Sildenafil treatment for portopulmonary hypertension

Abstract

Portopulmonary hypertension (POPH) is regarded as a subtype of pulmonary arterial hypertension (PAH); however, established PAH therapies have not been evaluated for this condition. The current authors treated 14 patients (four male, 10 female; mean (range) age 55 (39-75) yrs) with moderate (n = 1) or severe (n = 13) POPH caused by alcoholic liver disease (n = 7), chronic viral hepatitis (n = 3), autoimmune hepatitis (n = 3), and hepatic manifestation of hereditary haemorrhagic teleangiectasia (n = 1) with oral sildenafil. Eight patients were newly started on pulmonary vasoactive treatment, while six patients were already on treatment with inhaled prostanoids (iloprost, n = 5; treprostinil, n = 1). During treatment with sildenafil, mean +/- sd 6-min walk distance increased from 312 +/- 111 m to 397 +/- 99 m after 3 months, and 407 +/- 97 m after 12 months. Mean +/- sd pro-brain natriuretic peptide levels decreased from 582 +/- 315 ng x mL(-1) to 230 +/- 278 ng x mL(-1), and to 189 +/- 274 ng x mL(-1) after 3 and 12 months, respectively. Two patients died after 1 and 2 months from liver failure and cardiac failure, respectively. There was a similar response to sildenafil treatment after 3 and 12 months in patients on monotherapy and those on combination therapy. In conclusion, sildenafil might be effective in monotherapy and in combination therapy with inhaled prostanoids in portopulmonary hypertension, leading to significant improvement by 3 months and sustained response over 12 months.

Full text

Sildenafil treatment for portopulmonary
hypertension
F. Reichenberger*, R. Voswinckel*, E. Steveling*, B. Enke*, A. Kreckel*,
H. Olschewski
#
, F. Grimminger*, W. Seeger* and H.A. Ghofrani*
ABSTRACT: Portopulmonary hypertension (POPH) is regarded as a subtype of pulmonary arterial
hypertension (PAH); however, established PAH therapies have not been evaluated for this
condition.
The current authors treated 14 patients (four male, 10 female; mean (range) age 55 (39–75) yrs)
with moderate (n51) or severe (n513) POPH caused by alcoholic liver disease (n57), chronic
viral hepatitis (n53), autoimmune hepatitis (n53), and hepatic manifestation of hereditary
haemorrhagic teleangiectasia (n51) with oral sildenafil. Eight patients were newly started on
pulmonary vasoactive treatment, while six patients were already on treatment with inhaled
prostanoids (iloprost, n55; treprostinil, n51). During treatment with sildenafil, mean¡SD 6-min
walk distance increased from 312¡111 m to 397¡99 m after 3 months, and 407¡97 m after
12 months. Mean¡SD pro-brain natriuretic peptide levels decreased from 582¡315 ng?mL
-1
to
230¡278 ng?mL
-1
, and to 189¡274ng?mL
-1
after 3 and 12 months, respectively. Two patients died
after 1 and 2 months from liver failure and cardiac failure, respectively. There was a similar
response to sildenafil treatment after 3 and 12 months in patients on monotherapy and those on
combination therapy.
In conclusion, sildenafil might be effective in monotherapy and in combination therapy with
inhaled prostanoids in portopulmonary hypertension, leading to significant improvement by
3 months and sustained response over 12 months.
KEYWORDS: Inhaled prostanoids, portopulmonary hypertension, pulmonary circulation, sildenafil
Patients with liver diseases are at risk of
developing pulmonary vascular compli-
cations [1]. Among these, portopulmon-
ary hypertension (POPH) is a rare but severe
complication affecting 2–10% of patients with
liver cirrhosis. It is associated with increased
mortality due to obstructive pulmonary vasculo-
pathy and has a major impact on treatment
options for underlying liver disease [2].
