Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

The syndrome of inappropriate antidiuretic hormone (SIADH) is a condition commonly found in individuals hospitalized for central nervous system (CNS) injury. SIADH is a syndrome characterized by excessive release of antidiuretic hormone (ADH or vasopressin) from the posterior pituitary gland or any other source, resulting in hyponatremia, and sometimes fluid overload. Syndrome of inappropriate antidiuretic hormone production (SIADH) leads to excessive water retention and thus a decrease in sodium concentration. SIADH may be occur as a result of central nervous system diseases, cancers, pulmonary diseases, and some drugs. Signs and symptoms of SIADH vary widely. Some patients with SIADH may become severely ill while others may have no symptoms at all. Common symptoms include nausea, vomiting, loss of appetite, fatigue, weakness, and altered consciousness. Blood tests of hyponatremia (sodium <135 mEq/L) and low serum osmolality (< 280 mOsm/kg) may prompt the diagnosis of SIADH. Treatment of SIADH depends on the cause. Restriction of water intake and supplementation of sodium may lead to improvement. Prognosis of SIADH varies depending on the cause.

In 1951, Leaf and Mambi first described SIADH. Later it was described by Dr Frederic Bartter in two patients with lung cancer from Boston (MA) and Bethesda (MD), in 1957.

SIADH may be classified into several sub-types based on the pattern of arginine vasopressin (AVP) secretion in response to a range of plasma osmolalities into type A, type B, type C, and type D.

Syndrome of inappropriate antidiuretic hormone production is a condition in which the body develops an excess of water and a decrease in the concentration of electrolytes. SIADH may be caused by a central nervous system diseases, cancers, pulmonary diseases, or some drugs. ADH is normally produced by the posterior pituitary gland to prevent water loss in the kidneys. In SIADH, ADH level rises above the normal level. Aquaporins are localized on storage vesicles in the cytoplasm of the epithelial cells which make up the collecting ducts of the kidneys. High ADH level stimulates mass fusion of aquaporin-carrying storage vesicles with the plasma membrane. High aquaporin density facilitates high diffusion of water across the plasma membrane. Excess water is reabsorbed from the nephrons and is returned to the blood. A mutation affecting the gene for the renal V2 receptor might cause SIADH.

Syndrome of inappropriate antidiuretic hormone is caused by excess of renal water reabsorption through inappropriate antidiuretic hormone secretion. There are various causes attributed to SIADH ranging from malignancies, medications, central nervous system causes, and infectious. Some of the most common causes of SIADH include malignancies, like small cell lung cancer and medications, such as selective serotonin reuptake inhibitors and carbamazepine.

Syndrome of inappropriate antidiuretic hormone (SIADH) must be differentiated from other causes of hyponatremia, such as cerebral salt wasting syndrome, adrenal insufficiency, hypopituitarism, and psychogenic polydipsia.

Syndrome of inappropriate antidiuretic hormone (SIADH) can occur at any age. Its incidence depends upon various possible etiologies. Prevalence of SIADH was estimated to be 2500-3000 cases per 100,000 individuals. The incidence and prevalence of SIADH in particular is less thoroughly studied in the literature. Hospitalized patients with plasma sodium concentration <125 mmol/l show an overall mortality of 28000 per 100,000 patients. The incidence of SIADH increases with age. The prevalence and incidence of SIADH does not vary by gender. There is no racial predilection to SIADH.

The most common risk factors of Syndrome of inappropriate antidiuretic hormone (SIADH) are malignancy, pulmonary disorders, CNS disorders, and medications.

There is insufficient evidence to recommend routine screening for SIADH.

The symptoms of SIADH can occur at any age. If left untreated, it can lead to complications, such as confusion, seizures, stupor, and coma. Some of the complications of SIADH treatment are include cerebral edema and central pontine myelinolysis, which are seen with rapid sodium correction. The prognosis of SIADH depends primarily on its cause. If the cause is medications, SIADH usually improves after discontinuing the medications. SIADH secondary to an infection, improves with the treatment of the infection. SIADH secondary to cancers, has poor outcome. Patients with SIADH have different signs, symptoms and prognosis depending on the etiology of SIADH. Serum sodium concentration at short-term follow-up is predictive of long-term survival.

