Hyponatremia in

Cirrhosis
Pathogenesis, Clinical
Significance, and Management
 Overview
 Definition
 Prevalence
 Types
 Pathogenesis
 Clinical significance
 Management
Hyponatremia in
Cirrhosis
Definition
 Definition
 defined
as a reduction in serum sodium
below 130 mmol/L

 the
lower limit of normal of serum sodium
concentration is 135 mmol/L

Gine´s P,, et al. Hyponatremia in cirrhosis: from pathogenesis to treatment.

HEPATOLOGY 1998;28:851-864.
Hyponatremia in
Cirrhosis
Prevalence
Prevalence
Death
21.6% of cirrhotic Focal deicits
Hyponatremic at Seizures
Na <130 mmol/L Agitation
Confusion
Lethargy
Headache
Difficulty
49.4% of cirrhotic Hyponatremic at concentrating
Na < 135 mmol/L
Nausea and
vomiting
Anorexia

Angeli P, Wong F, Watson H, Gines P. Hyponatremia in cirrhosis: results

of a patient population survey. HEPATOLOGY 2006;44:1535-1542
Hyponatremia in
Cirrhosis
Types
 Types of Hyponatremia
Hyponatremia

Hyperosmolar
Hyperglycemia hyposmolar
manitol

Normovolemic
Hypervolemic Hypovolemic
Hyponatremia
hyponatremia hyponatremia
SIADH
 hypovolemic hyponatremia
 contraction of plasma
volume
 lack of edema and
ascites R/O
 overdiuresis
signs of dehydration
prerenal renal failure

GI loss
 encephalopathy is
common
 hypervolemic or dilutional
hyponatremia
 Hyponatremia develops
in the setting of expanded
extracellular fluid volume
and plasma volume with
ascites and edema
 urine Na excretion is
usually < 10 mEq/L and
urine osmolality is high
relative to plasma
osmolality
Hyponatremia in
Cirrhosis
Pathogenesis
water balance
water balance
kidney tubules

Site of action of AVP

 Water Handling in the Collecting Duct –
AVP effect
H2O
Aquaporin 2
H2O
H2O
H2O

Serum Na
H2O

Apical membrane

cAMP

Aquaporin3,4
V2

Basolateral membrane
AVP
Water Handling in the Collecting Duct -
AVP Absent
18 L
Osm
No AVP Osm 300
50
H2O

H2O

H2O

H2O

H2O
Osm
50
Aquaporin 2

18 L Osm 1200
Water Handling in the Collecting Duct -
AVP Present
18 L
AVP Osm 300
Osm
50
H2O
H2O

H2O
H2O
H2O

H2O

Osm
1200 Aquaporin 2

0.5 L Osm 1200

Regulators of AVP release

Non osmotic stimulus

 Pathogenesis of hyponatremia
in cirrhosis
systemic
Advanced Portal
Vascular
cirrhosis HTN
resistance

Non osmotic effective

AVP secretion arterial BP

Arterial Tubular water

V1 V2
vasoconstriction reabsobtion

Solute Free
BP water retention

hyponatremia
Hyponatremia in
Cirrhosis
Clinical significance
 Normonatremia Hyponatremia

ICP ICP

Na Na Na Na H2 O
Na Na Na Na Na Na Na
H2 O
Na Na K
K K K K ICF H2O ICF
KKKK K K K KH2O
Na Na Na K

KKKK H2 O KKKK
H2O
Na Na Na Na
Na Na Ca K K K K H2 O
Gln
H2OMIP Na Na Ca
Gln MIP
H2O K K K K
KKKK KKKK
H2O KKKK
H2O H2O
H2 O Na Na Na
H2 O
Na Na Na Na Na Na K Na Na Na Na
ECF ECF H2O
 Hyponatremia Hyponatremia
Rapid adapt Slow adapt
ICP ICP

Na Na Na Na H2 O
Na Na Na
H2 O
Na Na K
KKKK H2O ICF
KKKK K K K KH2O
Na Na Na K

KKKK KKKK
H2 O Na Na Na Na
H2O
Na Na Ca K K K K H2 O
Gln
H2OMIP ICF Na Na Ca
H2O K K K K Gln MIP
KKKK KKKK
H2O KKKK
H2O H2O
H2 O Na Na Na
H2 O
Na Na Na Na Na Na K Na Na Na Na
ECF ECF H2O
Brain Adaptation to
Hyponatremia
 Effects of hyponatremia
Na 135
No symptoms
In cirrhotic
Anorexia
Nausea and

