...
(from brain swelling) *
Death Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...


Causes

Causes of SIADH include conditions that dysregulate ADH secretion in the central nervous system, tumors that secrete ADH, drugs that increase ADH secretion, among other causes. Cancer accounts for an estimated 24% of cases of SIADH, with 25% of those causes due to small cell lung cancer. Medications or drugs are responsible for 18% of cases of SIADH. This is due to a variety of mechanisms including: stimulation of ADH release (
opiates An opiate is an alkaloid substance derived from opium (or poppy straw). It differs from the similar term ''opioid'' in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain ( ...
, ifosfamide,
vincristine Vincristine, also known as leurocristine and sold under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin lym ...
,
platinum-based antineoplastic Platinum-based antineoplastic drugs (informally called platins) are chemotherapeutic agents used to treat cancer. Their active moieties are coordination complexes of platinum. These drugs are used to treat almost half of people receiving chemoth ...
s and
MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...
(also known as ecstasy)); enhancers of ADH effect ( non-steroidal anti-inflammatories); ADH analogues (
desmopressin Desmopressin, sold under the trade name DDAVP among others, is a medication used to treat diabetes insipidus, bedwetting, hemophilia A, von Willebrand disease, and high blood urea levels. In hemophilia A and von Willebrand disease, it should ...
,
oxytocin Oxytocin is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. Present in animals since early stages of evolution, in humans it plays roles in behavior that include Human bonding, ...
); and vasopressin receptor 2 activators (
selective serotonin reuptake inhibitors Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...
(SSRIs),
haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychos ...
,
carbamazepine Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...
,
cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
, and
chlorpropamide Chlorpropamide is an antidiabetic drug, belonging to the sulfonylurea class of organic compounds. It is used to treat diabetes mellitus type 2. It is a long-acting first-generation sulfonylurea. Mechanism of action Like other sulfonylureas, ch ...
). Of the causes of medication induced syndrome of inappropriate antidiuresis, antidepressants (especially SSRIs) are the most common culprit. Central nervous system (CNS) disorders or conditions may cause SIADH in 9% of cases, this includes
subarachnoid hemorrhage Subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space—the area between the arachnoid (brain), arachnoid membrane and the pia mater surrounding the human brain, brain. Symptoms may include a thunderclap headache, severe heada ...
(56% of CNS causes), pituitary surgery (35% of CNS causes), brain cancer, infections, stroke and head trauma. No cause of inappropriate antidiuresis is initially found in 17–60% of cases. A list of common causes is below:


Pathophysiology

Normally there are homeostatic processes in the body which maintain the concentration of body
solutes In chemistry, a solution is defined by IUPAC as "A liquid or solid phase containing more than one substance, when for convenience one (or more) substance, which is called the solvent, is treated differently from the other substances, which are ...
within a narrow range, both inside and outside cells. The process occurs as follows: in some hypothalamic cells there are osmoreceptors which respond to hyperosmolality in body fluids by signalling the posterior pituitary gland to secrete ADH. This keeps serum
sodium Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
concentration – a proxy for solute concentration – at normal levels, prevents
hypernatremia Hypernatremia, also spelled hypernatraemia, is a high concentration of sodium in the blood. Early symptoms may include a strong feeling of thirst, weakness, nausea, and loss of appetite. Severe symptoms include confusion, muscle twitching, and ...
and turns off the osmoreceptors. Specifically, when the serum sodium rises above 142 mEq/L, ADH secretion is maximal (and thirst is stimulated as well); when it is below 135 mEq/L, there is no secretion. ADH activates V2 receptors on the basolateral membrane of principal cells in the renal collecting duct, initiating a cyclic AMP-dependent process that culminates in increased production of water channels (aquaporin 2), and their insertion into the cells' luminal membranes. ''Excessive'' ADH causes an ''inappropriate'' increase in the reabsorption in the kidneys of solute-free water ("free water"): excess water moves from the
distal convoluted tubule The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule. Physiology It is partly responsible for the regulation of potassium, sodium, calcium, and pH. On its apical surface (lum ...
s (DCTs) and collecting tubules of the
nephron The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structu ...
s – via activation of
aquaporins Aquaporins, also called water channels, are channel proteins from a larger protein family, family of major intrinsic proteins that form Ion channel pore, pores in the cell membrane, membrane of cell (biology), biological cells, mainly facilitati ...
, the site of the ADH receptors – back into the circulation. This has two consequences. First, in the
extracellular fluid In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 50–60% (range 45 to 75%) of total body weight; women and the obese typically ha ...
(ECF) space, there is a dilution of blood solutes, causing hypo
osmolality In chemistry, molality is a measure of the amount of solute in a solution relative to a given mass of solvent. This contrasts with the definition of ''molarity'' which is based on a given volume of solution. A commonly used unit for molality is ...
, including a low sodium concentration – hyponatremia. here is no expansion of the ECF volume because as it attempts to expand, aldosterone is suppressed and atrial natriuretic peptide (ANP) is stimulated: both of these hormones cause isotonic ECF fluid to be excreted by the kidneys sufficient to keep ECF volume at a normal level.] Also, virtually simultaneously to these ECF events, the
intracellular space Intracellular space is the interior space of the plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and prote ...
(ICF) volume expands. This is because the osmolality of the ECF is (transiently) less than that of the ICF; and since water is readily permeable to cell membranes, solute-free water moves from the ECF to the ICF compartment by
osmosis Osmosis (, ) is the spontaneous net movement or diffusion of solvent molecules through a selectively permeable membrane, selectively-permeable membrane from a region of high water potential (region of lower solute concentration) to a region of ...
: ''all'' cells swell. Swelling of
brain cell Brain cells make up the functional tissue of the brain. The rest of the brain tissue is the structural stroma that includes connective tissue such as the meninges, blood vessels, and ducts. The two main types of cells in the brain are neurons, ...
s –
cerebral edema Cerebral edema is excess accumulation of fluid ( edema) in the intracellular or extracellular spaces of the brain. This typically causes impaired nerve function, increased pressure within the skull, and can eventually lead to direct compres ...
– causes various
neurological Neurology (from , "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the nervous system, which comprises the brain, the s ...
abnormalities which in acute and/or severe cases can result in
convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is often used as a synony ...
,
coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...
, and
death Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...
. The normal function of ADH on the
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
s 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 The collecting duct system of the kidney consists of a series of tubules and ducts that physically connect nephrons to a minor calyx or directly to the renal pelvis. The collecting duct participates in electrolyte and fluid balance through rea ...
and causes the retention of water, but ''not'' solute. Hence, ADH activity effectively dilutes the blood (decreasing the concentrations of solutes such as sodium), causing
hyponatremia Hyponatremia or hyponatraemia is a low concentration of sodium in the Serum (blood), blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symp ...
; this is compounded by the fact that the body responds to water retention by decreasing
aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...
, thus allowing even more sodium wasting. For this reason, a high urinary sodium excretion will be seen. The abnormalities underlying type D syndrome of inappropriate antidiuretic hormone hypersecretion concern individuals where vasopressin release and response are normal but where abnormal renal expression and translocation of
aquaporin 2 Aquaporin-2 (AQP-2) is found in the apical cell membranes of the kidney's collecting duct principal cells and in intracellular vesicles located throughout the cell. It is encoded by the gene. Regulation It is the only aquaporin regulated b ...
, or both are found. It has been suggested that this is due to abnormalities in the secretion of
secretin Secretin is a hormone that regulates water homeostasis throughout the body and influences the environment of the duodenum by regulating secretions in the stomach, pancreas, and liver. It is a peptide hormone produced in the S cells of the duodenum ...
in the brain and that "Secretin as a neurosecretory hormone from the posterior pituitary, therefore, could be the long-sought vasopressin independent mechanism to solve the riddle that has puzzled clinicians and physiologists for decades." There are no abnormalities in total body sodium metabolism. Hyponatremia and inappropriately concentrated urine (UOsm >100 mOsm/L) are seen.


Diagnosis

Diagnosis is based on clinical and laboratory findings of low serum osmolality and low serum sodium. Urinalysis reveals a highly concentrated urine with a high fractional excretion of sodium (high sodium urine content compared to the serum sodium). A suspected diagnosis is based on a serum sodium under 138. A confirmed diagnosis has seven elements: 1) a decreased effective serum osmolality – <275 mOsm/kg of water; 2) urinary sodium concentration high – over 40 mEq/L with adequate dietary salt intake; 3) no recent diuretic usage; 4) no signs of ECF volume depletion or excess; 5) no signs of decreased arterial blood volume – cirrhosis, nephrosis, or congestive heart failure; 6) normal adrenal and thyroid function; and 7) no evidence of hyperglycemia (diabetes mellitus), hypertriglyceridemia, or hyperproteinia (myeloma). There are nine supplemental features: 1) a low BUN; 2) a low uric acid; 3) a normal creatinine; 4) failure to correct hyponatremia with IV normal saline; 5) successful correction of hyponatremia with fluid restriction; 6) a fractional sodium excretion >1%; 7) a fractional urea excretion >55%; 8) an abnormal water load test; and 9) an elevated plasma AVP.