Symptoms of SIADH depend on the level of sodium in the blood and the rate at which the level of sodium falls. Symptoms may be non-specific, such as generalized fatigue and weakness; but in case of severe disease, symptoms, such as irritability, nausea, vomiting, muscle weakness and cramps, loss of appetite, confusion, personality changes, hallucinations, seizures, stupor, and coma may be seen.

Physical examination of patients with syndrome of inappropriate antidiuretic hormone (SIADH) is usually remarkable for ill and sometimes confused appearance, orthostatic hypotension, Cheyne-Stokes respiration, dysarthria, altered mental status, confusion, disorientation, delirium, generalized muscle weakness, generalized seizures, coma, myoclonus, tremor, asterixis, hyporeflexia, and ataxia.

Laboratory findings which are helpful in diagnosing syndrome of inappropriate antidiuretic hormone (SIADH) include serum electrolytes (especially sodium), blood urea nitrogen (BUN), creatinine, glucose levels, and osmolality. Laboratory findings in patients with SIADH may show hyponatremia (sodium <135 mEq/L) and low serum osmolality (< 280 mOsm/kg). Patients with SIADH have elevated urinary sodium level (> 20 mMol/L) and urine osmolality (generally > 100 mOsm/L). Patients with SIADH also have low BUN, normal creatinine, hypouricemia, and hypoalbuminemia.

Electrocardiogram (EKG) may be helpful in the diagnosis of SIADH. Findings on an EKG suggestive of SIADH are like classic Brugada like pattern, include downward coving of ST-segment and T-wave inversion in the anterior precordial leads. The EKG changes will be normalized after the sodium levels were corrected.

An x-ray may be helpful in the diagnosis of Lung cancer, which is one of the most common causes of SIADH. The findings include hilar/perihilar mass and mediastinal widening.

Chest CT scan may be helpful in the diagnosis of lung cancer, which is one of the most common cause of SIADH. Findings on CT scan suggestive of lung cancer include numerous enlarged lymph nodes and direct infiltration of adjacent structures.

Brain MRI may be helpful in the diagnosis of SIADH. Findings on MRI suggestive of SIADH include brain abscess, subarachnoid hemorrhage, and meningitis.

There are no ultrasound findings associated with SIADH.

There are no other imaging findings for SIADH.

There are no additional diagnostic findings for SIADH.

Treatment of syndrome of inappropriate antidiuretic hormone (SIADH) depends on the etiology. For immediate improvement, all patients with syndrome of inappropriate antidiuretic hormone (SIADH) require strict restriction of their daily water intake and correction of serum sodium levels. The serum sodium can be corrected depending on the initial sodium levels of the patient. Mild cases can be managed easily with exclusive fluid restriction. Moderate cases of SIADH are treated with loop diuretics and normal saline; whereas, 3% hypertonic saline may be used in severe cases. In emergency settings, vasopressin-2 receptor antagonists (conivaptan or tolvaptan) are used. The definitive treatment of SIADH involves treatment of the underlying condition. Urea, demeclocycline, and lithium are also used in the treatment of SIADH.

The definitive treatment of SIADH involves treatment of the underlying condition. SIADH resulting from a carcinoma may require surgery, radiation therapy, or chemotherapy.

Effective measures for the primary prevention of SIADH include regular monitoring of drugs by the health care provider and screening for cancers.

There are no secondary preventive measures available for SIADH.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

SIADH may be classified into several sub-types based on the pattern of arginine vasopressin (AVP) secretion in response to a range of plasma osmolalities into type A, type B, type C, and type D.

SIADH may be classified into several sub-types based on the pattern of arginine vasopressin (AVP) secretion across a range of plasma osmolalities:^[1][2][3]

This classification scheme includes Fenske’s^[4] observation on copeptin levels, which is “secreted in an equimolar amount to arginine vasopressin (AVP) but can easily be measured in plasma or serum with a sandwich immunoassay.”^[5] Normal observations for copeptin are:

• Level during euvolemia: 2 and 38 pmol/L“^[4]. Another view is “Median copeptin levels were significantly higher in the male volunteers compared with the females [median (range): 4.3 (0.4-44.3) compared with 3.2 (1.0-14.8) pmol/l”^[6] and levels are modulated by gender (higher in males), eGFR higher when eGFR lower), left atrial size (higher when LA larger), and longer echocardiographic deceleration times (prolonged ventricular filling)^[6].
• Slope of change during hypertonic saline infusion: “slope of 0.74 pmol/L and mOsM/kg H₂O … (95% confidence interval [95% CI], 0.66 to 0.83)”^[4]

