Syndrome of inappropriate antidiuretic hormone secretion

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Syndrome of inappropriate antidiuretic hormone secretion
Other namesSchwartz-Bartter syndrome, syndrome of inappropriate antidiuresis (SIAD)
Specialty Endocrinology
Symptoms Lack of appetite, nausea, vomiting, abdominal pain, seizures and coma [1]

The syndrome of inappropriate antidiuretic hormone secretion (SIADH), also known as the syndrome of inappropriate antidiuresis (SIAD), [2] is characterized by a physiologically inappropriate release of antidiuretic hormone (ADH) either from the posterior pituitary gland, or an abnormal non-pituitary source. [1] Unsuppressed ADH causes a physiologically inappropriate increase in solute-free water being reabsorbed by the tubules of the kidney to the venous circulation leading to hypotonic hyponatremia (a low plasma osmolality and low sodium levels). [2]

Contents

The causes of SIADH are commonly grouped into categories including: central nervous system diseases that directly stimulate the hypothalamus to release ADH, various cancers that synthesize and secrete ectopic ADH, various lung diseases, numerous drugs that may stimulate the release of ADH, enhance ADH effects, act as ADH analogues in the body, or stimulate the vasopressin receptor 2 at the kidney (the site of ADH action); or inherited mutations leading to a gain of function of the vasopressin-2 receptor (a very rare occurrence). [2] 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. [2]

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: plasma hypertonicity activates these receptors, ADH is released into the blood stream, the kidney increases solute-free water reabsorption and return to the circulation, and the hypertonicity is alleviated. [2] 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. [2] Inappropriate (increased) ADH secretion causes a physiologically inappropriate water reabsorption by the kidneys. This causes the extracellular fluid (ECF) space to become hypo-osmolar, including a low sodium concentration (hyponatremia). [2] In the intracellular space, 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 cells causes various neurological abnormalities, which in severe or acute cases can result in convulsions, coma, and death. The symptoms of chronic syndrome of inappropriate antidiuresis are more vague, and may include cognitive impairment, gait abnormalities, or osteoporosis. [2]

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. [2] In those in which an underlying cause cannot be found, or is untreatable, treatments are targeted to alleviating correcting the hypoosmolality and hyponatremia. [2] These include restriction of fluid intake, using salt tablets (sometimes with diuretics), urea supplements, or increasing the protein intake. [2] The vasopressin receptor 2 blocker tolvaptan may also be used. [2] The presence of cerebral edema, or other moderate to severe symptoms, may necessitate intravenous hypertonic saline administration with close monitoring of the serum sodium levels to avoid overcorrection. [2]

SIADH was originally described in 1957 in two people with small-cell carcinoma of the lung. [3]

Signs and symptoms

Gastro-intestinal

Musculoskeletal

Neuro-muscular

Respiratory

Neurological

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. [2] 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, ifosfamide, vincristine, platinum-based antineoplastics and MDMA (also known as ecstasy); enhancers of ADH effect (Non-steroidal anti-inflammatories); ADH analogues (desmopressin, oxytocin); and vasopressin receptor 2 activators (selective serotonin reuptake inhibitors (SSRIs), haloperidol, carbamazepine, cyclophosphamide, and chlorpropamide). [2] Of the causes of medication induced syndrome of inappropriate antidiuresis, antidepressants (especially SSRIs) are the most common culprit. [2] Central nervous system (CNS) disorders or conditions may cause SIADH in 9% of cases, this includes subarachnoid hemorrhage (56% of CNS causes), pituitary surgery (35% of CNS causes), brain cancer, infections, stroke and head trauma. [2] No cause of inappropriate antidiuresis is initially found in 17-60% of cases. [2]

A list of common causes is below: [5]

Pathophysiology

Normally there are homeostatic processes in the body which maintain the concentration of body solutes 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. [6] This keeps serum sodium concentration - a proxy for solute concentration - at normal levels, prevents hypernatremia and turns off the osmoreceptors. [7] 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. [8] 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. [9]

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 tubules (DCTs) and collecting tubules of the nephrons - via activation of aquaporins, the site of the ADH receptors - back into the circulation. This has two consequences. First, in the extracellular fluid (ECF) space, there is a dilution of blood solutes, causing hypoosmolality, including a low sodium concentration - hyponatremia. [There 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 (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: all cells swell. Swelling of brain cells - cerebral edema - causes various neurological abnormalities which in acute and/or severe cases can result in convulsions, coma, and death.[ citation needed ]

