Syndrome of inappropriate antidiuretic hormone secretion

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The syndrome of inappropriate antidiuretic hormone secretion (SIADH), also known as the syndrome of inappropriate antidiuresis (SIAD),

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

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

Signs and symptoms

Gastro-intestinal

• Anorexia
• Nausea

Musculoskeletal

• Muscle aches
• Generalized muscle weakness^[4]

Neuro-muscular

• Myoclonus^[4]
• Decreased reflexes^[4]
• Ataxia^[4]
• Pathological
  reflexes^[4]
• Tremor^[4]
• Asterixis^[4]

Respiratory

• Cheyne-Stokes respiration^[4]

• Dysarthria^[4]
• Lethargy
• Confusion^[4]
• Delirium^[4]
• Seizures^[4]
• Coma (from brain swelling)^[4]
• Death^[4]

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

A list of common causes is below:[5]

Pathophysiology

Normally there are

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 (U_Osm >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

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]

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

• 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.^[2]
• 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.[2] Raising the serum sodium concentration too rapidly may cause central pontine myelinolysis (also known as osmotic demyelination).^[18] 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.^[2] If overcorrection does occur, a 5% dextrose in water infusion may be given to temporarily lower sodium levels.^[2] 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.^[2]

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.^[19]
  • Urea: oral daily ingestion has shown favorable long-term results with protective effects in myelinosis and brain damage.^[19] Limitations noted to be undesirable taste and is contraindicated in people with cirrhosis to avoid initiation or potentiation of hepatic encephalopathy.
  • Conivaptan – an antagonist of both V_1A and V₂ vasopressin receptors.^[19]
  • 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.^[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]

References