Classification	Features
Type A	Accounts for about 60-70% of SIADH Excessive secretion of arginine vasopressin (AVP) is noted “Plasma copeptin consistently >38 pmol/L with a copeptin slope <95% CI for that of healthy persons (i.e., <0.66 pmol/L/mOsM/kg H2O)”[4] Associated with lung cancer and nasopharyngeal tumors Patients are more susceptible to development of severe hyponatremia
Type B	Accounts for (20–40%) of the cases “Any plasma copeptin concentration with a positive copeptin slope >0.25 pmol/L/mOsM/kg H2O, but a low osmotic threshold <95% CI for that of healthy persons (i.e., <281 mOsM/kg H2O)”[4] Type B may include reset osmostat, “characterized by a decline in plasma copeptin levels with increasing saline-stimulated serum osmolality…baseline hypovolemia could not be identified [in these patient]”[4] Secretion of AVP occurs at lower than normal plasma osmolalities
Type C	Failure to suppress AVP secretion at plasma osmolalities below the osmotic threshold “Plasma copeptin concentration between 2 and 38 pmol/L with a copeptin slope between −0.25 and 0.25 pmol/L/mOsM/kg H2O”[4] Reset osmostat may be a Type C rather than Type b, “reset osmostat may in part be considered as a less severe variant of the type C defect…, where responsivity to osmotic challenges is completely lost. Copeptin release in this subtype was stable at levels within the normal physiologic range but was not suppressed by hypotonicity or stimulated in response to osmotic stimulation; thus, it deviates from the previously described type C”[4] Occurs due to dysfunction of inhibitory neurons in the hypothalamus, leading to persistent low-grade basal AVP secretion
Type D	Low or undetectable AVP levels and circulating AVP response is not defective “Plasma copeptin concentration consistently <2 pmol/L regardless of the copeptin slope”[4] Nephrogenic SIADH (NSIAD) may be attributed to this condition Associated with gain-of-function mutations in the vasopressin-2 (V2) receptor leading to a clinical picture of SIADH, with undetectable AVP levels The condition is inherited in an X-linked manner, although heterozygous females may have inappropriate anti-diuresis of varying degrees.
Type E	“Any plasma copeptin concentration with a copeptin slope <−0.25 pmol/L/mOsM/kg H2O…Theoretically, an alternative explanation of type E could be a reversed osmotic response from stimulation to inhibition”[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Syndrome of inappropriate antidiuretic hormone production is a condition in which the body develops an excess of water and a decrease in the concentration of electrolytes. SIADH may be caused by a central nervous system diseases, cancers, pulmonary diseases, or some drugs. ADH is normally produced by the posterior pituitary gland to prevent water loss in the kidneys. In SIADH, ADH level rises above the normal level. Aquaporins are localized on storage vesicles in the cytoplasm of the epithelial cells which make up the collecting ducts of the kidneys. High ADH level stimulates mass fusion of aquaporin-carrying storage vesicles with the plasma membrane. High aquaporin density facilitates high diffusion of water across the plasma membrane. Excess water is reabsorbed from the nephrons and is returned to the blood. A mutation affecting the gene for the renal V2 receptor might cause SIADH.

The normal function of antidiuretic hormone (ADH) on the kidneys is to control the amount of water reabsorbed by kidney nephrons. ADH acts on the distal portion of the renal tubule (distal convoluted tubule) as well as the collecting duct and causes the retention of water. Owing to the water retention, dilution of the blood and hyponatremia occurs.

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• ADH is normally produced by the posterior pituitary gland.
• In SIADH, ADH level rises above the normal level.
• Aquaporins are localized on storage vesicles in the cytoplasm of the epithelial cells which make up the collecting ducts of the kidneys.
• High ADH level stimulates mass fusion of aquaporin-carrying storage vesicles with the plasma membrane.
• High aquaporin density facilitates high diffusion of water across the plasma membrane.
• Excess water is reabsorbed from the nephrons and is returned to the blood.

• Developmentally, Mammalian brain have evolved in times of water scarcity.
• 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. Then, these 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.
• This leads to less water reabsorption, thereby increasing urine output, decreasing urine osmolality, and increasing (normalization of) blood osmolality.
• In general, the plasma sodium concentration is the primary osmotic determinant of AVP release. In SIADH, there is non physiological secretion of AVP. There is enhanced water reabsorption, leading to dilutional hyponatremia.