Development of POPH has been associated with
portal hypertension, but it can occur at any stage
of liver diseases, with increasing incidence
dependent on the severity of hepatic impairment
[3]. Patients with POPH are at high risk of severe
complications during liver transplantation [4].
POPH is regarded as a subtype of pulmonary
arterial hypertension (PAH) [5]. However, newly
developed treatment strategies for PAH have
been neither studied nor approved for POPH.
Furthermore, POPH has been explicitly excluded
from recent published randomised controlled
trials on PAH [6].
Currently available compounds for pulmonary
vasoactive treatment have been successfully used
in POPH, even enabling successful liver trans-
plantation [7, 8]. So far, case reports and a case
series have been published showing clinical,
functional and haemodynamic benefit on treat-
ment with intravenous and inhaled prostanoids,
oral bosentan or combination therapy [9–13].
The phosphodiesterase-5 inhibitor sildenafil is
currently licensed for the treatment of PAH. It
has the advantage of being an oral compound
with pulmonary vasoselective action but no
hepatotoxicity [14]. The successful use of silde-
nafil in POPH has recently been reported in two
case studies [15, 16].
The current authors evaluated long-term silde-
nafil treatment of POPH, the primary objectives
being safety and efficacy as either monotherapy
or in combination with inhaled prostanoids.
PATIENTS AND METHODS
In the current authors’ tertiary referral centre for
pulmonary vascular diseases, all patients with
PAH associated with liver disease were evaluated
AFFILIATIONS
*Pulmonary Vascular Diseases Unit,
University of Giessen Lung Center,
Dept of Internal Medicine, University
Hospital Giessen, Giessen Germany.
#
Division of Chest Medicine,
University Hospital Graz, Graz,
Austria.
CORRESPONDENCE
F. Reichenberger
University of Giessen Lung Center
University Hospital Giessen
Klinikstrasse 36
35392 Giessen
Germany
Fax: 49 6419942599
E-mail: Frank.Reichenberger@
innere.med.uni-giessen.de
Received:
February 28 2006
Accepted after revision:
June 15 2006
European Respiratory Journal
Print ISSN 0903-1936
Online ISSN 1399-3003
For editorial comments see page 466.
EUROPEAN RESPIRATORY JOURNAL VOLUME 28 NUMBER 3 563
Eur Respir J 2006; 28: 563–567
DOI: 10.1183/09031936.06.00030206
CopyrightßERS Journals Ltd 2006
c

to ascertain: 1) the degree of liver cirrhosis and the
underlying aetiology of liver disease; 2) symptoms related
to PAH according to World Health Organization (WHO)
classification; 3) exercise capacity using 6-min walking
distance (6-MWD) according to American Thoracic Society
guidelines [17]; and 4) haemodynamic parameters using
right-heart catheterisation.
Pulmonary vasoactive treatment was started when patients
were in WHO functional stage III–IV, with an impaired
exercise tolerance and moderate-to-severe pre-capillary pul-
monary hypertension with increase of mean pulmonary
arterial pressure (mPAP) .35 mmHg [1], and a pulmonary
vascular resistance (PVR) .500 dyne?s?cm
-5
[18].
None of the patients in the present study were being treated
with b-blocking agents. Patients on prostanoid treatment
received either iloprost 6 inhalations?day
-1
with a total daily
dose of 30 mg(n55), or treprostinil 4 inhalations?day
-1
with a
total daily dose of 120 mg(n51) at mouthpiece using an
ultrasonic inhalation device. Sildenafil treatment was started
with increasing dosage, reaching 50 mg three times daily
within 3 weeks in all patients. Follow-up included: clinical
assessment; measurement of 6-MWD; laboratory studies
including liver function tests and pro-brain natriuretic peptide
(pro-BNP) measurement; and right-heart catheterisation after
3 months and 12 months.