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), causing hyponatremia; this is compounded by the fact that the body responds to water retention by decreasing aldosterone, 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, or both are found. [10]

It has been suggested that this is due to abnormalities in the secretion of secretin 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." [10] There are no abnormalities in total body sodium metabolism. [11] Hyponatremia and inappropriately concentrated urine (UOsm >100 mOsm/L) are seen [12]

Diagnosis

Diagnosis is based on clinical and laboratory findings of low serum osmolality and low serum sodium. [13]

Urinalysis reveals a highly concentrated urine with a high fractional excretion of sodium (high sodium urine content compared to the serum sodium). [14] 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). [1]

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. [5]

Differential diagnosis

Antidiuretic hormone (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) 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 (CHF) and cirrhosis 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. [15]

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. [16]

Most cases of hyponatremia in children are caused by appropriate secretion of antidiuretic hormone rather than SIADH or another cause. [17]

Treatment

Managing SIADH depends on whether symptoms are present, the severity of the hyponatremia, and the duration. Management of SIADH includes: [5]

Medications

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. [2] The incidence of SIADH rises with increasing age with residents of nursing homes being at highest risk. [20]

History

The condition was first described at separate institutions by William Schwartz and Frederic Bartter in two people with lung cancer. [21] [3] Criteria were developed by Schwartz and Bartter in 1967 and have remained unchanged since then. [21] [22]

Society and culture

The condition is occasionally referred to by the names of the authors of the first report: Schwartz-Bartter syndrome. [23] 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. [24]

Related Research Articles

<span class="mw-page-title-main">Diabetes insipidus</span> Condition characterized by large amounts of dilute urine and increased thirst

Diabetes insipidus (DI), alternately called arginine vasopressin deficiency (AVP-D) or arginine vasopressin resistance (AVP-R), is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. Complications may include dehydration or seizures.

Hyponatremia or hyponatraemia is a low concentration of sodium in the 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. Symptoms can be absent, mild or severe. Mild symptoms include a decreased ability to think, headaches, nausea, and poor balance. Severe symptoms include confusion, seizures, and coma; death can ensue.

<span class="mw-page-title-main">Vasopressin</span> Mammalian hormone released from the pituitary gland

Human 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 then travels down the axon terminating in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular fluid hypertonicity (hyperosmolality). AVP has two primary functions. First, it increases the amount of solute-free water reabsorbed back into the circulation from the filtrate in the kidney tubules of the nephrons. Second, AVP constricts arterioles, which increases peripheral vascular resistance and raises arterial blood pressure.

<span class="mw-page-title-main">Renal physiology</span> Study of the physiology of the kidney

Renal physiology is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, and other electrolytes; clearance of toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.

<span class="mw-page-title-main">Supraoptic nucleus</span> ADH secreting nucleus of the hypothalamus.

The supraoptic nucleus (SON) is a nucleus of magnocellular neurosecretory cells in the hypothalamus of the mammalian brain. The nucleus is situated at the base of the brain, adjacent to the optic chiasm. In humans, the SON contains about 3,000 neurons.

<span class="mw-page-title-main">Desmopressin</span> Medication

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 only be used for mild to moderate cases. It may be given in the nose, by injection into a vein, by mouth, or under the tongue.

Cerebral salt-wasting syndrome (CSWS), also written cerebral salt wasting syndrome, is a rare endocrine condition featuring a low blood sodium concentration and dehydration in response to injury (trauma) or the presence of tumors in or surrounding the brain. In this condition, the kidney is functioning normally but excreting excessive sodium. The condition was initially described in 1950. Its cause and management remain controversial. In the current literature across several fields, including neurology, neurosurgery, nephrology, and critical care medicine, there is controversy over whether CSWS is a distinct condition, or a special form of syndrome of inappropriate antidiuretic hormone secretion (SIADH).

<span class="mw-page-title-main">Demeclocycline</span> Chemical compound

Demeclocycline is a tetracycline antibiotic which was derived from a mutant strain of Streptomyces aureofaciens.

Plasma osmolality measures the body's electrolyte–water balance. There are several methods for arriving at this quantity through measurement or calculation.

