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SIADH  

Mark Goodarzi, M.D.

SYNDROME OF INAPPROPRIATE ADH

NORMAL PHYSIOLOGY
L-Arginine vasopressin (AVP, ADH), a nonapeptide, is synthesized in the bodies of magnocellular neurons in the paired supraoptic nuclei and paraventricular (lateral to the 3rd ventricle) nuclei and transported down axons which form the pituitary stalk in granules bound to neurophysin & glycoprotein to be stored in the posterior pituitary axon terminals. Stores are sufficient for 5-10 days of maximum antidiuresis or one month of normal antidiuresis. AVP is released in free form (does not bind to neurophysin at blood pH), and is degraded in the brain, liver, and kidney. AVP is also transported directly to the anterior pituitary, where is stimulates ACTH secretion.
AVP has antidiuretic activity by binding V2 receptors in kidney, stimulating cAMP production by adenyl cyclase, which leads to synthesis & insertion of aquaporin-2 water channels in cells of the collecting tubules, allowing water reabsorption in the hypertonic medulla. Water exits basolaterally via constitutively expressed aquaporins 3 and 4. Absence of AVP leads to excretion of large volumes of dilute urine.
Other effects of AVP: acts at a pressor agent at supraphysiologic levels (as in severe hypovolemia) by binding V1a receptors on blood vessels, which increase intracellular calcium and cause smooth muscle contraction. V1a receptors are found on vascular smooth muscle, liver, brain, renal medulla, testes, and platelets. AVP stimulates hepatic glycogenolysis via the V1a receptor. A new V3 (V1b) receptor has been cloned; like the V1a receptor, it acts via phospholipase C. It is found in the anterior pituitary, kidney, and in corticotropic pituitary tumors.
Regulation of AVP release: Integration of AVP secretion and thirst maintains plasma osmolality tightly at 280-290 mOsm/kg.
  1. Plasma osmolality: Anterior hypothalamic osmoreceptors (anterior to the 3rd ventricle) are very sensitive to changes in Posm (respond to change as low as 1%), and suppress AVP release when Posm < 280 mOsm/kg. Posm values less than those necessary to turn off AVP will not result in any increase in water excretion (18-20 L/d maximum), unless intake is extreme. As Posm increases, there is a linear increase in [AVP]. When Posm exceeds 292-5 mOsm/kg, plasma AVP reaches levels (~ 6 pg/mL) sufficient for maximum antidiuresis (Uosm > 800 mOsm/kg, Uvol < 2 L/d), with no further decrease in urine volume with higher Posm. Thirst is stimulated at 290 mOsm/kg.
  2. Plasma volume: Baroreceptors (stimulated by hypervolemia, inhibited by hypovolemia) inhibit AVP release via cranial nerves IX, X. The atrial cardiopulmonary low-pressure baroreceptors are less sensitive than osmoreceptors, requiring a 5-10% decrease in blood volume before AVP is released. Severe hypovolemia, however, triggers the sino-aortic high-pressure baroreceptors to cause exponential increases in AVP, which may be high enough to exert a pressor effect.
  3. Interaction of osmo- and baroreceptors: A decrease in left atrial pressure (as in hypovolemia, hypotension) leads to a reduction of the osmotic threshold and increases the sensitivity for osmotic AVP release. Volume expansion dampens the sensitivity for osmotic AVP release.
  4. Nausea is a very potent and rapid stimulus for AVP release, even up to 100-1000 times basal level. May be responsible for increases in AVP seen with chemotherapy, DKA, vasovagal reactions, motion sickness, hypoxia. Pain and emotional stress may also stimulate AVP release, as can IV metoclopramide. Hypoglycemia may also stimulate AVP release, which then stimulates glycogenolysis.
Thirst regulation: osmoreceptors located nearby (not the same) initiate thirst at a higher Posm than the threshold for AVP release. Hypovolemia also triggers thirst even if Posm is normal.

