SIADH: Syndrome of Inappropriate Antidiuretic Hormone Secretion

SIADH In Short

SIADH is the abbreviation for Syndrome of Inappropriate Antidiuretic Hormone secretion. The antidiuretic hormone (ADH) is secreted by the pituitary gland but also by some tumors. ADH controls water excretion in the kidneys (diuresis).

When too much ADH is secreted (due to various brain or lung disorders, or cancers) or when ADH has the excessive effect (due to certain medications), the kidneys will retain too much water. This in turn will result in a drop of blood sodium levels (hyponatremia) with symptoms like dizziness, headache, nausea, weakness or seizures.

SIADH Definition

SIADH is defined as hyponatremia and hypo-osmolality due to an inappropriate [increased] secretion of the ADH despite normal plasma volume, which results in water retention ^[1].

Pathophysiology

The antidiuretic hormone (ADH) is secreted by the neurohypophysis (the posterior part of the pituitary gland); its main effect is the inhibition of water excretion in the kidneys (diuresis).

The physiological stimulus for the secretion of the antidiuretic hormone (ADH) is either a decrease of blood volume (hypovolemia) or an increase of the blood osmolality. The secretion of the ADH in the absence of hypovolemia or increased osmolality is referred as “inappropriate.” The main consequence of the increased ADH secretion is water retention without sodium retention, which results in dilutional hyponatremia. Water retention tends to increase blood volume, which triggers the release of the natriuretic peptide, which stimulates the excretion of sodium ^[1].

NOTE: Hyponatremia in SIADH is not caused by sodium loss but by water retention, so it can be treated by water restriction ^[1].

Causes of SIADH

• Lung diseases and conditions: mycoplasma pneumonia, Legionnaires’ disease, tuberculosis, abscess, aspergillosis, asthma, chronic obstructive pulmonary disease (COPD), pneumothorax, pulmonary hypertension, pulmonary embolism, empyema, pulmonary fibrosis, cystic fibrosis, use of positive-pressure mechanical ventilation
• Brain disorders: brain tumor, abscess, cyst, subarachnoid hemorrhage, stroke, encephalitis, meningitis, multiple sclerosis, cerebral sarcoidosis, acute intermittent porphyria, hydrocephalus (in infants), other causes of increased intracranial pressure, psychosis (schizophrenia in combination with antipsychotics), senile atrophy
  • Other brain-related causes: stress, pain, nausea
  • Other neurological disorders: spinal injury or lesion, Guillain-Barre syndrome (acute polyneuropathy), autonomic polyneuropathy, Herpes zoster virus in the chest wall
• Cancer: lung cancer (small-cell or oat cell carcinoma), cancer of the pleura (mesothelioma), pancreatic, duodenal, pharyngeal, laryngeal, ovarian, prostatic, colonic cancer, cancer of the thymus and other cancers, neurofibroma, leukemia, lymphoma, paraneoplastic syndrome.
• Surgery due to anesthetics, pain, intravenous infusion of hypotonic or even isotonic fluids
• Drugs:
  • Anesthetics (general): barbiturates (phenobarbital, thiopental), halothane, nitrous oxide
  • Antibiotics: ciprofloxacin
  • Antidepressants: SSRIs (fluoxetine, paroxetine), tricyclics (amitriptyline), MAO inhibitors (phenelzine)
  • Antidiabetics (oral): chlorpropamide, metformin, tolbutamide 
  • Antiepileptics: carbamazepine, sodium valproate
  • Antifungals: griseofulvin
  • Antiparkinsonics: bromocriptine
  • Antipsychotics: haloperidol, phenothiazines (chlorpromazine)
  • Chemotherapeutics: cisplatin, cyclophosphamide, ifosfamide, methotrexate, vinblastine, vincristine
  • Cholesterol-lowering drugs: clofibrate
  • Heart drugs: antiarrhythmics (amiodarone, lorcainide), ACE inhibitors (lisinopril, losartan); beta-agonists (isoproterenol, theophylline)
  • Hormones: acetylcholine, desmopressin or DDAVP (to treat diabetes insipidus, nocturia in adults or enuresis in children), oxytocin in large doses (to induce labor), triiodothyronine, vasopressin
  • Non-steroid anti-inflammatory drugs (NSAIDs): ibuprofen, naproxen, indomethacin
  • Opiates and opioids: morphine, tramadol ^[4]
  • Proton pump inhibitors (omeprazole)
  • Other drugs: interferon-alfa and -gamma, nicotine (cigarette smoking)
  • Drugs that stimulate thirst and drinking, which may lead to hyponatremia: amitriptyline, amphetamine, ecstasy (MDMA), fluoxetine, fluphenazine, haloperidol, sertraline, thiothixene
• Other causes: HIV/AIDS, temporal (giant cell) arteritis, sepsis, iatrogenic, idiopathic and hereditary SIADH.
  
