management of hyponatremia in liver disease

1. Hyponatremia-
in Liver disease
Dr.Gowtham Krishna J.

2. Introduction
• Definition- Reduction in serum Na-130 mmol/l
(But pts with cirrhosis manifest with clinic and pathogenic features at
<135 mmol/l)
• Prevalence-Serum Na-
–<135 -- 49.4%
–<130 – 21.6%
–<120 – 1.2%

3. Types - Hyponatremia
Hypovolemic hyponatremia
1. Contraction of plasma
volume, lack of edema, ascitis ,
prerenal renal failure,signs of
dehydration
2.Causes-
Kidney - overdiuresis-
treatment with diuretics
Losses from the GIT
3.Hepatic encephalopathy-
common(rapid reduction in
serum osmolality)
Hypervolemic hyponatremia
1.Expanded ECF and plama
volume with ascitis and edema
2. Causes
Marked impairment of renal
solute free water excretion-
renal retention.
Non osmotic hypersecretion of
AVP
3.Renal Impairment will be
mostly present

4. Pathogenesis
Systemic circln
(V1 receptors)Kidney
(V2 receptors)
Arterial pressure

5. Isoosmotic-
determines
fluid delivered
to distal tubule

6. V2 AVP Receptor
Principal collecting duct cells of kidneys

7. Brain adaptation to hyponatremia
Decreased Na
Loss of intracellular e- K
(1st 24 hrs)
Loss of LMW –organic osmolytes
REGULATION OF BRAIN VOLUME
Effectiveness on preventing edema depends on
•Severity of hyponatremia
•Rate of reduction of serum sodium conc.
•More effective in chronic rather than acute
(Myoinositol,glutamine,choline
etc.)
Glia specific water
pore(AQP 1,4)
Na-K ATPase system
dependent clearance of
water and solute.
Estrogen
AVP (leads to decreased cerebral
perfusion and decrease ATP
availability for ion exchange
Glial cells(no effect on neurons

8. Signs
• Headache
• Disorientation
• Confusion
• Focal neurological deficits
• Seizures
Death due to cerberal herniation
• Most important factor is rate of fall
• Acute > Chronic-incidence of neurological symptoms
The relatively low incidence of
neurological manifestations in patients
with cirrhosis and hypervole-
mic hyponatremia is related to the fact
that in most of these patients
hyponatremia is chronic rather than
acute, and this gives sufficient time for
the brain to adjust to hypo-osmolality of
the extracellular fluid.

9. • Changes in brain occuring during recovery from
hyponatremia
– Electrolytes correct quickly but organic osmolytes
correction is slow(particularly in areas associated with
ODS) particularly if duration of hypoNa is long.
– More important when correction occurs rapidly
– Lack of adequate brain adaptation to the normalised
osmolality of the ECF may lead to important brain
damage-Osmotic Demyelination Syndrome.

10. Glial cellRapid correction
of Na+
synthesis of organic
osmolytes and the
upregulation of ion
pumps-ATP depletion
Shrinks to counter osmolar change-the
resultant shrinkage of the glial cells may
lead to axonal shear damage,BBB

11. • According to the expert panel
recommendations for treating hyponatremia,
the rate of correction of hyponatremia should
be limited to <10 to 12 mEq/L in 24 hours
and <18 mEq/L in 48 hours.
• Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel
recommendations. Am J Med. 2013;126(10 suppl 1):S1-S4.
• Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med. 2000;342(21):1581-1589.

12. Role in Hepatic Encephalopathy
Second
osmotic
hit

13. Significance of Hyponatremia
• Na & Nh3 are major factors determining EEG abnormalities in cirrhosis
• Pt after TIPS-HypoNa major risk factor for HE
• Pts treated with Diuretics-Hypo Na is risk facor for HE
• Independent predictive factor for HE.
• Hyponatremia was an independent predictive factor of the impaired
health-related quality of life, the predictiveness being independent of
that of liver function tests and Child-Pugh or Model for End-Stage Liver
Disease scores
• Patients with cirrhosis and hyponatremia are at increased risk of
developing central pontine myelinolysis after transplantation, and this
is related to a rapid change in serum sodium in the early postoperative
period.
• Ginès P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management. Hepatology. 2008
Sep;48(3):1002-10.
• Gine`s P, Wong F, Smajda Lew E, Diamand F. Hyponatremia is a major determinant of impaired health-related quality of life in cirrhosis
with ascites [Abstract]. HEPATOLOGY 2007;46:567A.

14. Contd…
• Serum Na before onset of SBP is a independent predictor of
renal failure triggered by SBP (Savio John et al)
• Serum Na is an earlier and most sensitive test than serum
creatinine to detect circulatory dysfunction resulting renal
failure and death. (Savio John et al)

15. Treatment
• Hypovolemic hyponatremia-
– Fluid resuscitataion
– Withdrawal of precipitating factor(diuretic)
• Hypervolemic hyponatremia
– Fluid restriction
– Hypertonic saline
– Correction of hypokalemia
– Albumin infusion
– Pharmacological therapy-Enhance renal solute water
excretion
• Treatment indicated when serum Na <120 meq/L or
during neurological symptoms.