• A mutation affecting the gene for the renal V2 receptor might cause SIADH.
• Congenital nephrogenic diabetes insipidus is characterized by a resistance of the renal collecting duct to the action of the arginine vasopressin hormone responsible for the inability of the kidney to concentrate urine.
• Inactivating mutations of the V2 receptor gene leading to a loss of function of the mutated receptors are implicated in the X-linked form.^[1]
• SIADH due to lesion in the hypothalamus is secondary to mutation in the transient receptor potential vanilloid type 4 (TRPV4) gene.^[2]

• SIADH is most commonly associated with:^[3][4][5]
  • Malignancies
  • Central nervous system disorders
  • Medications
  • Pulmonary disorders

There are no gross pathology findings associated with SIADH. However, SIADH may be associated with squamous cell carcinoma of the lung, which exhibits the following gross pathology findings:

• Cavitations
• Tissue necrosis
• Fibrosis
• Keratinization

There are no microscopic findings associated with SIADH. However, SIADH may be associated with squamous cell carcinoma of the lung, which exhibits the following microscopic pathology findings:^[6][7]

• Keratin pearls
• Intercellular bridges
• Prominent peripheral palisading of tumor cells with scanty cytoplasm 
• Nuclear atypia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Syndrome of inappropriate antidiuretic hormone is caused by excess of renal water reabsorption through inappropriate antidiuretic hormone secretion. There are various causes attributed to SIADH ranging from malignancies, medications, central nervous system causes, and infectious. Some of the most common causes of SIADH include malignancies, like small cell lung cancer and medications, such as selective serotonin reuptake inhibitors and carbamazepine.

• Head injury
• Subarachnoid hemorrhage
• Cancers
  • Lung cancer (especially small cell lung cance, as well as other small-cell malignancies of other organs)
• Infections
  • Brain abscess
  • Pneumonia
  • Lung abscess
• Medications
  • Chlorpropamide
  • Cyclophosphamide
  • Carbamazepine
  • Selective serotonin reuptake inhibitors
  • Methylenedioxymethamphetamine (MDMA, commonly called Ecstasy)^[1][2][3]

Chemical / poisoning	Mesothelioma
Cardiovascular	No underlying causes
Chemical / poisoning	Mesothelioma
Dermatologic	No underlying causes
Drugs	Cyclophosphamide, Desmopressin, Monoamine oxidase inhibitors, Nicotine, Oxytocin, Pergolide, Phenothiazines, SSRIs, Tricyclic antidepressants,Monoamine oxidase inhibitors, Vasopressin, Vinblastine, Vincristine, Bromocriptine, Clofibrate, Prostaglandins, Melphalan, Interferon-alpha, Tacrolimus, Diclofenac, Ibuprofen, Fentanyl, Amiodarone, Hydrochlorthiazide, Clonidine, Levodopa, Rituximab, Methylenedioxymethamphetamine, Leveteiracetam, Quinolones
Ear Nose Throat	No underlying causes
Endocrine	Carcinoid, Hypopituitarism, Hypothyroidism
Environmental	Mesothelioma
Gastroenterologic	Carcinoid, Duodenal carcinoma, Pancreatic cancer
Genetic	Agenesis corpus collosum, Amyotropic lateral sclerosis, Hydrocephalus, Midline defects, Multiple sclerosis
Hematologic	Thymoma, Acute intermittent porphyria
Iatrogenic	No underlying causes
Infectious Disease	AIDS, Bacterial pneumonia, Brain abscess, Encephalitis, Lung abscess, Lung cavitation, Meningitis, Tuberculosis
Musculoskeletal / Ortho	Amyotropic lateral sclerosis, Ewing’s sarcoma, Polyradiculitis
Neurologic	Agenesis corpus collosum, Amyotropic lateral sclerosis, Brain abscess, Carcinoid, Cavernous sinus thrombosis, Delirium tremens, Encephalitis, Hydrocephalus, Meningitis, Multiple sclerosis, Peripheral neuropathy, Polyradiculitis, Stroke, Subarachnoid hemorrhage, Subdural hemorrhage, Guillain-Barre Syndrome, Traumatic brain injury
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	Ovarian cancer
Oncologic	Bronchial adenoma, Carcinoid, Duodenal carcinoma, Ewing’s sarcoma, Lung carcinoma, Mesothelioma, Ovarian cancer, Pancreatic cancer, Thymoma
Opthalmologic	No underlying causes
Overdose / Toxicity	Delirium tremens
Psychiatric	Phenothiazines, Psychosis
Pulmonary	Asthma, Bacterial pneumonia, Bronchial adenoma, Carcinoid, Lung abscess, Lung carcinoma, Lung cavitation, Mesothelioma, Pneumothorax, Tuberculosis
Renal / Electrolyte	No underlying causes
Rheum / Immune / Allergy	Asthma
Sexual	No underlying causes
Trauma	Pneumothorax
Urologic	No underlying causes
Miscellaneous	Positive pressure ventilation, Transsphenoidal surgery , Polyarteritis Nodosa