As data are normally distributed, results are shown as
mean¡SD. To detect statistical significant differences between
groups, two-sided unpaired t-tests were used. For the
assessment of treatment effects, two-sided paired t-tests were
used. For subgroup analysis, ANOVA (a50.05) and post hoc
analysis were applied. Bonferroni correction was used for
correction of multiple comparisons [19].
RESULTS
Among 32 patients with POPH, 20 patients with advanced
disease (i.e. moderate or severe stage of the disease according
to recent guidelines [1]) were identified. Of these, 12 patients
were already receiving therapy with inhaled iloprost (n57),
inhaled treprostinil (n52) or endothelin-receptor blockers
(n53). Sildenafil treatment was considered in newly diagnosed
patients and in patients not stable on current therapy. Six
patients were stable on treatment with endothelin-receptor
blockers (n53) or inhaled prostanoids (iloprost, n52; trepros-
tinil, n51) and were not included in the study.
Sildenafil treatment was started in 13 patients with severe and
one patient with moderate POPH but in WHO functional class
III (four male, 10 female; mean age 55¡12 yrs). Six patients
had already been on active treatment with inhaled prostanoids
(iloprost, n55; treprostinil, n51) for mean (range) 20 (3–
42) months, but required additional treatment. Underlying
aetiologies included liver cirrhosis caused by alcohol liver
disease (n57), or associated with viral hepatitis (n53), auto-
immune hepatic diseases (n53) or hepatic involvement in
hereditary haemorrhagic teleangiectasia (HHT; n51). Patients
were in either clinical stage Child A (n57), B (n56) or C (n51).
Concerning pulmonary hypertension, patients were in WHO
functional classes III (n510) and IV (n54) with a mean 6-MWD
at baseline of 307¡109 m.
Pre-capillary pulmonary hypertension was confirmed on right-
heart catheterisation with mPAP 55¡11 mmHg, cardiac index
of 2.2¡0.8 L?min
-1
?m
-2
and PVR of 1130¡688 dyne?s?cm
-5
.
One patient (patient 5) in WHO class III with mPAP 59 mmHg
and PVR 438 dyne?s?cm
-5
was also included in the study.
Within 3 months of treatment beginning, two patients had
died. The patient with hepatic involvement of HHT (patient
No. 13) was already in an advanced stage of liver cirrhosis
when referred for assessment of POPH. The patient died in
progressive liver failure 1 month after the start of sildenafil
therapy. There were no additional causes of liver disorder.
Notably, there were no signs of a bleeding event.
Patient No. 14, with severe POPH associated with viral liver
cirrhosis, initially improved on treatment with inhaled
iloprost; however, she required combination therapy with
sildenafil owing to the progression of the disease. The patient
died in cardiac failure 2 months after starting combination
therapy. Again, there were no signs of a bleeding event.
The other 12 patients completed 3 months’ follow-up, with an
increase in 6-MWD from 312¡111 m to 397¡99 m (p50.001).
There was a significant decrease in mPAP, from 55¡11 mmHg
to 46¡10 mmHg (p50.01), an increase in cardiac index from
2.2¡0,8 L?min
-1
to 2.8¡1.0 L?min
-1
(p50.06), and a significant
decrease in PVR from 1,070¡597 dynes?s?cm
-5
to 698¡358 dyne?
s?cm
-5
(p,0.05; table 1). Pro-BNP levels decreased from
582¡315 ng?mL
-1
to 230¡278 ng?mL
-1
(p50.06). Liver function
test, arterial partial pressure of oxygen (PO
2
) and haemoglobin
levels remained stable (table 2).
After 12 months’ follow up, 6-MWD was 407¡97 m (p,0.0001
from baseline), and pro-BNP levels had decreased further to
189¡274 mg?mL
-1
(p,0.05 from baseline). Haemodynamic
parameters showed mPAP of 51¡7 mmHg, cardiac index of
2.5¡0.6 L?min
-1
?m
-2
and PVR of 797¡358 dyne?s?cm
-5
, and
were not significantly different from baseline. Liver function
test remained stable, as did oxygenation and haemoglobin
levels (tables 1 and 2). There were no deaths among patients
who survived the first 3 months.