• References: ^[1,2,3,4,5]

Symptoms and Signs

Symptoms of SIADH are due to hyponatremia (water intoxication) and include a headache, nausea, vomiting, muscle weakness, irritability, thirst in the absence of dehydration and, in severe cases, confusion or seizures ^[1].

SIADH may present practically without any signs: there is typically no dehydration (normal skin turgor) or hypervolemia (no edema) and the blood pressure is normal. There may be signs from the underlying conditions, though, for example numbness or paralysis of the limb because of a brain disorder.

Workup, Lab Values

Bartter-Schwartz Criteria for Diagnosis of SIADH

• Hyponatremia with hypoosmolality
• Continued excretion of sodium with the urine
• Urine is not maximally dilute
• No signs of hypovolemia
• No other causes of hyponatremia
• Water restriction improves hyponatremia
• Reference: ^[1]

Blood Tests:

• Sodium (S-Na): <135 mmol/L
• Potassium: usually normal or mildly decreased (slight hypokalemia)
• Osmolality: <275 mOsm/kg
• ADH: increased
• Mildly decreased or normal plasma concentrations of creatinine, urea and uric acid
• Other tests: thyroid stimulating hormone – TSH (increased in hypothyroidism), cortisol (decreased in adrenal insufficiency)
• Reference: ^[1]

Urine Tests:

• Sodium: in regular sodium consumption usually >20 mmol/L; in a low-sodium diet may be lower than 20 mmol/L.
• Osmolality: >100 mOsm/kg, usually >280 mOsm/kg
• Blood urea nitrogen (BUN): low: <10 mg/dL
• Uric acid: decreased
• Reference: ^[1]

Imaging:

The following investigations can help find the cause of SIADH:

• Chest X-ray or bronchoscopy to check for lung diseases
• CT or MRI of the head to check for brain disorders
• Blood tests for tumor markers
• Tests to exclude heart, liver, adrenal and thyroid disease
• Reference: ^[1]

Differential Diagnosis

Before making a diagnosis of SIADH, one has to rule out other conditions with hyponatremia and euvolemia (or conditions without obvious dehydration or edema):

• Cerebral salt-wasting syndrome (CSWS)
• Hypothyroidism
• Adrenal insufficiency
• Hypopituitarism
• Hyperglycemia
• Psychogenic polydipsia
• Pseudohyponatremia due to hyperlipidemia or hyperproteinemia
• Waldenstrom’s hypergammaglobulinemia
• Other causes of hyponatremia
• References: ^[1,3]

Treatment

Treatment of SIADH may include water restriction (500-1,500 mL/day or lower), hypertonic saline (3% NaCl), isotonic saline (0.9% NaCl) in combination with loop diuretics, such as furosemide (but never isotonic saline alone) and, in chronic or unresponsive cases, AVP antagonists (aquaretics), such as tolvaptan or demeclocycline. Details of treatment are described in the article about hyponatremia.

SIADH vs Diabetes Insipidus

In both SIADH and diabetes insipidus the antidiuretic hormone (ADH) is involved.

• In SIADH, there is increased ADH secretion, which results in water retention (decreased urine output) and drop of blood sodium levels (hyponatremia).
• In diabetes insipidus, there is decreased ADH secretion or decreased effect f ADH on the kidneys, which results in increased diuresis (increased urine output) and increased blood sodium levels (in the case of insufficient drinking).

• References

  1. Thomas CP, Syndrome of Inappropriate Antidiuretic Hormone Secretion, Overview Emedicine
  2. Syndrome Of Inappropriate Antidiuretic Hormone Secretion  Drugs.com
  3. Pillai BP et al, 2011, Syndrome of inappropriate antidiuretic hormone secretion: Revisiting a classical endocrine disorder  PubMedCentral
  4. O’Donoghue D et al, 2009, SIADH and hyponatraemia: foreword  PubMed Central
  5. Simon EE, Hyponatremia Clinical Presentation Emedicine