Syndrome of inappropriate antidiuretic hormone secretion

A syndrome of inappropriate antidiuretic hormone secretion (SIADH) results from an abnormally high circulating level of antidiuretic hormone (ADH or vasopressin or arginine-vasopressin or AVP) relative to the clinical context, or an equivalent "ADH-like" substance.

It is biologically defined as an excess of free water, leading to hypo-osmolar hyponatremia in clinically normovolemic patients (the water excess is generally subclinical due to intracellular retention, although clinically apparent hypervolemic states are possible) with increased urinary sodium concentration. Urea and uric acid levels are typically low.

This syndrome is common both in outpatient settings (more frequently in elderly polymedicated patients) and in hospitals (mainly in intensive care). Contrary to what its name suggests, the clinical-biological syndrome is not always caused by "inappropriate secretion" (e.g., exogenous administration, renal potentiation).

As a rule, in the absence of another obvious etiology (particularly iatrogenic), the discovery of SIADH should systematically suggest a paraneoplastic syndrome (especially related to bronchogenic carcinoma).

Pathophysiological elements

Vasopressin (ADH) is synthesized in neuron bodies located in the hypothalamus before migrating along their axons and being stored in the axonal terminals located in the posterior pituitary. Under physiological conditions, ADH release is primarily triggered by an increase in plasma osmolality (neuronal osmoreceptors) and a decrease in plasma volume (atrial volume receptors) and blood pressure (aortic and carotid baroreceptors). Opposite conditions inhibit its release.

ADH binds to V2 receptors in the renal collecting ducts, stimulating the synthesis of aquaporins (water channels). Due to the cortico-medullary gradient, this results in free water reabsorption by the collecting ducts.

An "appropriate" ADH hypersecretion can be observed in numerous pathological conditions in response to hypotension and/or hypovolemia (hemorrhages, diarrhea, vomiting, third-space formation, diuretic treatment, water deprivation, circulatory failure,...) or sodium retention (ascites, nephropathies, congestive heart failure, myxedema, treatment with anti-inflammatories or fludrocortisone,...). In these cases, natriuresis generally remains adapted to these conditions due to the renin-angiotensin system response.

An "inappropriate" secretion of ADH may result from hypothalamo-pituitary or ectopic hypersecretion. Potentiation of the renal effect of ADH or exogenous administration will produce the same clinical-biological syndrome. In these cases, hypo-osmolarity, hyponatremia, and increased natriuresis are constantly observed due to the excess free water stimulating glomerular filtration and atrial natriuretic factor secretion. Water retention is almost exclusively intracellular. The onset of these abnormalities is usually chronic and of limited severity (experimentally demonstrated ADH escape phenomenon and attainment of a "steady state"). Under such conditions, the administration of "physiological" saline (0.9% NaCl) paradoxically tends to worsen hyponatremia (renal sodium excretion and tubular fluid reabsorption). However, this phenomenon can be circumvented by using infusions with a higher sodium concentration (to be effective, the sodium concentration in the infusion must exceed that of the urine) and/or forcing the kidneys to dilute the urine (concomitant administration of urea, mannitol, or a loop diuretic).

Etiologies

The most common causes of SIADH are iatrogenic and paraneoplastic (prevalence varies across studies [selection bias], with up to 80% of SIADH cases attributed to small cell bronchogenic carcinoma). As a rule, any discovery of SIADH without an obvious explanation or persisting after correction of a presumed etiology should prompt a cancer investigation.

It should be noted that the exact mechanism inducing SIADH is not clearly identified for all its etiologies, and the coexistence of ectopic secretion and hypothalamo-pituitary ADH hypersecretion is possible. However, these etiologies can be roughly classified as follows:

Hypothalamo-pituitary hypersecretion of ADH

• Neuropsychiatric disorders, central nervous system infections, brain lesions (trauma, stroke, tumors),…
• Pulmonary infections, pulmonary embolisms, bronchiectasis, status asthmaticus,...
• Iatrogenic
  • Post-operative
  • Chemotherapies : IV cyclophosphamide, vincristine, vinblastine
  • Anti-epileptics : carbamazepine
  • Neuroleptics
  • Antidepressants : tryptizol, redomex, prozac, sipralexa, serlain, seroxat, floxyfral, efexor, cymbalta, remergon, trazolan,…
  • Non-steroidal anti-inflammatory drugs, morphine,…
• Endocrine : glucocorticoid deficiency, hypothyroidism, anterior pituitary insufficiency, adrenal insufficiency,…
• Idiopathic

Ectopic production of ADH or ADH-like

• Paraneoplastic syndromes (bronchogenic cancers, brain, duodenum, pancreas, thymus, lymphomas,…)

Renal potentiation of ADH or "nephrogenic SIADH"

• Iatrogenic : chlorpropamide, carbamazepine, cyclophosphamide.
• Constitutional : activating mutations of the V2 receptor

Exogenous administration of ADH or ADH-like substances (vasopressin, oxytocin, desmopressin)

Anecdotal.

Clinical presentation

The possible clinical manifestations, primarily neurological (osmotic cerebral edema), are those of hyponatremia and depend on its severity and speed of onset. In outpatient settings, symptoms are generally absent or nonspecific (e.g., unexplained falls in elderly patients).

There may be slight to moderate weight gain, but edema is not observed. Increased mucous membrane moisture and decreased appetite for water and food can also be seen.

Diagnostic Approach and Complementary Tests

Clinical and biological assessments are often sufficient to establish SIADH, with confirmation via a water load test being exceptionally necessary. This test, conducted under hospital supervision, involves administering 20 ml of water/kg over 15 minutes. In the case of SIADH: there is a delay in the elimination of the ingested volume (normally completed in < 5 hours) and no decrease in ADH secretion. This test can also differentiate between true inappropriate endogenous secretion and renal hypersensitivity to ADH or exogenous administration.