Although patients who were receiving prostanoid therapy
prior to the study period had significantly worse baseline
haemodynamic parameters, there was no statistically signifi-
cant difference between patients with combination therapy and
patients with first-line sildenafil monotherapy concerning 6-
MWD at baseline and at 3 and 12 months’ follow-up (table 3;
fig. 1).
Patients with Child A liver cirrhosis had a better response to
sildenafil therapy, with a significant increase in 6-MWD after
3 months’ therapy; however, by 12 months there was no
statistical significant difference between the 6-MWD of Child
A and Child B patients (fig. 2). During the whole study period,
there were no reported bleeding events or episodes of visual
disturbance in patients.
DISCUSSION
POPH comprises a distinct aetiology of PAH. However, it was
not investigated in recent randomised controlled trials on
treatment for pulmonary hypertension [6, 14]. Consequently,
the treatment of POPH is dependent on compassionate use of
compounds currently available to treat PAH. The available
SILDENAFIL IN PORTOPULMONARY HYPERTENSION F. REICHENBERGER ET AL.
564 VOLUME 28 NUMBER 3 EUROPEAN RESPIRATORY JOURNAL

data on the efficacy and safety of pulmonary vasoactive
therapy in this patient population are sparse. In the current
retrospective study, a significant clinical, functional and
haemodynamic improvement was found over 3 months’
treatment with oral sildenafil in patients with severe POPH.
Successful treatment of POPH has been reported using
prostanoids or endothelin-receptor antagonists, with observa-
tion times of 3–12 months [9–13]. Subcutaneous, i.v. or inhaled
prostanoids are associated with considerable side-effects or
require significant patient commitment, and the endothelin-
receptor antagonist bosentan is associated with an increased
risk of hepatotoxicity (occurring in ,10% of patients) [20].
Sildenafil combines the advantage of oral treatment for severe
PAH with an excellent risk-profile regarding hepatic side-
effects in these patients with impaired liver function.
In the current study, two patients died, 1 and 2 months after
initiation of sildenafil treatment, respectively. One patient died
owing to liver failure in advanced liver cirrhosis due to HHT.
This patient was not eligible for liver transplantation due to
severe pulmonary hypertension [2, 4]. The second patient
suffered from liver cirrhosis due to viral hepatitis. Despite
combination therapy with inhaled iloprost and sildenafil, she
developed progressive pulmonary vascular disease and died
in right-heart failure.
Although six patients already received inhaled prostanoids
with effective dosing, additional pulmonary vasoactive ther-
apy was required for functional stabilisation. Combination of
sildenafil add-on therapy with inhaled prostanoids resulted in
a favourable improvement after 3 and 12 months, similar to
that shown by patients being treated with sildenafil mono-
therapy. The effects seen in the current study were comparable
to those seen in patients with other forms of PAH [21, 22].
Differences in response to treatment with regard to the origin
of liver disease were found neither in the current study nor in
previous reports [1–4]. In the current study, patients with a
milder degree of liver cirrhosis showed a significant improve-
ment in exercise capacity after 3 months’ sildenafil therapy
compared with patients in advanced stages of liver disease
(fig. 2). Although this effect might be related to the small
sample size, it should be considered in forthcoming investiga-
tions.
Although there was a slight deterioration in haemodynamic
parameters after 12 months, patients remained in a stable
clinical and functional condition. In addition, pro-BNP levels
remained stable. In the current study, a sildenafil dose 2.5
times as high as the currently approved dosage for treatment
of PAH was used. Sildenafil dosage was not increased further
owing to the potential for bleeding.
None of the patients in the current study experienced bleeding
events or required blood transfusions while on chronic
sildenafil treatment. Notably, there were no reported episodes
of gastrointestinal haemorrhage, as has been reported pre-
viously [23, 24]. The two deceased patients showed no signs of
a fatal bleeding event and died from liver failure and cardiac
failure, respectively.
