Etiology

Under pathological conditions, the pituitary gland and other cells may synthesize and secrete arginine vasopressin (AVP, the antidiuretic hormone) independently of serum osmolality or circulating volume.[4] Inappropriate antidiuresis may also result from increased activity of vasopressin in the collecting duct or from a gain-of-function mutation in its type 2 receptor.[4] Causes of SIADH include:[2][4]

  • Drugs: multiple drugs have been linked to increased AVP release or enhanced potential of AVP, including:[4]​

    • Antidepressants such as selective serotonin-reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors, and venlafaxine

    • Anticonvulsants such as carbamazepine, oxcarbazepine, valproate, and lamotrigine

    • Antipsychotics such as phenothiazines (e.g., chlorpromazine) and butyrophenones (e.g., haloperidol)

    • Antidiabetic agents such as first-generation sulfonylureas (e.g., chlorpropamide, tolbutamide)

    • Chemotherapeutic agents such as vinca alkaloids, platinum compounds, ifosfamide, melphalan, cyclophosphamide, methotrexate, and pentostatin

    • Vasopressin analogs such as desmopressin, oxytocin, terlipressin, and vasopressin

    • Other drugs such as opioids, methylenedioxymethamphetamine (MDMA), levamisole, interferon, clofibrate, nicotine, amiodarone, proton-pump inhibitors, monoclonal antibodies, and nonsteroidal anti-inflammatory drugs (NSAIDs).

  • Pulmonary processes: including pulmonary infections such as bacterial pneumonia, viral pneumonia, pulmonary abscess, tuberculosis, or aspergillosis; asthma; cystic fibrosis; positive-pressure ventilation; or lung cancers, especially small cell lung cancer.[4]

  • Malignancy: carcinomas (including lung, oropharynx); malignant diseases of the gastrointestinal (stomach, duodenum, pancreas) or genitourinary (ureter, bladder, prostate, endometrium) tracts; thymoma; lymphomas; sarcomas (e.g., Ewing sarcoma); and olfactory neuroblastoma.[4]

  • Central nervous system (CNS) disorders: CNS infections (encephalitis, meningitis, brain abscess, Rocky Mountain spotted fever, HIV-associated opportunistic CNS infections, malaria); vascular causes and masses (brain trauma, subdural hematoma, subarachnoid hemorrhage, stroke, and brain tumors); other CNS disorders (hydrocephalus, cavernous sinus thrombosis, multiple sclerosis, Guillain-Barre syndrome, Shy-Drager syndrome, delirium tremens, acute intermittent porphyria).[4]

  • Other stimuli for AVP release: such as anesthesia and postoperative state, nausea, vomiting, pain, stress, and endurance exercise.[4]

  • Nephrogenic syndrome of inappropriate antidiuresis or pseudo-SIADH. This is due to gain-of-function mutations in the vasopressin 2 (V2) receptor, which is constitutively active. This initiates aquaporin-2 placement into the apical membrane of cortical collecting duct cells and corresponding free water permeability, in face of appropriately low serum AVP levels.[3]

Other proposed, but unconfirmed, mechanisms include:

  • The presence of an unknown antidiuretic substance (other than AVP) that stimulates the AVP V2 receptor.[1]

  • Post-AVP V2 receptor defect. Aquaporin-2 channel activity is inappropriately stimulated downstream of the AVP V2 receptor. This could be via intracellular stimulation or dysfunction of the aquaporin-2 channel itself.[1]

Pathophysiology

Arginine vasopressin (AVP or antidiuretic hormone) is produced in the hypothalamus and delivered to the posterior pituitary for release into systemic circulation.

Secretion of AVP is mediated by several mechanisms. Osmotic pressure is the most sensitive and important stimulus for AVP release and is mediated by osmoreceptors in the hypothalamus. Sodium concentration greatly influences osmotic pressure. A decrease in osmolality, as minimal as 1% to 2%, rapidly suppresses AVP secretion and induces free water diuresis.[11]

Arterial pressure reduction also stimulates AVP release, but typically there must be a significant reduction of 10% to 20%, as sensed by baroreceptors in the left atrium and aorta. It appears that arterial pressure provokes AVP release by lowering the set point of the osmoregulatory system.[11] Other nonosmotic stimuli for AVP release include stress, nausea, pain, and vasovagal stimulation.

Inappropriate release of AVP can occur with malignancy, pulmonary processes, central nervous system disorders, and certain drugs. Often there is a concomitant resetting of the osmostat that also contributes to AVP effect and hyponatremia. AVP exerts its effect by stimulating the AVP V2 receptor, located on the basolateral side of the principal cell. These receptors may also be activated by other, currently undiscovered antidiuretic substances.[3]

AVP V2 is a G-protein-coupled receptor that, when stimulated, initiates adenylate cyclase and leads to increased intracellular cyclic adenosine monophosphate (cAMP).[12] Elevated cAMP signals placement of vesicle-encased aquaporin-2 channels in the principal cell apical membrane, facilitating free water absorption in the collecting tubule.

Resulting concentrated urine, coupled with free water intake in excess of what can be excreted, leads to hyponatremia.[1] This is especially true in the case of exercise-associated hyponatremia, in which excessive water intake is coupled with increased nonosmotic release of AVP through stress and pain. Extracellular volume increases and plasma renin/aldosterone secretion is suppressed to cause a natriuresis, further aggravating hyponatremia.[1]

Classification

Clinically accepted classification of SIADH[1][2]

Type A: unregulated release of arginine vasopressin (AVP). Approximately 30% of patients. Marked increase in plasma AVP levels that fluctuate in a manner unrelated to changes in plasma osmolarity/sodium during infusion of hypertonic saline.

Type B: slow leak of AVP. Approximately 30% of patients. Milder increase in plasma AVP in comparison to type A. Plasma AVP remains stable during hypertonic saline infusion and only rises when serum sodium levels reach normal range.

Type C: reset osmostat. Approximately 30% of patients. Low AVP levels during hyponatremic state; however, AVP levels rise inappropriately during hypertonic saline infusion before hyponatremia is corrected.

Type D: pseudo-SIADH. Approximately 10% of patients. Low or undetectable AVP. Low levels of AVP during hyponatremic state with apparent normal osmoregulation of AVP release. Antidiuresis occurs through an alternative mechanism, one of which is nephrogenic syndrome of inappropriate diuresis (SIAD), a genetic disorder characterized by gain-of-function mutation of vasopressin 2 receptor.[3]

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