Severity of symptoms
vomiting
Serum Na

Difficulty
concentrating
Headache

Confusion
Lethargy

Agitation
Seizures
Na 110 Focal deficits
death
onset
 cirrhosis
hyperammonemia hyponatremia

Increase glutamine synthesis

Increase Astrocyte
intracellular decrease
Osmolality extracellular
Osmolality

H2O shift from

Extracelluar fluid H2O shift from
Extracelluar fluid

Astrocyte
swelling
Astrocyte
dysfunction

Increase Hepatic
Ammonia encephalopathy
Low Na
Hyponatremia & Complications
of Cirrhosis
Refractory HRS
ascites

Hyponatremia
SBP

Encephalopathy
 Odds Ratios for Different
Complications of Cirrhosis
according serum Na
3.5 3.4 3.45

2.5 2.36

2 encephalopathy
1.69 1.75 SBP
1.5 1.44 1.48
HRS
1 0.93 GI Bleed

0.5

0
131–135 mmol/L <130 mmol/L

ANGELI ET AL. HEPATOLOGY, December 2006

 Probability of encephalopathy
development according serum Na
1
0.9
0.8
0.7 No of pts 59
0.6
Na<135
0.5
Na >135
0.4
0.3
0.2
0.1
0
0 20days 40days 60days 100days

GINE`S AND GUEVARAHEPATOLOGY, Vol. 48, No. 3, 2008

 Hyponatremia & refractory
ascites
100%
13.10% 18.50%
90%
29.40%
80% 14.50% P value
13.70% <.001
70%
60% 17.10%
Refractory
50% Recidivant
40% other
72.40% 67.90%
30%
53.60%
20%
10%
0%
>135 mmol/L 131–135 mmol/ <130 mmol/L

ANGELI ET AL. HEPATOLOGY, December 2006

Hyponatremia and Mortality among
Patients
on the Liver-Transplant Waiting List
MELDNa = MELD − Na − [0.025 × MELD ×
(140 − Na)] + 140

Serum Sodium Concentration and the Relative Risk of Death

after Adjustment for the MELD Score.
W. Ray Kim et alN Engl J Med 2008;359:1018-26.
 Hyponatremia and Mortality among
Patients
on the Liver-Transplant Waiting List
90%
)%( Probability of Death at 90 Days

80%
70%
60%
50% Observed

40% Predicted
30% MELDNa
Predicted
20%
MELD
10%
0%
10 11–12 13–14 15–16 17–18 19–20 21–22 23–26 27–31 32–40

observed probability of death for the 2006 data and the predicted probability according to the MELDNa and MELD
scores in 10 groups (deciles) of patients.

W. Ray Kim, n engl j med 359;10

 Early post transplant mortality
increase with hyponatremia
95%
96%
94%
92% P < 0.05
90%
88%
86% 84% Na <130
84% Na >130
82%
80%
78%
3 months survival in pts with cirrhosis
post transplant

London˜o MCet alGastroenterology 2006;130:1135-1143.

Hyponatremia in
Cirrhosis
Management
 Management

hyponatremia

Hypovolmic Hypervolmic
hyponatremia hyponatremia

Fluid restriction
Saline ?Hypertonic saline
DC diuretics ?Albumin
vaptans
 Fluid restriction
 Fluid restriction (1-1.5 L/day) is currently
the standard of care for the management
of hypervolemic hyponatremia in cirrhosis
 the efficacy in improving serum sodium
concentration more than 5 mmol/L ranged
from 0% to 26% (as placepo vs Vaptans)

Gerbes AL, et al., Gastroenterology 2003;124:933-939

Gine`s PHEPATOLOGY 2008;48. do
Gine`s PJ Hepatol 2007;46:90A.
.
 Hypertonic saline
 Efficacy is limited
 Risk of osmotic
demylination
 Exacerbate edema &
ascites
 its use in the
management of
hypervolemic
hyponatremia cannot
be recommended
 albumin
 Improve serum
sodium concentration
in a few studies
 the number of
patients included has
been low
 follow-up has been
short

