Hepatopulmonary Syndrome

Hypoxia in a hepatic patient

INTRINSIC LUNG DISEASE
Specific Liver Diseases

Portal Hypertension, Cirrhosis

Pulmonary Vascular Changes




RELATED TO LIVER DISEASE




COPD, Asthma, CHF



INTRINSIC LUNG DISEASE
RELATED TO LIVER DISEASE
Pulmonary vascular disorders 20-30%
Chronic obstructive pulmonary disease 17%
Asictes, hepatic hydrothorax 5%
Congestive heart failure 5%
Specific liver diseases 3%
Deconditioning 2%
Asthma 1%
Fallon et al, Gastro 2008;135:1168-1175
Dilation
60%
Normal
32%
Constriction
8%
THE PULMONARY VASCULATURE IN LIVER
DISEASE

HPS
HPS: Definition

Hypoxemia in cirrhosis
due to
IPVD (saline bubble contrast echo)

Intrinsic Cardiopulmonary disease
MAA scan role
Data needed for MELD exception




HEPATOPULMONARY SYNDROME (HPS)
DEFINITION
HPS is characterized by a defect in arterial oxygenation
Induced by pulmonary vascular dilatation and pulmonary
AV shunting in the setting of liver disease.

HEPATOPULMONARY SYNDROME (HPS)
DEFINITION
Cirrhosis and/or portal hypertension

Arterial p0
2
< 70mmHg or A-aPO
2
> 20 mmHg

Intrapulmonary vasodilatation
Rodriguez-Roisin, Thorax 1992, Eur Respir J 2004

A-aPO
2
: 150- PaCO
2
/0.8 PaO
2
NL age corrected A-aPO
2
: 10 + (age-20) (0.43)
HPS: DIAGNOSIS
Arterial Blood Gas : PaO2 < 70 mmHg

Cardiopulmonary Evaluation

Intrapulmonary vasodilatation
Contrast echocardiography (CE)
Lung perfusion scan (MAA)

Diagnosis of HPS
Chest radiograph and pulmonary function tests are
helpful to exclude other cardiopulmonary abnormalities.
Causes of hypoxemia in a cirrhotic patient include,
ascites, atelectasis, COPD, and hepatic hydrothorax.
The presence of AV shunting establishes the diagnosis
of HPS regardless the presence of cardiopulmonary
disease by radiography.


HPS: SPECTRUM OF DISEASE

Portal vein thrombosis Gupta Gastro 2001

IVC obstruction Binay Gastro 2000

Acute hepatitis Regev AJ Vir Hep 2001, Fuhrmann, Gastro 2006

Chronic hepatitis Teuber Eur J Int Med 2002


HPS: Frequency/Severity

268 OLT evaluations (6 centers)

AaPO2 103/268 38%
IPVD 117/268 44%
HPS 44/268 16%
- AaPO2 40 (22-79)
- PaO2 65 (35-90)
- MELD 13 (7-23)




Mechanism
The exact mechanism is unknown.
Alteration in the production or clearance of chemical
mediators causing intrapulmonary vascular dilatation
and significant AV shunting.
Hypoxia is due to inability of oxygen to diffuse through
the markedly dilated lung capillaries (V/Q mismatch).

Mechanism
Nitric oxide, a potent vasodilator, is exhaled in larger
quantities in patients with HPS and normalizes
following OLT.
Gram negative intestinal endotoxemia in portal HTN
associated with increased NO release can induce
pulmonary vasodilatation.

Mechanism
Capillary vasodilataion is most pronounced at the lung
bases leading to platypnea and orthodeoxia.
Pulmonary vasodilataion leads to increased pulmonary
blood flow and increased COP.
This leads to V/Q mismatch.

PORTAL HYPERTENSION MECHANISMS
VARICES
CARDIAC
Endothelial cell
Stellate cell
Nitric oxide
Constriction
Fibrosis
Nitric oxide
Vasodilation
Angiogenesis
Splanchnic
Systemic Vasodilation
Intrahepatic
Vasoconstriction
Inflammatory cells
ASCITES
HRS
PSE
Pulmonary
HPS, POPH
Portal Hypertension
Cirrhosis
Portosystemic shunting
HPS
Pulmonary
vasodilatation
? Angiogenesis
Normal
Pulmonary
Microvasculature
Abnormal ABGs
40-50% 40-60%
50%
Rodriguez-Roisin et al , Thorax 1992, Eur Respir J 2004
Clinical presentation
Typically, dyspnea, platypnea, and orthodeoxia.
Cyanosis in 90% of cases.
Clubbing
Spider nevi are common and represent a cutaneous
marker of intrapulmonary vascular dilatation.