Nephrogenic diabetes insipidus, recently renamed as arginine vasopressin resistance (AVP-R) and also previously known as renal diabetes insipidus, is a form of diabetes insipidus primarily due to pathology of the kidney. This is in contrast to central or neurogenic diabetes insipidus, which is caused by insufficient levels of vasopressin. Nephrogenic diabetes insipidus is caused by an improper response of the kidney to vasopressin, leading to a decrease in the ability of the kidney to concentrate the urine by removing free water.

<span class="mw-page-title-main">Primary polydipsia</span> Medical condition

Primary polydipsia and psychogenic polydipsia are forms of polydipsia characterised by excessive fluid intake in the absence of physiological stimuli to drink. Psychogenic polydipsia which is caused by psychiatric disorders, often schizophrenia, is often accompanied by the sensation of dry mouth. Some forms of polydipsia are explicitly non-psychogenic. Primary polydipsia is a diagnosis of exclusion.

The actions of vasopressin are mediated by stimulation of tissue-specific G protein-coupled receptors (GPCRs) called vasopressin receptors that are classified into the V1 (V1A), V2, and V3 (V1B) receptor subtypes. These three subtypes differ in localization, function and signal transduction mechanisms.

The osmostat is the regulatory center in the hypothalamus that controls the osmolality of the extracellular fluid. The area in the anterior region of the hypothalamus contains the osmoreceptors, cells that control osmolality via the secretion of antidiuretic hormone (ADH).

Frederic Crosby Bartter was an American endocrinologist best known for his work on hormones affecting the kidney and his discovery of syndrome of inappropriate antidiuretic hormone and Bartter syndrome. He had a separate interest in mushroom poisoning.

<span class="mw-page-title-main">Satavaptan</span> Chemical compound

Satavaptan is a vasopressin-2 receptor antagonist which was investigation by Sanofi-Aventis and was under development for the treatment of hyponatremia. It was also being studied for the treatment of ascites. Development was discontinued in 2009.

<span class="mw-page-title-main">Mozavaptan</span> Chemical compound

Mozavaptan (INN) is a vasopressin receptor antagonist marketed by Otsuka. In Japan, it was approved in October 2006 for hyponatremia caused by syndrome of inappropriate antidiuretic hormone (SIADH) due to ADH producing tumors.

A vasopressin receptor antagonist (VRA) is an agent that interferes with action at the vasopressin receptors. Most commonly VRAs are used in the treatment of hyponatremia, especially in patients with congestive heart failure, liver cirrhosis or SIADH.

Hypoosmolar hyponatremia is a condition where hyponatremia is associated with a low plasma osmolality. The term "hypotonic hyponatremia" is also sometimes used.

<span class="mw-page-title-main">Potomania</span> Medical condition

Potomania is a specific hypo-osmolality syndrome related to massive consumption of beer, which is poor in solutes and electrolytes. With little food or other sources of electrolytes, consumption of large amounts of beer or other dilute alcoholic drinks leads to electrolyte disturbances, where the body does not have enough nutrients known as electrolytes, namely sodium, potassium, and magnesium. The symptoms of potomania are similar to other causes of hyponatremia and include dizziness, muscular weakness, neurological impairment and seizures, all related to hyponatremia and hypokalaemia. While the symptoms of potomania are similar to other causes of hyponatremia and acute water intoxication, it should be considered an independent clinical entity because of its often chronic nature of onset, pathophysiology, and presentation of symptoms.

<span class="mw-page-title-main">Adipsia</span> Medical condition

Adipsia, also known as hypodipsia, is a symptom of inappropriately decreased or absent feelings of thirst. It involves an increased osmolality or concentration of solute in the urine, which stimulates secretion of antidiuretic hormone (ADH) from the hypothalamus to the kidneys. This causes the person to retain water and ultimately become unable to feel thirst. Due to its rarity, the disorder has not been the subject of many research studies.

