Basics
Description
Inappropriate secretion of antidiuretic hormone (ADH) or ADH-like peptide in the presence of low serum sodium, low serum osmolality, and high urine osmolality and in the absence of renal, adrenal, or thyroid pathology
Epidemiology
Incidence
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can occur at any age. Its incidence depends on the various possible etiologies.
Risk Factors
Genetics
Genetic causes of SIADH are exceedingly rare. However, rare cases have been described with gain-of-function mutations in the vasopressin-2 receptor contributing to SIADH and undetectable serum ADH levels.
Pathophysiology
- ADH is synthesized within the neurons of the hypothalamus, transported in conjunction with neurophysin down the supraopticohypophyseal tract, and stored in the posterior pituitary.
- ADH acts on the renal collecting ducts.
- Interaction of ADH with its receptors forms intracellular cyclic AMP (cAMP), which increases water permeability through insertion of aquaporins (water channels) in renal collecting ducts and consequently enhances reabsorption of free water.
- SIADH results when elevated concentrations of ADH or ADH-like peptides cause free water retention and hypervolemia, leading to hyponatremia. Three possible mechanisms include
- Increased hypothalamic production of ADH (e.g., CNS disorders such as stroke or meningitis)
- Independent production of ADH or ADH-like substances from ectopic sources (e.g., lung oat cell carcinoma or olfactory neuroblastoma)
- Decreased venous return that stimulates atrial volume receptors and thereby leads to ADH release (e.g., heart failure, cirrhosis, pulmonary and intrathoracic diseases, such as tuberculosis).
Etiology
- Idiopathic
- CNS pathology, causing increased secretion of ADH or ADH-like peptides: meningitis, head trauma, neurosurgical procedures, encephalitis, brain tumor, brain abscess, hydrocephalus, hypoxia, subarachnoid hemorrhage, cerebral venous thrombosis
- Ectopic production of ADH or ADH-like peptides: oat cell carcinoma of the lung, bronchogenic carcinoma, olfactory neuroblastoma, and pancreatic carcinoma
- Pulmonary disease (leading to secondary elevation in ADH secretion or ADH-like peptides): tuberculosis, viral or bacterial pneumonia, asthma, cystic fibrosis, pneumothorax, positive pressure ventilation
- Drugs (which mimic ADH or stimulate its release): vincristine, cyclophosphamide, carbamazepine, chlorpropamide, phenothiazines, clofibrate, nicotine, SSRIs
- Iatrogenic exogenous administration of ADH: vasopressin infusion for treatment of diabetes insipidus, excess desmopressin (DDAVP) in conjunction with fluid intake
- Severe, prolonged nausea
- Postoperative patient (e.g., as part of triple-phase response after hypothalamic-pituitary surgery, after transsphenoidal pituitary surgery)
- Rocky Mountain spotted fever
Diagnosis
History
- Unusual water intake (suspicious for psychogenic polydipsia)
- Review of intake and output for inpatients
- Decreased urine output
- Anorexia, lethargy
- Weight gain or weight loss
- Renal disease
- Vomiting
- Diarrhea
- Use of diuretics
- Burns
- Heart disease
- Liver disease
- Brain injury: trauma, surgery, hypoxia, toxin
Physical Exam
- A complete neurologic and physical exam must be performed. Classically, patients with SIADH manifest subtle signs of hypervolemia but without increased urine output.
- With or without edema
- No signs of dehydration
- Signs of fluid overload
- Absent hyperpigmentation of skin creases/gums (presence suggests Addison disease)
- Hyponatremia; may cause lethargy or irritability and muscle cramps. In severe cases, patients may lose deep tendon reflexes, seize, or be comatose.
Alert
- Pitfall: Failure to distinguish SIADH from other causes of hyponatremia such as adrenal insufficiency, hypothyroidism, or cerebral salt wasting (CSW) can result in erroneous medical management and lead to worsening hyponatremia.
- Patients with SIADH are still capable of producing urine; basing the diagnosis on urine volume alone can be misleading.
Diagnostic Tests & Interpretation
Lab
- Specific tests
- Simultaneous urinary osmolality, serum osmolality, and serum sodium (order a basic metabolic panel)
- Urine sodium: usually >30 mmol/L (but not usually >100 mmol/L)
- Serum uric acid: sometimes low in SIADH
- Presence of hyponatremia (serum sodium <130 mEq/L), decreased serum osmolality (<260 mOsm/kg), with an inappropriately elevated urinary osmolality (>260 mOsm/L)
- Plasma ADH concentration: diagnostic but not helpful for rapid diagnosis
- Nonspecific tests
- Fractional renal excretion of sodium: Net sodium loss is normal or elevated and depends on sodium intake.
- Urinary specific gravity: helpful but not as specific as urine osmolality
- Blood glucose: Hyperglycemia results in hypertonic hypernatremia (benign).
- Triglycerides: Hyperlipidemia causes hypertonic hypernatremia (benign).
Imaging
Head MRI with special cuts of the pituitary and hypothalamus if concern of CNS etiology.
Differential Diagnosis
- Hypovolemic hyponatremia (e.g., hyponatremic dehydration, seen after running a marathon)
- Euvolemic hyponatremia (e.g., hypothyroidism, adrenal insufficiency)
- Hypervolemic hyponatremia (e.g., CHF, cirrhosis, nephrotic syndrome)
- Diuretics
- Total body sodium loss through vomiting, nasogastric suction, diarrhea, or increased intestinal secretions
- Renal failure
- Severe potassium depletion
- Water intoxication
- CSW: excess production or effects of atrial and/or brain natriuretic peptide hormones
- Reset hypothalamic osmostat
- Rocky Mountain spotted fever
- Hypertonic hyponatremia (sometimes called "pseudohyponatremia, " although blood sodium is low with normal total body sodium stores) with hyperglycemia (diabetic ketoacidosis), severe hyperlipidemia, or after administration of mannitol
Treatment
Medication
- For emergency use only: hypertonic saline (1.5 " 3% NaCl)
- Diuretics should be avoided because they worsen hyponatremia.