Differential diagnosis

Antidiuretic hormone Mammalian vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the ''AVP'' gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It ...
(ADH) is released from the posterior pituitary for a number of physiologic reasons. The majority of people with hyponatremia, other than those with excessive water intake (
polydipsia Polydipsia is excessive thirst or excess drinking.Porth, C. M. (1990). ''Pathophysiology: Concepts of altered health states''. Philadelphia: J.B. Lippincott Company. The word derives , which is derived . Polydipsia is a nonspecific symptom in v ...
) or renal salt wasting, will have elevated ADH as the cause of their hyponatremia. However, not every person with hyponatremia and elevated ADH has SIADH. One approach to a diagnosis is to divide ADH release into appropriate (not SIADH) or inappropriate (SIADH). Appropriate ADH release can be a result of hypovolemia, a so-called non-osmotic trigger of ADH release. This may be true hypovolemia, as a result of dehydration with fluid losses replaced by free water. It can also be perceived hypovolemia, as in the conditions of
congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF typically pr ...
(CHF) and
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...
in which the kidneys perceive a lack of intravascular volume. The hyponatremia caused by appropriate ADH release (from the kidneys' perspective) in both CHF and cirrhosis have been shown to be an independent poor prognostic indicator of mortality. Appropriate ADH release can also be a result of non-osmotic triggers. Symptoms such as nausea/vomiting and pain are significant causes of ADH release. The combination of osmotic and non-osmotic triggers of ADH release can adequately explain the hyponatremia in the majority of people who are hospitalized with acute illness and are found to have mild to moderate hyponatremia. SIADH is less common than appropriate release of ADH. While it should be considered in a differential, other causes should be considered as well. Cerebral salt wasting syndrome (CSWS) also presents with hyponatremia, there are signs of dehydration for which reason the management is diametrically opposed to SIADH. Importantly CSWS can be associated with subarachnoid hemorrhage (SAH) which may require fluid supplementation rather than restriction to prevent brain damage. Most cases of hyponatremia in children are caused by appropriate secretion of antidiuretic hormone rather than SIADH or another cause.


Treatment

Managing SIADH depends on whether symptoms are present, the severity of the hyponatremia, and the duration. Management of SIADH includes: * Treating the underlying cause when possible. * Mild and asymptomatic hyponatremia is treated with adequate solute intake (including salt and protein) and fluid restriction with fluids (from all sources) restricted to 1–1.5 liters of fluid per day. Long-term fluid restriction may maintain the person in a symptom-free state as well as correcting the hyponatremia, but efficacy is limited by difficulties in patient adherence. * Moderate or severe hyponatremia, or hyponatremia with severe symptoms is treated by raising the serum sodium level by 1–2 mmol per liter per hour for the first few hours with a goal of raising levels less than 8–10 mmol per liter in the first 24 hours and 18 mmol per liter in the first 48 hours. Raising the serum sodium concentration too rapidly may cause central pontine myelinolysis (also known as osmotic demyelination). Sodium correction should be no greater than 10 mEq/L/day, with a correction no greater than 8 mEq/L/day in those at high risk of osmotic demyelination. If overcorrection does occur, a 5% dextrose in water infusion may be given to temporarily lower sodium levels. total of 8 mmol per liter during the first day with the use of furosemide and replacing sodium and potassium losses with 0.9% saline. * For people with severe symptoms (severe confusion, convulsions, or coma) hypertonic saline (3%) 1–2 ml/kg IV in 3–4 h may be given.


Medications

** Demeclocycline can be used in chronic situations when fluid restrictions are difficult to maintain; demeclocycline is the most potent inhibitor of Vasopressin (ADH/AVP) action. However, demeclocycline has a 2–3 day delay in onset with extensive side effect profile, including skin photosensitivity, and nephrotoxicity. ** Urea: oral daily ingestion has shown favorable long-term results with protective effects in myelinosis and brain damage. Limitations noted to be undesirable taste and is contraindicated in people with cirrhosis to avoid initiation or potentiation of
hepatic encephalopathy Hepatic encephalopathy (HE) is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stag ...
. **
Conivaptan Conivaptan, sold under the brand name Vaprisol, is a non-peptide inhibitor of the receptor for anti-diuretic hormone, also called vasopressin. It was approved in 2004 for hyponatremia (low blood sodium levels). Additionally, Conivaptan is used ...
– an antagonist of both V1A and V2 vasopressin receptors. ** Tolvaptan – an antagonist of the vasopressin receptor 2.


Epidemiology

40% of all hospitalized adults aged 65 and older have hyponatremia, with an estimated 25–40% of those cases being due to inappropriate antidiuresis. The incidence of SIADH rises with increasing age with residents of nursing homes being at highest risk.