Goal-directed therapy is the current challenge in PAH, and
specific targets might be achievable with growing evidence for,
and availability of, combination therapy [25].
TABLE 1 Individual patient characteristics, baseline haemodynamics and response to therapy
Patient Sex Age yrs Liver
cirrhosis
Child
stage
Treatment mPAP CI PVR 6-MWD
Base
mmHg
3 months
mmHg
12 months
mmHg
Base
L?min
-1
3 months
L?min
-1
12 months
L?min
-1
Base
dyne?s?cm
-5
3 months
dyne?s?cm
-5
12 months
dyne?s?cm
-5
Base m 3 months
m
12 months
m
57 49 56 2.5 3.4 2.4 1074 621 984 385 468 396
2F 46 Alcoholic A sil 48 52 54 1.4 2.0 1.6 1143 851 998 334 442 403
3F 58 Alcoholic A sil 36 20 30 2.5 2.4 2.3 552 359 423 312 410 420
4M 48 Alcoholic B sil 47 38 42 2.7 4.3 3.2 548 269 343 368 398 450
5M 48 Alcoholic B sil 59 56 56 3.6 2.9 3.0 438 530 540 430 416 434
6M 60 Viral B sil 51 52 54 3.5 3.8 3.3 543 521 554 329 370 425
7F 75 PBC B sil 58 52 52 2.3 1.7 1.9 1263 1467 1245 58 130 143
8F 59 Alcoholic A sil/ilo 71 51 56 2.3 2.8 3.1 867 509 594 360 480 494
9F 63 Alcoholic A sil/ilo 50 49 53 1.4 1.8 2.2 1362 1047 1050 262 421 435
10 F 45 Immune A sil/ilo 76 44 48 1.3 2.4 2.5 2616 891 780 150 390 417
11 M 49 Viral A sil/ilo 49 42 52 1.8 4.6 2.4 984 311 725 443 519 534
12 F 75 Immune B sil/ilo 59 49 54 1.7 1.8 1.6 1446 997 1333 317 322 335
Mean¡SD 55¡11 55¡11 46¡10
#
51¡72.2¡0.8 2.8¡1.0
#
2.5¡0.6 1070¡597 698¡358
"
797¡323
+
312¡111 397¡99
1
407¡97
e
13
##
F 39 HHT C sil 46 3.3 513 363
14
##
F 69 Viral B sil/tre 64 1.0 2467 183
mPAP: mean pulmonary arterial pressure; CI: cardiac index; PVR: pulmonary vascular resistance; 6-MWD: 6-min walking distance; F: female; sil: sildenafil; M: male; PBC: primary biliary cirrhosis; ilo: inhaled iloprost; HHT:
hereditary haemorrhagic teleangiectasia; tre: inhaled treprostinil;
#
:p50.01 versus baseline;
"
:p50.02 versus baseline;
+
:p50.09 versus baseline;
1
:p50.001 versus baseline;
e
:p50.0001 versus baseline;
##
: patient
died during study. 1 mmHg 50.133 kPa.
F. REICHENBERGER ET AL. SILDENAFIL IN PORTOPULMONARY HYPERTENSION
c
EUROPEAN RESPIRATORY JOURNAL VOLUME 28 NUMBER 3 565

In the patient sample of the current study, starting combination
therapy with oral sildenafil on top of chronic inhaled
prostanoid treatment leads to a significant and sustained
haemodynamic and functional improvement without signifi-
cant side-effects. However, further additional therapy includ-
ing i.v. epoprostenol might be required when liver
transplantation is planned or patients are not stable on
combination therapy [1].
There are major limitations in the current study. The rather low
number of patients with heterogeneous aetiology of liver
disease might indicate a selection bias. Subgroup analyses or
potential side-effects require further investigation.
