Syndrome of Inappropriate Secretion of Antidiuretic Hormone E22.2

The syndrome is named after the U.S. internists William Benjamin Schwartz (b. 1922) and Frederic Crosby Bartter (1914-1983).

Inadequate ADH secretion syndrome (Schwartz-Bartter syndrome) is a disorder of regulation of water and electrolyte balance in which inappropriately (inadequately) high secretion of antidiuretic hormone (ADH - hormone, also: vasopressin) results in decreased excretion of water (water retention) and loss of sodium (hyponatremia). Vasopressin (also called antidiuretic hormone or ADH) helps regulate the amount of water in the body by controlling how much water is excreted by the kidneys. Vasopressin decreases the excretion of water by the kidneys. As a result, more water, which decreases the concentration of sodium in the body, is retained. Too low a level of sodium in the blood is called hyponatremia.

Vasopressin is adequately produced and released by the pituitary gland when blood volume (the amount of fluid in the blood vessels) or blood pressure decreases, or when electrolyte levels (such as sodium) rise too high.

Excretion of vasopressin is said to be inadequate if

• blood volume is normal or too high
• blood pressure is normal or too high
• the electrolyte concentration is too low
• there are no other appropriate reasons for excretion of vasopressin
• When vasopressin is secreted in these situations, fluid retention occurs and blood sodium levels fall.

There are several causes of Schwartz-Bartter syndrome. In 80% of cases, the syndrome occurs as a paraneoplastic syndrome in small cell lung cancer. Other less common causes may include:

Meningitis, encephalitis, traumatic brain injury, severe zoster disease (Foppiani L 2018).

Pneumonia, tuberculosis and certain medications (e.g. cytostatics such as vincristine, cyclophosphamide; indometacin, carbamazepine, tricyclic antidepressants, morphine, nicotine, barbiturates) can also lead to this clinical picture. It is not uncommon for patients to experience transient inadequate secretion of ADH after surgical procedures.

This leads to an uncoupling of the regulatory circuit and thus to uninhibited ADH secretion. The resulting excess of ADH causes the retention of free water in the kidney and thus a decrease in urine volume and an increase in body weight. This is often accompanied by an increased feeling of thirst. After distribution in the body, the excess free water first leads to an expansion of the fluid space outside the cells (extracellular), then, as a result of the concentration gradient of the fluids in the bodym, to an increase of the fluid in the intracellular space. Thus, in the absence of sodium intake, sodium excretion also decreases, increasing water retention and decreasing the amount of urine excreted. Regulation of sodium excretion by the kidney is preserved when blood serum sodium is low. The concentration of ADH in the blood at this time is within its normal range, but is elevated relative to the low concentrations of other substances in the blood due to dilution of the blood (low plasma osmolarity).

Thus, inadequate ADH secretion is biochemically characterized by, among other things, dilution of the blood (low plasma osmolarity), lack of fluid in the urine (high urine osmolarity) (urine to plasma ratio >1), and low blood sodium levels (hyponatremia).

• Reduced urine output with highly concentrated urine
• Weight gain
• Dizziness
• Nausea
• Impaired consciousness
• Seizures

These symptoms result from excessively increased water retention (water intoxication) and the resulting hyponatremia.

The diagnosis results from the exact anamnesis, the symptomatology and the results of the laboratory tests of the blood and urine. Important: Ask about drinking quantity, urine quantity and changes in body weight. An increase of 5-10% in body weight in a short period of time for an unexplained reason, is an important indication of Schwartz-Bartter syndrome. The following tests and laboratory parameters are diagnostic:

• Decreased serum osmolality (< 270 mosmol/kg).
• dilutional hyponatremia ([Na+] < 135 mmol/l in serum)
• elevated central venous pressure
• no edema or ascites
• low urine volume per time
• inappropriately high urine osmolality / urine specific gravity
• inappropriately high urine sodium concentration ( > 20 mmol/liter)

Determination of ADH concentration in blood is of little use. In fact, practice shows that the values can be normal or elevated, but by no means have to be elevated. This is due, among other things, to the instability of the ADH molecule. As an alternative, therefore, copeptin, a prohormone synthesized together with ADH in the hypothalamus, is usually determined.

The increase in extracellular and intracellular volume increases the risk of fluid accumulation in the brain (cerebral edema), which can be fatal without treatment. Schwartz-Bartter syndrome can also be asymptomatic.

The therapy of the triggering underlying disease is in the foreground. After successful therapy, Schwartz-Bartter syndrome usually heals spontaneously (spontaneous remission).

The symptomatic therapy of Schwartz-Bartter syndrome consists of a drinking restriction (water restriction), which alone usually leads to an improvement of the symptoms. In addition, a slow infusion of isotonic (0.9%) or hypertonic (10%) saline (sodium chloride solution) can be given to compensate for the hyponatremia. It should also be noted that hyponatremia is usually accompanied by hypokalemia, i.e., a deficiency of potassium in the blood. Therefore, additional potassium should be given, which releases sodium from the cells and thus helps to balance the hyponatremia in the extracellular space.

In cases of water intoxication, furosemide (Lasix®), a loop diuretic, can be given in addition to hypertonic saline to flush water out of the body.

Medication-wise, Schwartz-Bartter syndrome can be treated with direct ADH antagonists called vaptans. Vaptans sit on the ADH receptors in the kidney, blocking the action of ADH and thus promoting the excretion of electrolyte-free water. Tolvaptan has been available as an oral ADH antagonist in Germany since August 2009 (Morris JH et al. 2018).

1. Foppiani L (2018) SIADH with Severe Hyponatremia in an Elderly Man with Herpes Zoster Infection: A Causal or Casual Association? Intern Med 57:3393-3398
2. Morris JH et al (2018) Rapidity of Correction of Hyponatremia Due to Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following Tolvaptan. Am J Kidney Dis 71:772-782.
3. Peri A et al (2017) SIADH: differential diagnosis and clinical management. Endocrine 55(1):311-319.