McCormick PA Gut 1990;31:204-207

Jalan R, J Hepatol 2007;46:232A
 Vaptans

Mozavaptan Conivaptan
 Vaptans mechanism of action

H2O
Aquaporin 2
H2O
H2O
H2O
H2O

Apical membrane

Serum Na
cAMP

Aquaporin3,4
V2

Basolateral membrane AVP

VAPTAN
 Vaptans
Specific
Current Studies Route of
Status of
in Patients Administratio Receptor Name
Clinical
with n
Development
Cirrhosis

Approved in USA No IV V1a/V2 Conivaptan

Phase 2 Yes Oral V2 Lixivaptan

Oral
Phase 3 Yes V2 Satavaptan

Oral
phase3 No V2 Tolvaptan

Approved in Oral
Japan
Yes V2 Mozavaptan

Oral
Phase 2 Yes V2 M-0002

GINE`S AND GUEVARA HEPATOLOGY, Vol. 48, No. 3, 2008

 the Effects of Vaptans on Serum Sodium
Concentration in Patients with
Cirrhosis, Ascites, and Hyponatremia
Responder End-of-
Baseline Dosage
s (% Treatment Duration of
Serum (Number of Compound Authors
of Serum Treatment
Sodium Patients)
Patients)* Sodium
127± 1
NR 126 ±1 Placebo (8)
126 ±1
NR 129 ±2 25 mg bid (8)
122 ±1
NR 127 ±3 7 days 125 mg bd Lixivaptan Wong et a
(10)
125±1
NR 132 ±1 250 mg bid (7)

5% 128 ±4 127 ±3 Placebo (20)

45% 130 ±7 128 ±4 7 days 100 mg (22) Lixivaptan Gerbes et a
67% 132 ±7 126 ±4 200 mg (18)

26% 128 ±7 126 ±4 Placebo (28)

50% 131 ±6 127 ±5 5 mg (28)
14 days Satavaptan Gine`s et a
54% 133 ±5 128 ±4 12.5 mg (26)
82% 134 ±6 126 ±6 25 mg (28)

GINE`S AND GUEVARA HEPATOLOGY, Vol. 48, No. 3, 2008

 Short-Term Effects
Mean serum sodium concentration in patients with cirrhosis,
ascites, and hyponatremia randomized to treatment with placebo
or satavaptan (5, 12.5, or 25 mg/day) for 14 day

No of pts 57

Gine`s PJ Hepatol 2007;46:90A.

 Gine`s P. Wong F, Watson H. Long-term improvement of serum sodium
by the V2-receptor antagonist satavaptan in patients with cirrhosis and
hyponatremia [Abstract]. J Hepatol 2007;46:90A.
48 wk
Satavaptan long term effect

Diuretics permitted
Aim S.Na 135-145
Titrate upto 50 mg
Randomization

Satavaptan
5mg 47 pts
Placepo
pts 26

73 pts
2:1
RANDOMISED
CONTROLED
PLACEPO
BLINDED
14 DAYS
DOUBLE

TRIAL

wk 0
 Satavaptan long term effect
138

136
No. of pts. 73
Median serum sodium

134

132 satavaptan
130 placepo

128

126

124
wk 0 wk 12 wk 20 wk 40

Gine`s P. Wong F, Watson H. Long-term improvement of serum sodium

by the V2-receptor antagonist satavaptan in patients with cirrhosis and
hyponatremia [Abstract]. J Hepatol 2007;46:90A.
 Satavaptan
?? end of story
 Vaptans
side effects
 29% of pts with cirrhosis treated with
vaptans reported thirst
 hypernatremia (S. Na 145 mmol/L) only
2%-4% of treated patients (altered mental
status i.e. Encephalopathy is risk factor)
 Serum Na increase by 8 mmol/l in 1st
days 4-14% but no of central pontine
myelinolyis reported

GINE`S AND GUEVARA HEPATOLOGY, Vol. 48, No. 3, 2008

 Management
why should we treat hyponatremia?
 Allow patients to drink fluids normally and
avoid fluid restriction
 vaptans may prevent the reduction in S.
Na seen in patients under diuretic therapy
 May prevent encephalopathy
 May improve quality of life in cirrhotic
 May reduce the frequency and severity of
neurological complications after T’X

Gine`s P, HEPATOLOGY 2007;46:567A.