16. Water restriction
• 1-1.5 L/day or to a level sufficient to induce
negative water balance.
• Intake < UOP (to account for endogenous
production of water by the body)
• Sodium restriction (2g/day)
• Not routinely suggested-only for neuro
symptoms and Na <120

17. Hypertonic saline
• Indicated
– symptomatic patients who are intolerant or
unresponsive to free water restriction
– Profound hyponatremia(<110)
– Within hrs of LTP to prevent likelihood an emergent
rapid correction in OR when the serum Na levels are
somewhat higher(120-130)
– As hypertonic sodium chloride infusion leads to
increasing ascitis and edema mostly avoided in
hypertonic hypoNa.

20. Correction of hypokalemia
• Decreased K promotes HE
– Increases renal ammonia synthesis
– Since renal blood flow is diminished during potassium
depletion(increased plasma renin activity) and increased with a
high potassium intake , this could represent one factor
contributing to the change in urinary ammonium excretion. A
change in renal blood flow, however, might also alter ammonia
production by modifying the amount of substrate (glutamine)
presented to the renal tubular cells.(tannen et al.)
– increases fracion of unionised ammonia in the plasma.
• Raises Na level
– As K is as osmotically active as Na supplementation increases
serum sodium and osmolality.

21. Albumin Infusion
• Expensive and impractical
• Short term benefits
• Long term benefits are not studied

22. Pharmacologic Therapy
• K-Opioid agonists-
– Inhibit release of ADH from neurohypophysis.
– Niravoline(0.5-2 mg)-no sustained aquaretic
effect.
– Associated with major neurological side effects

23. V2 receptor blockade
• administration of vaptans for a short period of time (1‐2 weeks in
most of the studies) is associated with a significant improvement
of the low serum sodium levels .
• The increase in serum sodium concentration occurs within the first
few days of treatment and ranges from 2 to 7 mmol/L on average.
• A normalization of serum sodium concentration is observed in 27%
to 54% of patients. Moreover, in approximately one‐third of
additional patients, serum sodium increases more than 5 mmol/L
but does not reach normal values.
• In short‐term studies, no significant effects have been observed
on renal function, circulatory function, and activity of the
renin‐angiotensin‐aldosterone system.
• Plasma AVP levels increase consistently during treatment. An
increase in urinary sodium excretion has not been observed
consistently in all studies.

24. • Tolvaptan, satavaptan and lixivaptan are all oral agents
which selectively block the V2 receptor.
• The intravenous agent, conivaptan, which blocks both V2
and V1 receptors may lead to further reduction in blood
pressure, increase the risk of variceal bleeding via the V1a
receptor blockade.
• Tolvaptan is a selective nonpeptide V2 receptor antagonist
and when this drug was added to standard diuretic therapy
for periods ranging from 25 to 60 d in patients with heart
failure, treated patients had significantly lower weight and
improvement in edema as well as serum sodium levels
compared to those who received placebo.
• But prolonged followup revealed increased mortality risk
and hence the drug was withdrawn from the market.
• Demeclocycline(ADH antagonist) –nephrotoxic potential
hence avoided.

25. Caution
• Terlipressin, by virtue of its strong effect on vasopressin V1
receptor, has therapeutic potential in portal hypertensive
bleeding as well as hepatorenal syndrome.
• Terlipressin is also a partial agonist of renal vasopressin V2
receptors and acute reduction in serum sodium level has
been documented in patients who are initiated on
terlipressin.
• The resultant hyponatremia, although severe in some
patients, is usually reversible after withdrawal of
terlipressin therapy. Hence serum sodium levels should be
monitored while patients are on therapy with terlipressin.

26. Benefits of treating hyponatremia
• Pts can drink fluids normally and thus avoid fluid
restriction.
• Achieve effective doses of diuretics and improve the
response to therapy in patients with difficult-to-
treat ascites
• Reduces HE risk
• improve quality of life in patients with cirrhosis
• in patients awaiting liver transplantation,
• the normalization of the serum sodium
concentration before transplantation may help
reduce the frequency and severity of neurological
complications after transplantation.

27. Summary
• Hyponatremia is very common in patients with cirrhosis and the routine
correction of asymptomatic hyponatremia is not recommended.
• The main indications for correction of hyponatremia are presence of
neurologic symptoms that might be due to hyponatremia and serum sodium
less than 120 mEq/L.
• The only exception is in patients who are likely to receive liver transplantation
within hours when their serum sodium concentration is less than 130 mEq/L to
avoid rapid correction in the operating room as it may be associated with
serious neurological complications.
• Correction of hypokalemia and fluid restriction are the mainstays of treatment.
• Administration of hypertonic saline may be considered in a monitored setting
to correct profound hyponatremia (serum sodium < 110 mEq/ L) and in the
immediate pre-liver transplant period to prevent the risk of osmotic
demyelination syndrome.
• No vasopressin receptor antagonist is currently approved by the FDA for
treatment of hyponatremia in patients with liver disease or cirrhosis. The
availability of selective and efficacious oral V2 receptor antagonists, without
major side effects, will be a major development for the management of
hyponatremia.