References

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  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Adrogué, Horacio J.; Madias, Nicolaos E. (19 October 2023). "The Syndrome of Inappropriate Antidiuresis". New England Journal of Medicine. 389 (16): 1499–1509. doi:10.1056/NEJMcp2210411. PMID   37851876. S2CID   264305156.
  3. 1 2 Schwartz, William B.; Bennett, Warren; Curelop, Sidney; Bartter, Frederic C. (1957). "A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone". The American Journal of Medicine. 23 (4): 529–42. doi:10.1016/0002-9343(57)90224-3. PMID   13469824. reproduced as a Milestone in Nephrology with author commentary in Schwartz, William B.; Bennett, Warren; Curelop, Sidney; Bartter, Frederic C. (2001). "A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. 1957" (PDF). Journal of the American Society of Nephrology. 12 (12): 2860–70. doi: 10.1681/ASN.V12122860 . PMID   11729259.
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  6. ↑ Antunes-Rodrigues, J; de Castro, M; Elias, LL; Valença, MM; McCann, SM (January 2004). "Neuroendocrine control of body fluid metabolism". Physiological Reviews. 84 (1): 169–208. doi:10.1152/physrev.00017.2003. PMID   14715914.[ needs update ]
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  9. ↑ Kwon, TH; Hager, H; Nejsum, LN; Andersen, ML; Frøkiaer, J; Nielsen, S (May 2001). "Physiology and pathophysiology of renal aquaporins". Seminars in Nephrology. 21 (3): 231–8. doi:10.1053/snep.2001.21647. PMID   11320486.[ needs update ]
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  11. ↑ Onitilo, A. A.; Kio, E.; Doi, S. A. R. (2007). "Tumor-Related Hyponatremia". Clinical Medicine & Research. 5 (4): 228–37. doi:10.3121/cmr.2007.762. PMC   2275758 . PMID   18086907.
  12. ↑ Adrogué, Horacio J.; Madias, Nicolaos E. (2000). "Hyponatremia". New England Journal of Medicine. 342 (21): 1581–9. doi:10.1056/NEJM200005253422107. PMID   10824078.
  13. ↑ Gross, P (April 2012). "Clinical management of SIADH". Therapeutic Advances in Endocrinology and Metabolism. 3 (2): 61–73. doi:10.1177/2042018812437561. PMC   3474650 . PMID   23148195.
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  15. ↑ Pillai, Binu P.; Unnikrishnan, Ambika Gopalakrishnan; Pavithran, Praveen V. (September 2011). "Syndrome of inappropriate antidiuretic hormone secretion: Revisiting a classical endocrine disorder". Indian Journal of Endocrinology and Metabolism. 15 (Suppl3): S208–S215. doi: 10.4103/2230-8210.84870 . ISSN   2230-8210. PMC   3183532 . PMID   22029026.
  16. ↑ Sen J, Belli A, Albon H, et al. (2003). "Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage". The Lancet Neurology. 2 (10): 614–621. doi:10.1016/s1474-4422(03)00531-3. PMID   14505583. S2CID   38149776.
  17. ↑ Rivkees, Scott A (2008). "Differentiating appropriate antidiuretic hormone secretion, inappropriate antidiuretic hormone secretion and cerebral salt wasting: the common, uncommon, and misnamed". Current Opinion in Pediatrics. 20 (4): 448–52. doi:10.1097/MOP.0b013e328305e403. PMID   18622203. S2CID   41194368.
  18. ↑ Ashrafian, H.; Davey, P. (2001). "A review of the causes of central pontine myelinosis: yet another apoptotic illness?". European Journal of Neurology. 8 (2): 103–9. doi:10.1046/j.1468-1331.2001.00176.x. PMID   11430268. S2CID   37760332.
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  20. ↑ Upadhyay, A; Jaber, BL; Madias, NE (July 2006). "Incidence and prevalence of hyponatremia". The American Journal of Medicine. 119 (7 Suppl 1): S30-5. doi:10.1016/j.amjmed.2006.05.005. PMID   16843082.[ needs update ]
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  23. ↑ Schwartz-Bartter syndrome at Who Named It?
  24. ↑ Feldman, BJ; Rosenthal, SM; Vargas, GA; Fenwick, RG; Huang, EA; Matsuda-Abedini, M; Lustig, RH; Mathias, RS; Portale, AA; Miller, WL; Gitelman, SE (5 May 2005). "Nephrogenic syndrome of inappropriate antidiuresis". The New England Journal of Medicine. 352 (18): 1884–90. doi:10.1056/NEJMoa042743. PMC   5340184 . PMID   15872203.
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