Clinical Types of HPS
Type I HPS: characterized by vascular dilatation at the
precapillary level, close to the normal gas exchange
units of the lung.
Type II HPS: characterized by focal larger dilatations
amounting to AV shunting distant from gas exchange
units.
100% oxygen inhalation improves type I HPS PaO2 but
not type II.

HPS: Screening
200 OLT evaluations
Pulse oximetry overestimates PaO2
Spo
2
<96% would lead to ABG in ~12% of cohort

Abrams, Liver Transplantation, 2002
4 Chamber View
Contrast Echocardiography
Immediate Post-Contrast
Delayed Post Contrast
HPS: MAA scan
Abrams, Gastroenterology 1998
50
60
70
80
90
100
-20 0 20 40 60 80 100
W
a
k
e

t
i
m
e

P
a
O
2

m
m
H
g

TST-SpO2<90%
Controls (n=10)
HPS (n=10)
Median TST-SpO2 <90%
HPS (25%) vs. Controls (0%)
p = 0.0005
Nocturnal pulse oximetry and HPS
Palma et al. Hepatology 47: 1257-63, 2008

0
20
40
60
80
100
Dyspnea Clubbing Spiders
HPS (30)
non-HPS (181)
HPS: CLINICAL FEATURES
Martinez, 2001, Sood, 1998
93-100%
20-49%
46-64%
8%
73-100%
44-70%
Prognosis of HPS
The median survival time in cirrhotic patients with HPS
is ~ 10.6 months compared to 40.8 months in cirrhotic
patients without HPS.
Survival is worse when PaO2 is low ( 50 mmHg).
The leading cause of death is shock secondary to GI
bleeding.

Portal Hypertension
Chronic Liver Disease
CXR, ABG, PFT, Chest CT
Abnormal gas exchange
No intrinsic
cardiopulmonary disease
Contrast Echocardiogram
Normal
No HPS
Delayed Shunting
(>3 heartbeats)
HPS

Abnormal gas exchange
Intrinsic cardiopulmonary
disease

Contrast Echocardiogram
MAA if hypoxia and delayed
shunting
Swanson, Hepatology 2005
24 months
Schenk, Gastroenterology 2003
HPS: Natural history without OLT
(n=20)
(n=70)
5 mmHg/year
87 months
Survival effect
Progression over time
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48
P
e
r
c
e
n
t


S
u
r
v
i
v
i
n
g

Follow up time in months
HPS: SURVIVAL PRIOR TO LT
Adapted from: Schenk et al Gastroenterology 2003 125:1042-52


HPS (n=27)
Non HPS (n=84)
P = 0.018
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48
P
e
r
c
e
n
t


S
u
r
v
i
v
i
n
g

Follow up time in months
Adapted from: Swanson et al 2005 Hepatology 41: 1122-1129

HPS (n=37)
Non HPS (n=47)
P = 0.0003
HPS: SURVIVAL PRIOR TO LT
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48
P
e
r
c
e
n
t


S
u
r
v
i
v
i
n
g

Follow up time in months
UAB
Columbia
Mayo Clinic
UNC
U. Colorado
Tufts-NEMC
Adapted from: Fallon et al Gastroenterology 2008 135: 1168-75
HPS (n=72)
Non HPS (n=146)
P = 0.013 (adjusted for age, gender, BMI, MELD, LT, PaO2)
HPS: SURVIVAL PRIOR TO LT
HPS: Markov model
CP-A
No-HPS
CP-B/C
No-HPS
CP-A
HPS
Death
CP-B/C
HPS
OLT
HPS: Modeling
Discounted Analysis (3%) Cost
Incremental
Cost
Life
Expectancy
Incremental
Life
Expectancy ICER
Pulse-oximetry $284,710 ------ 11.310 --------
Dyspnea-fatigue index $285,200 $490 11.313 0.003 years $163,333
No screening $291,898 $6,690 11.131 - 0.182 years Dominated
Discounted Analysis (3%) Cost
Incremental
Cost
Life
Expectancy
Incremental
Life
expectancy ICER
No screening $289,495 ------ 12.04 --------
Pulse Oximetry $299,719 $10,224 12.27 0.23 years $45,452
Dyspnea-Fatigue Index $300,278 $559 12.28 0.01 years $55,900
All Patients with HPS Eligible for OLT
Patients with HPS and PaO2 > 50mmHg Eligible for OLT
1) Uniform diagnostic data for exception

