Syndrome of inappropriate antidiuretic hormone overview

# Overview
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.

# Historical Perspective
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.

# Classification
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.

# Pathophysiology
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.

# Causes
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.

# Differential diagnosis
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.

# Epidemiology and Demographics
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.

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

# Screening
There is insufficient evidence to recommend routine screening for SIADH.

# Natural History, Complications, and Prognosis
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.

# Diagnosis

## History and Symptoms
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
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
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  20 mMol/L) and urine osmolality (generally > 100 mOsm/L). Patients with SIADH also have low BUN, normal creatinine, hypouricemia, and hypoalbuminemia.

## Electrocardiogram
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.

## Xray
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.

## CT scan
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.

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

## Ultrasound
There are no ultrasound findings associated with SIADH.

## Other Imaging Findings
There are no other imaging findings for SIADH.

## Other Diagnostic Studies
There are no additional diagnostic findings for SIADH.

# Treatment

## Medical Therapy
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.

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

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

## Secondary prevention
There are no secondary preventive measures available for SIADH.