Although the current study was not sufficient to deduce
general treatment recommendations, the subjects were
TABLE 2 Characteristics of 12 patients completing 3 and 12 months’ follow-up
Baseline 3 months p-value versus
baseline
12 months p-value versus
baseline
NYHA class 3.3¡0.5 2.6¡0.5 0.001 2.8¡0.4 0.08
Pro-BNP ng?mL
-1
582¡315 230¡278 0.06 189¡274 0.03
PO
2
mmHg 72¡965¡24 0.2 74¡80.5
Bilirubin mg?dL
-1
1.8¡1.2 1.2¡0.9 0.02 1.1¡0.7 0.06
Haemoglobin g?dL
-1
14.1¡2.0 13.8¡1.4 0.7 14.3¡2.0 0.7
Data are presented as mean¡SD, unless otherwise stated. NYHA: New York Heart Association; pro-BNP: pro-brain natriuretic protein; PO
2
: partial pressure of oxygen.
1 mmHg 50.133 kPa.
TABLE 3 Baseline parameters comparing monotherapy
and combination therapy in the whole study
population
Monotherapy Combination
therapy
p-value
Subjects n 86
Male/female n 3/5 1/5
Age yrs 52¡12 60¡11 0.2
Child A/B/C n 3/4/1 4/2/0
NYHA 3.3¡0.5 3.3¡0.5 0.9
6-MWD m 316¡122 296¡101 0.9
Pro-BNP ng?mL
-1
396¡392 722¡189 0.2
mPAP mmHg 50¡761¡11 0.04
CI L?min
-1
?m
-1
2.7¡0.7 1.6¡0.4 0.005
#
PVR dyne?s?cm
-5
759¡338 1625¡747 0.01
#
PO
2
mmHg 68¡12 75¡8 0.23
Bilirubin mg?dL
-1
2.1¡1.8 2.3¡1.2 0.56
Haemoglobin g?dL
-1
14.1¡2.2 14.2¡1.5 0.89
Data are presented as mean¡SD, unless otherwise stated. NYHA: New York
Heart Association; 6-MWD: 6-min walking distance; pro-BNP: pro-brain
natriuretic protein; mPAP: mean pulmonary arterial pressure; CI: cardiac index;
PVR: pulmonary vascular resistance; PO
2
: partial pressure of oxygen;
#
:
pf0.01. 1 mmHg 50.133 kPa.
200
300
400
500
l
l
l
l
l
l
0312
Months
6-MWD m
FIGURE 1. A 6-min walking distance (6-MWD) after 3 and 12 months’ follow-
up treatment, comparing sildenafil monotherapy ($;n57) and sildenafil and
inhaled prostanoids combination therapy (#;n55). Data are presented as
mean¡SEM. There was no statistically significant difference between treatment
groups.
FIGURE 2. Follow-up after 3 and 12 months’ sildenafil treatment, comparing
degrees of hepatic impairment. Data are presented as mean¡SEM. Child A: m,
n57; Child B: ,,n55. There was a statistically significant difference between the
two groups at 3 months (post hoc ANOVA). *: p,0.01 versus baseline.
SILDENAFIL IN PORTOPULMONARY HYPERTENSION F. REICHENBERGER ET AL.
566 VOLUME 28 NUMBER 3 EUROPEAN RESPIRATORY JOURNAL

recruited from patients referred for assessment and therapy for
pulmonary hypertension to a large specialised centre for
pulmonary vascular diseases. In the current authors’ opinion,
the response to sildenafil treatment was sufficiently pro-
nounced and homogeneous to produce significant results.
In conclusion, sildenafil is a safe and well-tolerated therapy in
portopulmonary hypertension which may lead to significant
clinical, functional and haemodynamic improvement after
3 months and to a sustained response over 12 months either
as monotherapy or in combination with inhaled prostanoids.
ACKNOWLEDGEMENTS
The current study is part of the doctoral thesis of E. Steveling.
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