History

Through medullary lesioning in animals, Jungmann and Meyer from Germany induced polyuria and increased urinary salt excretion in 1913. Water intake restriction did not stop the polyuria, and salt continued to be excreted in the urine despite. In 1936, McCance defined the consequences of salt depletion in normal human. Patients with extra-renal salt losses complicated by hyponatremia were found to be common-place, and consistent with McCance's description, they excreted urine virtually free of sodium. In 1950, Sims et al, published their work that suggest observed relation between hyponatremia and pulmonary tuberculosis. Their work suggested that a primary reduction in cellular osmolarity may be the initiating factor in the development of this new syndrome (later called SIADH). The increased excretion of sodium at subnormal concentrations of this ion in the serum might represent an attempt to reduce extracellular tonicity to conform with a reduced cellular osmolarity. An eosinopenia response to epinephrine and the ability to reduce the excretion of sodium on a regime free of salt aids in differentiating this syndrome from
Addison's disease Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adr ...
. Almost a century after the pioneering work of
Claude Bernard Claude Bernard (; 12 July 1813 – 10 February 1878) was a French physiologist. I. Bernard Cohen of Harvard University called Bernard "one of the greatest of all men of science". He originated the term ''milieu intérieur'' and the associated c ...
(1813–1878) in animals, Peters et al, in 1950, reported three patients seen at Yale New Haven Hospital with hyponatremia associated with varying cerebral pathologies and severe dehydration. In each patient, urine sodium losses persisted despite hyponatremia and a high-salt diet. All three patients were unable to prevent urinary sodium loss despite low serum sodium levels and no evidence of extrarenal sodium loss. Their hyponatremia responded to salt therapy. They postulated that this provided evidence of an extra-pituitary cerebral structure mediating normal sodium metabolism but were unsure of its location or mechanism of action. A subsequent paper from the group at Yale attributed hyponatremia in neurologic disease to SIADH. In 1952, Welt et al, described another six patients with cerebral lesions exhibiting severe clinical dehydration, hyponatremia, a negative sodium balance, but no potassium retention. All responded to sodium chloride administration but administering aldosterone precursor 11-deoxycorticosterone did not reverse renal sodium loss. The authors felt neither pituitary nor adrenal insufficiency was involved, but that direct neural control of renal proximal tubular reabsorption of sodium was disrupted. In 1953, Leaf et al, demonstrated that exogenous administration of the antidiuretic hormone vasopressin resulted in hyponatremia and a natriuresis dependent on water retention and weight gain. This was not "salt wasting"; it was a physiologic response to an expanded intravascular volume. Vasopressin-ADH administration to normal humans was shown to result in water retention and urinary loss of electrolytes (primarily sodium) in other studies at the time. William Schwartz (1922–2009) attended Duke University after serving in the US Army in World War II. He observed that
sulfanilamide Sulfanilamide (also spelled sulphanilamide) is a sulfonamide antibacterial drug. Chemically, it is an organic compound consisting of an aniline derivatized with a sulfonamide group. Powdered sulfanilamide was used by the Allies in World War ...
increased excretion of sodium in patients with heart failure. This observation was the basis for the discovery and development of modern diuretic drugs. Frederic Bartter (1914–1983) worked on hormones affecting the kidney that led to the discovery of syndrome of inappropriate antidiuretic hormone (SIADH) in 1957 and Bartter syndrome in 1963. Schwartz-Bartter syndrome is named after these two scientists. The first reports of hyponatremia and renal sodium loss corrected by fluid restriction in patients with bronchogenic carcinoma were published by Bartter. At that time, no direct measurement of vasopressin was done. In summary, the condition was first described at separate institutions by William Schwartz and Frederic Bartter in two people with
lung cancer Lung cancer, also known as lung carcinoma, is a malignant tumor that begins in the lung. Lung cancer is caused by genetic damage to the DNA of cells in the airways, often caused by cigarette smoking or inhaling damaging chemicals. Damaged ...
. Criteria were developed by Schwartz and Bartter in 1967 and have remained unchanged since then.


Society and culture

The condition is occasionally referred to by the names of the authors of the first report: ''Schwartz-Bartter syndrome''. Because not all people with this syndrome have elevated levels of vasopressin, the term "syndrome of inappropriate antidiuresis" (SIAD) has been proposed as a more accurate description of this condition.


References


External links

{{DEFAULTSORT:Syndrome Of Inappropriate Antidiuretic Hormone Hypersecretion Pituitary disorders Syndromes Oncological emergencies Articles containing video clips