SIADH

Definition: AVP excess associated with hyponatremia without edema or hypovolemia. The AVP excess is inappropriate in the face of hypoosmolality.
Ectopic secretion of AVP has been documented from neoplasms and pulmonary tissue. Intracranial lesions likely stimulate AVP release from the neurohypophysis, as do some drugs (e.g. chlorpropamide, vincristine, carbamazepine). Other medications (e.g. chlorpropamide, NSAIDS) potentiate the antidiuretic action of secreted AVP. Hypothalamic SIADH likely involves the baro (volume) receptor system, with a lesion of this system in the chest or CNS resulting in decreased tonic inhibition of magnocellular neuron AVP release.
Excess AVP secretion or action results in concentrated urine (Uosm > 300 mOsm/kg), low Sosm (Uosm > Sosm), low serum sodium. Urine sodium is usually above 20 mmol/L due to volume expansion inhibiting proximal tubule sodium reabsorption, increased GFR, suppression of the renin-angiotensin-aldosterone system, and increased production of atrial natriuretic peptide. This naturiesis tends to normalize extracellular fluid volume. Urine sodium may be below 20 mmol/L if sodium intake is low. Blood urea nitrogen (< 10 mg/dL) and uric acid (< 4 mg/dL) concentrations are low due to plasma dilution and increase in excretion of nitrogenous compounds. Clinically significant edema is not present. Extracellular hypotonicity leads to intracellular edema, and severe symptoms may result from cerebral edema. Intracellular fluid volume is reduced after 48 hours by extrusion of osmoles (potassium, creatinine, glutamate, glutamine, taurine, myoinositol, glycerophosphorylcholine).
Clinical manifestations are those of water intoxication and depend on rate more than magnitude of development of hyponatremia. In acute hyponatremia, with serum sodium < 120 mmol/L, cerebral edema may result in headache, nausea, restlessness, irritability, muscle cramps, hyporeflexia, confusion, coma, seizures, permanent brain damage, brain-stem herniation, or death. In chronic hyponatremia half the patients are asymptomatic, even with sodium < 125 mmol/L. When sodium reaches 115-120 mmol/L, the common symptoms are anorexia, nausea, vomiting, headaches, abdominal cramps. In chronic hyponatremia there is a smaller increase in brain water for a given reduction in serum sodium. Even in asymptomatic individuals, sodium < 120 mmol/L should be treated because rapid clinical deterioration may occur.
SIADH-induced volume expansion & hypotonicity, via ill-defined mechanisms, act on collecting duct cells to decrease the content & action of aquaporins. This renal "escape" decreases the amount of water resorbed. This has implications for therapy, since this effect is reversed with water restriction, which may be why prolonged or severe water restriction is sometimes needed to successfully treat SIADH.
Isolated second phase: If only some vasopressinergic axons are damaged at surgery, there may be enough remaining neurons to avoid the 1st and 3rd phases of DI. Yet, the damaged axon termainals become necrotic and leak AVP 5-10 days after surgery. This lasts a few days and may be more severe if ACTH/cortisol deficiency is present (impaired free water excretion).

CAUSES of SIADH BY PROBABLE MAJOR MECHANISM OF ACTION

Increased hypothalmic production of ADH

A. Neuropsychiatric disorders*

    1. Infections: meningitis (tuberculous or bacterial), encephalitis, abscess, Herpes zoster
    2. Vascular: thrombosis, subarachnoid or subdural hemorrhage, temporal arteritis, cavernous sinus thrombosis, cerebrovascular accident
    3. Neoplasm: primary or metastatic
    4. Skull fracture, head injury
    5. Psychosis, delirium tremens
    6. Other: Guillain-Barré syndrome, acute intermittent porphyria, autonomic neuropathy, hypothalamic sarcoidosis, postpituitary surgery, multiple sclerosis, epilepsy, hydrocephalus, lupus erythematosus, Shy-Drager syndrome, peripheral neuropathy, spinal cord lesions

B. Drugs

    1. Intravenous cyclophosphamide* (increased sensitivity may also contribute)
    2. Carbamazepine (though increased sensitivity is probably important). Hyponatremia is more common with oxcarbazepine.
    3. Vincristine or vinblastine
    4. Thiothixene
    5. Thioridazine, other phenothiazines
    6. Haloperidol
    7. Amitriptyline, other tricyclic antidepressants or serotonin-reuptake inhibitors
    8. Monoamine oxidase inhibitors
    9. Bromocriptine
    10. Lorcainide
    11. Clofibrate
    12. General anesthesia
    13. Narcotics, opiate derivatives
    14. Nicotine