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Syndrome of inappropriate antidiuretic hormone (SIADH) must be differentiated from other causes of hyponatremia, such as cerebral salt wasting syndrome, adrenal insufficiency, hypopituitarism, and psychogenic polydipsia.

SIADH must be differentiated from cerebral salt wasting, adrenal insufficiency, hypopituitarism, hypothyroidism, and psychogenic polydipsia.^[1][2][3]

Differential Diagnosis	Similar Features	Differentiating Features
SIADH	Excessive release of antidiuretic hormone (ADH or vasopressin)  from the posterior pituitary gland or another source. Hyponatremia Fluid overload Hyponatremia <135 mmol/l Effective serum osmolality < 275 mOsm Urine sodium concentration > 40 mMol/l Plasma uric acid < 200 Absence of edema-inducing diseases, such as heart failure, liver cirrhosis, and nephrotic syndrome Normal adrenal and thyroid function	Weight loss (in case of malignancy) History of head trauma History of medication intake Positive family history
Cerebral salt wasting syndrome	Hyponatremia Urine sodium concentration > 40 mMol/l	Hypovolemia Intracranial diseases, such as: Tumor Trauma Hematoma
Adrenal insufficiency	Hyponatremia	Weight loss Sparse axillary hair Hyperpigmentation Orthostatic hypotension Fever Hypotension Eosinophilia Hyperkalemia Hypoglycemia Morning low plasma cortisol
Hypopituitarism	Hyponatremia	Fatigue Weight loss Decreased libido Decreased appetite Facial puffiness Anemia Infertility Cold intolerance Amenorrhea Inability to lactate in breast feeding women Decreased facial or body hair in men Short stature in children
Psychogenic polydipsia	Fluid overload Hyponatremia	Defect in the hypothalamus Polyuria Polydipsia Confusion Lethargy Psychosis Seizures

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

Syndrome of inappropriate antidiuretic hormone (SIADH) can occur at any age. Its incidence depends upon various possible etiologies. Prevalence of SIADH was estimated to be 2500-3000 cases per 100,000 individuals. The incidence and prevalence of SIADH in particular is less thoroughly studied in the literature. Hospitalized patients with plasma sodium concentration <125 mmol/l show an overall mortality of 28000 per 100,000 patients. The incidence of SIADH increases with age. The prevalence and incidence of SIADH does not vary by gender. There is no racial predilection to SIADH.

• SIADH is the most common cause of hyponatremia.^[1]
• Incidence of moderate and severe hyponatraemia in the United States ranges from a low of 1000 to 7000 per 100,000 among hospitalized patients.^[2]

• Prevalence of SIADH was estimated to be 2500-3000 cases per 100,000 individuals.
• Prevalence of hyponatremia in the United States has been estimated to be 1720 per 100,000 individuals.^[3]

• Hospitalized patients with plasma sodium concentration <125 mmol/l show an overall mortality of 28000 per 100,000 patients.^[4]

• The incidence of SIADH increases with age.^[5][6]

• The prevalence and incidence of SIADH does not vary by gender.
• The prevalence of hyponatremia is higher in females than males.^[7]

• There is no racial predilection to SIADH.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

The most common risk factors of Syndrome of inappropriate antidiuretic hormone (SIADH) are malignancy, pulmonary disorders, CNS disorders, and medications.

Common risk factors for SIADH, include:^[1][2][3][4]

• Increased age
• Psychotropic drugs
• Schizophrenia
• Smoking
• Cancers

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2]

There is insufficient evidence to recommend routine screening for SIADH.

There is insufficient evidence to recommend routine screening for SIADH.