SIADH

Question 1

definition

Answer 1

The syndrome of inappropriate antidiuretic hormone (SIADH) is characterised by hypotonic hyponatraemia, concentrated urine, and a euvolaemic state. The impairment of free water excretion is caused by increased arginine vasopressin (antidiuretic hormone or AVP) release. Pseudohyponatraemia due to hyperglycaemia, hyperlipidaemia, or hyperproteinaemia should be ruled out first. Renal failure, adrenal insufficiency, and appropriate release of AVP secondary to extracellular volume depletion (hypovolaemia, due to gastrointestinal or renal loss) or intravascular volume depletion (hypervolaemia due to congestive heart failure, cirrhosis of the liver, or nephrotic syndrome) must be ruled out in order to diagnose SIADH.

Question 2

aetiology

Answer 2

Possible aetiologies for SIADH include increased arginine vasopressin (AVP) release or responsiveness. These may be due to the following:

Drugs: multiple drugs have been linked to increased AVP release or enhanced potential of AVP, including SSRIs, amiodarone, carbamazepine, chlorpromazine, amitriptyline, NSAIDs, and many chemotherapeutic agents such as cyclophosphamide, vincristine, and vinblastine.
Pulmonary processes: including pulmonary infections and lung cancers, especially small cell lung cancer.
Malignancy: including lung, gastrointestinal, or genitourinary cancers; lymphomas; or sarcomas.
Central nervous system (CNS) disorders: including CNS infections, brain trauma, haemorrhage, multiple sclerosis, Guillain-Barre syndrome, and acute intermittent porphyria.
Other stimuli for AVP release: such as anaesthesia and postoperative state, nausea, vomiting, pain, and endurance exercise.
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.[2]

Question 3

signs

Answer 3

• euvolaemic hyponatraemia (Remember!! it’s not hypovolaemic or hypervolaemic!)

Question 4

symptoms

Answer 4

most of the effects come from the hyponatraemia

• nausea, vomiting
• neurological signs: seizures, delirium, headache

Question 5

investigations

Answer 5

1st investigations:

• serum sodium
• serum osmolality
• urine sodium
• urine osmolality
• serum urea

others:

• diagnostic trial of normal saline infusion (would treat if problem is dehydration but not SIADH. do not use this if patient has signs of hyponatraemia!)
• serum uric acid – usually not necessary. low levels indicate mild volume expansion in line with SIADH
• fractional excretion of sodium (confirms euvolaemic state)
• fractional excretion of urea (confirms euvolaemic state)
• serum TSH (rule out hypothyroid)
• serum cortisol (rule out addisonism)
• serum AVP (/ADH)

Question 6

treatment

Answer 6

severe (usually means with neuro symptoms):
acute
1. IV hypertonic saline + fluid restriction
\+ treat underlying cause 
\++ furosemide
chronic
1. IV hypetonic saline 
\+ vaptans (TOLVAPTAN or CONIVAPTAN)
\+ treat underlying cause
\++ furosemide

mild to moderate:
acute
1. treat underlying cause 
\+ fluid restriction
chronic
1. treat underlying cause
\+ vaptans 

asymptomatic:
1. fluid restriction + treat underlying cause

ongoing/persistent/chronic SIADH:
1. fluid restriction
\+ treat underlying cause
2. tolvaptan 
3. sodium chloride + furosemide
4. demeclocycline (bacteriostatic antibiotic which messes with the ADH receptors in the collecting tubule)

Question 7

complications

Answer 7

central pontine myelinolysis
(Occurs in people with longstanding SIADH who undergo overaggressive treatment of hyponatraemia.[24]

The brain adapts slowly to hyponatraemia by secretion of intracellular solutes such as sodium and potassium initially, followed by amino acids and myoinositol (organic osmolytes).

Overcorrection of hyponatraemia can subject solute-poor cerebral cells to shrinkage and CPM.

CPM is characterised by demyelination of pontine, basal ganglion, and cerebellar regions)

Question 8

prognosis

Answer 8

If the underlying cause is found and treated successfully, SIADH typically resolves. If the underlying condition persists, SIADH is difficult to manage, secondary to difficulty complying with necessary fluid restriction or medicines. Oral vasopressin antagonists such as tolvaptan offer hope for more successful long-term management of SIADH. However, due to reports of potentially fatal liver injury in patients with autosomal dominant polycystic kidney disease, tolvaptan should not be used for more than 30 days, and it should be avoided in patients with underlying liver disease including cirrhosis. The drug should be discontinued immediately in patients with signs or symptoms of liver injury (e.g., fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice, elevated LFTs). FDA Drug Safety Communication: FDA limits duration and usage of Samsca (tolvaptan) due to possible liver injury leading to organ transplant or death external link opens in a new windowThere are no long-term data on safety in patients taking tolvaptan but it has been used anecdotally long-term in selected cases with careful monitoring.

TAKE CAUTION WITH ECTOPIC ADH! always remember to look out for ectopic causes – small cell lung carcinomas, renal cell carcinomas etc.