C. Pulmonary disease

    1. Pneumonia*: viral, bacterial, fungal
    2. Tuberculosis
    3. Lung abscess, empyema
    4. Acute respiratory failure
    5. Positive pressure ventilation (via inhibition of low-pressure cardiopulmonary baroreceptors)
    6. Other: asthma, COPD, atelactasis, pneumothorax, cystic fibrosis

D. Postoperative patient*

E. Severe nausea

F. Pain

G. Infection with HIV

H. Idiopathic

 

 

Ectopic (nonhypothalamic) production of ADH

  1. Carcinoma: Small cell carcinoma of lung* (2/3 of patients with small cell have impaired water excretion), bronchogenic, duodenum, pancreas, thymus, olfactory neuroblastoma, bladder, prostate, uterus
  2. Lymphosarcoma, reticulum cell sarcoma, mesothelioma, Ewing sarcoma
  3. Hodgkin's disease, leukemia
  4. Pulmonary tuberculosis (?)

Potentiation of ADH effect

  1. Chlorpropamide*
  2. Carbamazepine
  3. Psychosis
  4. Intravenous cyclophosphamide
  5. Tolbutamide
  6. Prostaglandin-synthesis inhibitors (salicylates, NSAIDS)

Exogenous administration of ADH

  1. Vasopressin, desmopressin
  2. Oxytocin

Possible production of another antidiuretic compound (or increased sensitivity to very low levels of ADH)

  1. Prolactinoma
  2. Waldenstrom's macroglobulinemia

*Most common causes

 

DIAGNOSIS

Suspect SIADH in patients with concentrated urine (Uosm > 300 mOsm/kg) and hyponatremia in the absence of edema, orthostatic hypotension, or features of dehydration. Must rule out other causes of hyponatremia, particularly those causing euvolemic hyponatremia: cortisol deficiency, hypothyroidism, reset osmostat. Cardiac, renal, and hepatic function should be normal.
May be difficult to distinguish SIADH from salt wasting renal diseases (in both urine sodium > 20 mmol/L and FeNa > 1%). Fluid restriction to 600-800 mL/d for 2-3 days will result in weight loss and correction of hyponatremia and salt wasting in SIADH. Fluid restriction fails to correct hyponatremia and sodium wasting in salt-losing renal disease. A controversial disease entity, cerebral salt wasting syndrome, thought to result from a factor secreted in cerebral disease which causes proximal tubule sodium wasting, is very similar to SIADH (both have increased Uosm, urine sodium > 20 mmol/L, hyponatremia, Uosm > Sosm, low serum urate, increased FEurate, and in both hyponatremia corrects with fluid restriction). Patients with SIADH are euvolemic while those with CSWS are hypovolemic, but this determination is problematic. The only way to distinguish may be that with fluid restriction, serum urate and FEurate correct in SIADH but fail to correct in CSWS.
Water load test: Useful to differentiate low-set osmoreceptor (excrete water normally) from other conditions with hyponatremia and concentrated urine. Must first bring serum sodium > 125 mmol/L (by water restriction or saline administration). Water load (20 mL/kg up to 1,500 mL) is taken orally (in 10-20 min) and urine is collected hourly, with patient recumbent, for 4-5 hours in the morning. At least 65% of the water load should be excreted in 4 hr, or 80% in 5 hr, and the lowest Uosm, usually reached in the second hour, should be < 100 mmol/kg. Patients who fail to excrete the water normally should not take any further water that day (to prevent water intoxication). Failure to excrete the water load may occur in adrenal insufficiency or renal insufficiency, as well as in SIADH.