• Identification of the biological syndrome via biology and a 24-hour urine collection (or, if unavailable, a spot urine):
  • Hyponatremia (< 135 mEq/l), low plasma osmolality (< 280 mOsmol/kg), increased natriuresis (> 20 mEq/l), hypertonic urine relative to plasma (urine osmolality/plasma osmolality > 1). Typically, proteinemia, hematocrit, uricemia, and creatinine levels are decreased. Routine measurement of ADH is not performed, and although it is usually elevated, it can be normal.
• Medication history and withdrawal of suspect drugs
• Search for and treat pulmonary infections
• History and clinical examination focused on identifying neoplasia
• Search for bronchopulmonary cancer in the absence of another obvious cause or persistent SIADH despite correcting a presumed etiology:
  • History: Smoker?
  • Clinical examination: Adenopathy?, Digital clubbing?, Pancoast?
  • Chest X-ray or CT scan
  • Bronchoscopy
  • (NSE measurement = Neuron-Specific Enolase, a marker for SCLC)
• In case of doubt regarding SIADH:
  • Water load test
    • Involves administering 20 cc/kg of water to the fasting patient over 20 minutes, then collecting urine and taking blood samples every hour for 4 hours (sodium levels, plasma and urine osmolalities, and measurement of free water clearance).
    • The test is positive if hyponatremia worsens, free water clearance remains negative, and urinary osmolality remains higher than plasma osmolality.
    • Due to the expected worsening of hyponatremia, this test, rarely necessary, should only be performed under the supervision of experienced practitioners.
  • Sodium load test
    • Infusions rich in NaCl lead to a lesser increase in sodium levels than expected (see formula in the chapter dedicated to hyponatremias). Moreover, sodium levels often rapidly decline after stopping the infusion and tend to worsen (excretion of salt via natriuresis and retention of the infusion fluid).
  • Water restriction test
    • Involves restricting fluid intake to between 500 and 800 cc/day.
    • In SIADH, this will result in an increase in sodium levels and a decrease in natriuresis.
    • Diagnostic and therapeutic value.
  • Sodium restriction test
    • Despite a low-sodium diet, high natriuresis persists.
    • Helps to identify subtle SIADH cases.
• In case of negative findings: PET-CT scan to search for occult neoplasia.

Differential Diagnosis and Boundaries of SIADH

Clinically, it is quite broad (nonspecific symptoms) and cannot be thoroughly addressed here.

Biologically, the differential diagnosis is that of hyponatremia, with particular attention to the following causes:

• Iatrogenic hyponatremia due to thiazide diuretics.
  • Some toxins and medications, particularly thiazides, can induce a clinical-biological picture similar to SIADH (hypo-osmolar hyponatremia with increased natriuresis. Unlike SIADH, volume is decreased, but this is not always clinically obvious) but with a different mechanism. Thiazides inhibit distal tubular sodium reabsorption, leading to increased natriuresis and a subsequent decrease in free water retention. In this case, only a correct history can enable diagnosis.
• Severe hypothyroidism
  • It can also lead to a clinical-biological picture similar to SIADH. The mechanisms are poorly understood. It could involve both a true reactive hypersecretion of ADH (reduced cardiac index and alteration of the osmotic threshold for ADH secretion) and a decrease in renal clearance of ADH...
• ACTH deficiencies
  • They also induce hyponatremia with decreased uricemia. However, associated hypoaldosteronism will distinguish it from SIADH.
• Cerebral salt-wasting syndrome (CSW)
  • This differential diagnosis only arises in the context of hyponatremia in a setting of brain injury (meningoencephalitis, strokes, abscesses and empyemas, neurosurgery,...).
  • Biologically characterized by hypo-osmolar hyponatremia with increased natriuresis but... hypovolemic.
  • Mechanism unknown (inappropriate secretion of natriuretic peptide?)
  • However, the very existence of this syndrome is controversial, and the therapeutic significance of the difficult distinction between SIADH and CSW is questionable. See the specific chapters dedicated to CSW and the differentiation of these syndromes.

Therapeutic Management - Treatments

• Etiological treatment. Sometimes the only necessary one (especially when a toxic or iatrogenic cause is identified in a context of mildly or asymptomatic hyponatremia).
• Symptomatic treatment: see management of hyponatremia.
  • It should be noted that classically, based on theoretical grounds, water restriction is favored in SIADH. However, it has been shown that morbidity and mortality were significantly reduced in patients receiving hypertonic saline infusions compared to patients treated with water restriction. This is even more true in the context of acute brain injury (see specific chapter). It seems reasonable to reserve water restriction and/or administration of urea for cases of mild to moderate, asymptomatic hyponatremia and outside of acute neurological suffering. In other cases, saline infusions ("physiological" with urea or hypertonic) will be favored.
  • Other treatments (lithium, ADH antagonists, demeclocycline) have been proposed. They should be avoided due to insufficient experience and/or their side effects being disproportionate compared to conventional treatments.

Bibliography

EMC, Traité de néphrologie, Elsevier, 2018

Jameson JL et al., Harrison's Principles of Internal Medicine, 20th edition, McGraw Hill Higher Education, 2018

Palmer BF, Cerebral salt wasting, UpToDate, 2024

Sterns RH, Causes of hypotonic hyponatremia in adults, UpToDate, 2024

Sterns RH, Diagnostic evaluation of adults with hyponatremia, UpToDate, 2024

Sterns RH, Overview of the treatment of hyponatremia in adults, UpToDate, 2024

Sterns RH, Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), UpToDate, 2024