- ADH antagonists, such as tolvaptan, have been shown to be effective for treatment of SIADH in research trials for adults.
- Demeclocycline (for chronic SIADH)
- Oral urea (for chronic SIADH)
Additional Treatment
General Measures
- The most important aspects of therapy for SIADH are diagnosis and treatment of the underlying cause.
- If hyponatremic and Na > 120 mEq/L and no neurologic signs, first step in management is fluid restriction.
- Hyponatremia may result in seizure, which requires immediate treatment with 3% hypertonic saline until the seizure activity stabilizes. Despite the urgent need for correction of hyponatremia to address the severe neurologic symptoms, the rate of sodium correction should not exceed 12 mEq/L in 24 hours.
Inpatient Considerations
Admission Criteria
Patients with severe hyponatremia and/or neurologic manifestations will need to be admitted for correction of hyponatremia under close medical supervision.
IV Fluids
- Fluid restriction is essential to treat and prevent worsening hyponatremia. Thus, IV fluids, in general, are not recommended for patients with SIADH. If IV fluids are clinically necessary, a rate comparable to insensible losses (1/3 daily maintenance) is recommended with close attention to serum sodium levels.
- The hyponatremia in SIADH is due to free water retention and not due to decreased total body sodium content. For this reason, changing IV fluids from hypotonic solutions to hypertonic (normal saline) without restriction of the IV fluid rate will still result in worsening hyponatremia.
Discharge Criteria
- Depends on the primary etiology causing SIADH
- Generally, when the serum sodium is stabilized and the patient is neurologically stable
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- When to expect improvement: usually during the first 48 " 72 hours
- Signs to watch for: changes in neurologic status
Diet
Fluid restriction is the most important aspect in the treatment of SIADH. Generally, only fluids for insensible losses (1/3 daily maintenance) are recommended.
Prognosis
Based on the primary cause
Complications
- Severe hyponatremia can cause seizures and, rarely, brain damage. Correcting hyponatremia too quickly can lead to central pontine myelinolysis (CPM), a devastating demyelinating disease that impairs vital functions such as breathing.
- Susceptibility to CPM due to correction of hyponatremia is strongly influenced by the severity and preexisting duration of hyponatremia in the patient.
- Serum sodium should not be increased >12 mEq/L in 24 hours.
Additional Reading
- Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356(20):2064 " 2072. [View Abstract]
- Feldman BJ, Rosenthal SM, Vargas GA, et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med. 2005;352(18):1884 " 1890. [View Abstract]
- Fenske W, Allolio B. The syndrome of inappropriate secretion of antidiuretic hormone: diagnostic and therapeutic advances. Horm Metab Res. 2010;42(10):691 " 702. [View Abstract]
- Palmer BF. Hyponatremia in patients with central nervous system disease: SIADH versus CSW. Trends Endocrinol Metab. 2003;14(4):182 " 187. [View Abstract]
- Rivkees SA. Differentiating appropriate antidiuretic hormone secretion, inappropriate antidiuretic hormone secretion and cerebral salt wasting: the common, uncommon, and misnamed. Curr Opin Pediatr. 2008;20(4):448 " 452. [View Abstract]
Codes
ICD09
- 253.6 Other disorders of neurohypophysis
ICD10
- E22.2 Syndrome of inappropriate secretion of antidiuretic hormone
SNOMED
- 55004003 Syndrome of inappropriate vasopressin secretion (disorder)
FAQ
- Q: Is the use of diuretics beneficial in treating SIADH?
- A: No. Although diuretics may relieve the effects of volume overload, they can also worsen hyponatremia. Overall, diuretics usually cause more detriment than benefit.
- Q: What distinguishes SIADH from CSW?
- A: CSW occurs because of increased natriuresis from increased plasma and CSF levels of atrial natriuretic peptide (ANP) after neurologic insults (e.g., subarachnoid hemorrhage). Owing to the natriuresis, these patients become dehydrated with notable decreased plasma volume and elevated BUN. In contrast, patients with SIADH have free water overload, causing hyponatremia. CSW is associated with high urine output, in contrast to SIADH, which has low urine output. However, patients with SIADH who are treated with excess solute (3% saline) may exhibit a natural natriuresis and high urine output. Thus, polyuria alone should never be used to distinguish between CSW and SIADH. Net sodium loss is very high in CSW (>100 mmol/L), but SIADH has normal to slightly elevated net sodium loss; thus, urinary sodium levels are often not specific in distinguishing CSW from SIADH. Laboratory features of CSW include suppressed plasma aldosterone and often normal serum uric acid concentration. Note that plasma ADH concentration is high in SIADH and initially in CSW as well. However, in CSW, after the intravascular volume has been restored, ADH will decrease again, and patients may not exhibit elevated urine osmolality. In these patients, persistent hyponatremia with elevated urine osmolality is more suggestive of SIADH, which is far more common than CSW.
- Q: Why is it important to distinguish SIADH from CSW?
- A: Therapies differ dramatically for these conditions. Unlike the water restriction used to treat SIADH, treatment of dehydration in CSW requires replacement of ongoing salt and water losses. However, CSW is much less common than SIADH and appropriate diagnosis of each condition is necessary to avoid worsening of the hyponatremia by the treatment regimen.