TREATMENT
Patients with acute hyponatremia suffering from severe confusion, convulsions, or coma, should undergo fluid restriction plus administration of hypertonic (3%) saline (300-500 mL IV over 4-6 hr). The possibility of causing CHF is remote as long as fluid is restricted but may be further reduced by simultaneous administration of furosemide (which causes excretion of hypotonic fluid equivalent to 1/2NS). The goal sodium level should be 125 mmol/L. Sodium requirement = (125 – measured Na) x 0.6 x weight in kg.
If the hyponatremia is chronic (> 48 hr), the rate of correction should not exceed 8-12 mmol/L/day to avoid cerebral demyelination syndrome (demyelination of pontine and extrapontine neurons leading to quadriplegia, pseudobulbar palsy, seizures, coma, or death). Hepatic failure, alcoholism, potassium depletion, and malnutrition increase the risk of this complication. In general, 10 µL/kg/min of 3% saline results in an increase in SNa of ~0.5 meq/hr. In symptomatic patients, initial correction can be 1-2 mmol/L/hr as long as the total daily correction is less than 8-12 mmol/L. Even seizures are stopped by an average increase of only 3-7 mmol/L. The brain can only enlarge by ~10%; an initial rapid correction of 5-10% of measured sodium may be desirable to decrease cerebral edema. If the rate of correction is excessive, hypotonic solution or DDAVP can be given.
The underlying cause should be identified and treated, if possible, to cause resolution of the SIADH.
The treatment of choice is fluid restriction to <800 to 1,000 mL daily. Since this intake is almost always exceeded by urine output and insensible losses, a negative water balance ensues that results in gradual reduction in weight, rise in serum sodium and osmolality, and symptomatic improvement. Unless the underlying cause of SIADH can be corrected, fluid restriction should continue indefinitely, to maintain normonatremia. Total serum sodium may be depleted due to naturiesis, thus sodium may need to be given.
Loop, but not thiazide, diuretics reduce urine concentration and augment excretion of electolyte-free water, permitting relaxation of fluid restriction. In SIADH, loop diuretics combined with plentiful sodium intake (dietary or salt tablets) augments water loss. Note isotonic saline is unsuitable in SIADH; the resulting sodium rise is small and transient, with the infused salt being excreted in concentrated urine and thereby causing a net retention of water and worsening of hyponatremia. However, a careful trial of NS while following SNa and Uosm may be diagnostically useful, especially if volume status is uncertain: If Uosm drops and SNa increases, dehydration is diagnosed. If UNa increases and SNa stays the same or drops, SIADH is confirmed.
If water restriction is ineffective, demeclocycline can be given to inhibit AVP action on the renal tubule (induces nephrogenic DI by interfering with AVP-induced activation of the adenylate cyclase-cAMP system in the distal tubule and collecting ducts). Doses range from 600 to 1,200 mg/d in divided doses, onset of action in 5-14 days. Patients should be followed closely for renal failure (especially if there is hepatic failure or CHF), photosensitivity, bacterial superinfection, excessive drug-induced water loss and hypernatremia.
In development are agents which antagonize the effect of ADH on the V2 receptor.
Prognosis of SIADH depends on the cause. If caused by drugs or infections, withdrawal of the drug and treatment of the infection usually cures the SIADH. If due to malignancy, the SIADH is often incurable but can be controlled with vigorous water restriction.

Appendix: Hyponatremia

Determine osmolality. If normal (280-285 mOsm/kg), consider pseudohyponatremia (hyperlipidemia, hyperproteinemia; very rare given ion-specific electrodes) or isotonic infusions (e.g. mannitol). If hypertonic (> 285 mOsm/kg), consider hyperglycemia (Na depressed by 1.6 for every 100 mg/dl increase in glucose over 100 mg/dl) or hypertonic infusions (mannitol).
In hypoosmolar states (< 280 mOsm/kg) there is a water excretion defect (excess water input problem also possible but very rare and intake must exceed 7 L/d). Patients are either hypovolemic (accompanying sodium loss, which exceeds water loss), euvolemic, or hypervolemic (accompanying sodium retention, exceeded by water retention). Almost all (up to 95% of all hospitalized hyponatremic patients have elevated AVP levels) of these patients (except those with renal failure) have elevated ADH despite hypotonicity involved in water excretion problem; question is whether or not it is appropriate. Thus, measuring Uosm (or comparing it to Posm) is rarely diagnostically useful in this setting.