- RA ABG, bubble echo, CXR, PFTs IPVD, A-a gradient common
- MAA only if CXR/PFTs abnormal


2) Eligibility at PaO2 < 60mmHg Natural hx data, ABG decline


3) Prospective data to assess policy

- Screen listed pts (pulse oximetry q 12 months) ? Incidence, ? Influence of PaO2
- ABG q 3- 6 months with HPS exception pre and post OLT
- Track mortality, LOS, cause of death

RECOMMENDATION RATIONALE
HEPATOPULMONARY SYNDROME (HPS)
MELD EXCEPTION

Definition/Diagnosis
Frequency/Severity
Natural History
Impact of OLT
Modeling of screening
Recommendations


46% (14)
36% (12)
18% (5)
PaO
2
in HPS patients at LT evaluation
(31% of patients had HPS)

UAB
Columbia
Mayo Clinic
UNC
U. Colorado
Tufts-NEMC
LT EVALUATION
Pulse
Oximetry
96%
TTE
95%
CTTE
Shunt No shunt
ABGs
CXR, PFTs, Chest CT
Other causes
PaO2 60 PaO2>60
MELD
ABG 3-6m
Monitor
Treat
Low PO2 HPS
Abrams, Liver Transpl. 2002:8;391-6
Roberts, Liver Transpl. 2007:13:206-14
Arguedas, Clin Gastro Hepatol. 2007:5;749-54
Kochar, Dig Dis Sci. 2011:56;1862-8

HPS: Outcome with OLT
Type # Post-op Mortality Pre-op PaO2

Taile R 23 30% 51.4 (33-64)

Arguedas P 24 29% 43 (35-51)

Swanson R 24 21% 40.6 (33-51)

Schenk P 7 42% 66 (60-79)

Collison R 6 50% 57.2 (40-84)

Schiffer P 9 33% 60 (52-70)

93 34%
HPS: Outcome with OLT
Type # Post-op Mortality Pre-op PaO2

Taile R 23 30% 51.4 (33-64)

Arguedas P 24 29% 43 (35-51)

Swanson R 24 21% 40.6 (33-51)

Schenk P 7 42% 66 (60-79)

Collison R 6 50% 57.2 (40-84)

84 34%
PaO2 and MELD appear to
Influence outcome
Study Study design Sample
Size
Mean
PaO
2
mmHg
Length of
follow-up
(months)
Survival
Arguedas (2003) Prospective 24 54 12 71%
Taille (2003) Retrospective 23 51 17 69%
Schenk (2003) Prospective 7 68 58%
Swanson (2005) Retrospective 24 57 60 79%
Schiffer (2006) Prospective 9 60 6 67%
Deberaldini (2008) Retrospective 25 77 49 60%
Gupta (2009) Retrospective 21 50 20 95%
HPS: OUTCOME AFTER OLT
(2003)
(2008)
(2006)
(2003)
(2003)
(2005)
(2009)
40
50
60
70
80
50 60 70 80 90 100
P
a
O
2

(
m
m
H
g
)

1 Year Survival (%)
HPS: OUTCOME AFTER OLT
0
20
40
60
80
100
0 3 6 9 12
S
u
r
v
i
v
a
l

(
%
)

Follow up (months)
0
10
20
30
40
50
60
50
9
59
18
53
9
43
41
Alive
Expired
*
*
HPS FEATURES AND LT OUTCOME
Arguedas Hepatol. 2003:37;192-197
Treatment of HPS
Oxygen
Liver transplant

No effective medical treatment is available.
Somatostatin analogues, cyclooxygenase inhibitors, and immunosuppressive agents
have poor results.
Almitrine bismesylate (a selective pulmonary vasoconstrictor) shows promising
results.
Garlic (Allium sativum) powder has a modest effect.
TIPS.

Thank you to:
Mike Fallon for his slide sharing generosity