Evaluation of hypotonic hyponatremia:

ECF Volume

Urine Sodium

Diagnosis

Treatment

Predicted Response

Low: evidence of dehydration

< 20 meq/L

Total body sodium depleted with normal renal response

Replace with normal saline

Urine will become dilute and SNa increases
 

> 25 meq/L

Renal loss of sodium; renal disease; diuretics; Addison's disease

Replace with normal saline

Total 24-hr urine sodium remains high but becomes dilute and SNa increases

Normal or expanded

< 20 meq/L

Hyperaldosteronism due to inadequate circulating volume

Restrict water or give diuretic; treat underlying disease

Reduced edema and increased sodium; care with volume depletion
 

> 40 meq/L

SIADH with sodium loss due to volume expansion

Restrict water. Hypertonic saline? Demeclocycline?

Uosm increases further as urine volume falls, total urinary sodium falls, but SNa increases

Causes of hypotonic hyponatremia:

Low volume

Normal volume

Edematous

Renal: FeNa normal

Extrarenal: FeNa < 1%
Thiazide diureticsF
Cirrhosis
Renal failure
Salt wasting nephropathy
Cerebral salt wasting
Adrenal insufficiency
Diuretics
Osmotic diuresis (glucose, urea, mannitol)
Bicarbonaturia (RTA, disequilibrium stage of vomiting)
Ketonuria
GI losses (vomiting, diarrhea)
Third spacing (burns, bowel obstruction, muscle trauma, pancreatitis, peritonitis)
Blood loss
Excessive sweating (e.g. marathon runner)
SIADH (especially drugs, postoperative state)
Hypothyroidism
Isolated glucocorticoid deficiency
Reset osmostat
Decreased intake of solutes (beer potomania, tea-and-toast diet)
Psychogenic polydipsia
Congestive heart failure
Nephrotic syndrome
Renal failure (chronic or acute)
Pregnancy

REFERENCES (v1.2.6)

  1. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581-9.
  2. Maesaka JK, Gupta S, Fishbane S. Cerebral salt-wasting syndrome: does it exist? Nephron 1999;82:100-9.
  3. Miller M. Inappropriate antidiuretic hormone secretion. Curr Ther Endocrinol Metab 1994:5;206-9.
  4. Moses AM, Streeten DHP. Syndrome of inappropriate AVP secretion. In: Fauci A, et al., ed. Harrison's Principles of Internal Medicine. New York: McGraw-Hill Companies, Inc., 1998:2009-11.
  5. Oh MS, Carroll HJ. Cerebral salt-wasting syndrome. Nephron 1999;82:110-4.
  6. Robinson AG. Disorders of antidiuretic hormone secretion. Clin Endocrinol Metabol 1985;14:55-88.
  7. Zafonte RD, Mann NR. Cerebral salt wasting syndrome in brain injury patients: a potential cause of hyponatremia. Arch Phys Med Rehabil 1997;78:540-2.
Excessive water intake (primary polydipsia, dilute infant formula, sodium-free irrigant solutions [hysteroscopy, laparoscopy, transurethral prostatectomy], accidental intake of a large amount of water (e.g. swimming), multiple tap-water enemas) tend to cause hypotonic hyponatremia, unless the irrigant solution is isotonic (5% mannitol) instead of hypotonic (1.5% glycine or 3.3% sorbitol).
The most common causes of severe hyponatremia in adults are thiazides, postoperative hyponatremia and other causes of SIADH, psychogenic polydipsia, and transurethral prostatectomy.
Patients with hyponatremia induced by thiazides may be hypovolemic or euvolemic, depending on the magnitude of the sodium and potassium loss, stimulation of thirst, impaired urinary dilution, and water retention.
Hypotonic hyponatremia can be associated with normal or even high serum osmolality if sufficient amounts of solutes that can permeate cell membranes (ineffective osmoles such as urea, ethanol) have been retained (e.g. renal failure). Such patients are still subject to the risks of hypotonicity.
Psychiatric patients with excessive water intake often have plasma ADH levels which are not fully suppressed and urine that is not maximally dilute, thus contributing to water retention.
 

 

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