consensus report
Austrian consensus on the definition and treatment of portal hypertension and its complications (Billroth II)
13
1 3
N, N-bis(2-chloroethyl)-N-nitrosourea (BCNU) or
multiple alkylating agents [
94
] (Table
2
). As no estab-
lished causal treatment exists, management should
include prophylactic management strategies avoiding
the precipitating factors.
3. BCS and portal vein thrombosis have similar patho-
physiology where, in addition to local factors such
as liver abscess and abdominal trauma, the acquired
causes such as Behçet’s disease, hypereosinophilic
syndrome, and granulomatous venulitis are risk fac-
tors. Weak risk factors for BCS include factor V Leiden
and prothrombin gene mutations and oral contracep-
tive use (at least with earlier generation contracep-
tives until 1985) [
95
].
4. Investigations for vascular liver diseases as underlying
cause or precipitating factor should be carried out in
all patients with clinical manifestation of decompen-
sated portal hypertension.
Comprehensive guidelines [
95
], a systematic meta analy-
sis [
96
] and authoritative reviews [
97
–
99
] have been pub-
lished on vascular disorders of the liver, which allow us to
give the following recommendations:
Diagnosis
1. In all patients with first presentation or worsening of
portal hypertension, duplex sonography of the por-
tal vein and hepatic veins should be carried out to
exclude portal vein thrombosis or Budd-Chiari syn-
drome (III).
2. In patients with high clinical suspicion, contrast en-
hanced CT, MRI, or angiography should be carried
out despite normal ultrasound to exclude or confirm
portal vein thrombosis or Budd-Chiari syndrome (III).
3. Acute portal vein thrombosis (with or without con-
comitant intestinal infarction) should be considered
in all patients with abdominal pain for more than 24 h
(III).
4. Portal vein thrombosis and Budd-Chiari syndrome
should prompt investigations for local prothrombotic
conditions (infection, abscess, tumor, cysts, etc.) and
systemic thrombophilic conditions listed in Table
1
.
The absence of elevated platelet counts or elevated
hematocrit or negative testing for the JAK2 mutation
p.Val617Phe are insufficient to exclude myeloprolif-
erative disease (IIc).
5. Sinusoidal obstruction syndrome should be consid-
ered in patients who received total body irradiation or
drugs listed in Table
2
(typically patients being condi-
tioned for marrow transplantation),
who present with
portal hypertension and hyperbilirubinemia (IIc).
Management of noncirrhotic portal hypertension
1. Whenever possible, correct the underlying risk factor
for venous thrombosis (III).
2. The possibility for correcting venous outflow in BCS
by angioplasty or the possibility to increase portal
flow in BCS or PVT by insertion of a TIPS should be
evaluated by an experienced interventionist. TIPS im-
proves transplant-free survival in BCS but not in SOS
[
95
] (IIc).
3. Patients with PVT or BCS should receive anticoagula-
tion therapy for at least 3 months unless liver trans-
plantation is imminent. For patients with a permanent
prothrombotic condition, lifelong anticoagulation is
advisable. Low molecular weight heparins are initi-
ated and shifted to oral anticoagulation after stabili-
zation of the patient. In patients with high bleeding
risk, therapeutic drug monitoring of LMW heparin is
recommended (anti F Xa level 0.5–0.8 IU/ml). The tar-
get INR for oral anticoagulation is 2–3 (IIb).
4. Patients with PVT or BCS should be screened for
esophageal or gastric varices. Large varices should be
managed endoscopically before long term anticoagu-
lation is initiated (III).
5. Long term anticoagulation is recommended in pa-
tients with an unknown cause or thrombus extension
into the mesenteric vein (III).
6.
Liver transplantation should be considered in all
patients with noncirrhotic portal hypertension and
significant liver failure. This includes patients with
recently diagnosed BCS and patients with SOS and a
favorable hematological prognosis (III).
Hepato-pulmonary vascular disorders
Portopulmonary hypertension
Definition
Portopulmonary hypertension (PPHTN) is kind of pul-
monary hypertension that is associated with portal
hypertension.
PPHTN is defined as [
100
,
101
]:
1. Underlying disease with portal hypertension
2. Mean pulmonary artery pressure (PAPm) > 25 mmHg
6-mercaptopurine
6-thiogunanine
Actinomycin D
Azathioprine
Busulfan
Cytosine arabinoside
Cyclophosphamide
Dacarbazine
Gemzutumab-ozogamicin
Melphalan
Oxaliplatn
Urethane
Table 2. Drugs associated with SOS
14
Austrian consensus on the definition and treatment of portal hypertension and its complications (Billroth II)
consensus report
1 3
3. Mean pulmonary artery occlusion pressure < 15 mmHg
Pulmonary vascular resistance > 240 dyn×sec×cm
−5
is
recommended additionally by the ERS Task Force Pul-
monary-Hepatic Vascular Disorders [
101
].
Staging of severity [
2
]
Mild PAPm > 25 mmHg–< 35 mmHg
Moderate PAPm ≥ 35 mmHg–45 mmHg
Severe PAPm ≥ 45 mmHg
PPHTN is a frequent cause of pulmonary hypertension
[
102
]. Its prevalence in patients with cirrhosis that are
listed for liver transplantation ranges between 2–16 %
(II-2). PPHTN is the second most common cause of pul-
monary-hepato-pulmonary vascular disorder in patients
with cirrhosis [
103
–
109
] (II-2).
Diagnosis
Symptoms of portal hypertension usually occur prior to
symptoms of pulmonary hypertension (dyspnea, syn-
cope, chest pain) [
110
,
111
] (II-2). Patients with portal
hypertension and dyspnea at rest and during exercise
should be tested for presence of PPHTN. They should
undergo transthoracic echocardiographic evaluation
including contrast-enhanced echocardiography to rule
out hepatopulmonary syndrome (III).
Patients with estimated systolic pulmonary artery
pressure > 40–50 mmHg or signs of abnormal right
ventricular function via transthoracic echocardiogra-
phy should undergo pulmonary artery catheterization,
which is the gold standard for assessment of pulmonary
hemodynamics.
Preferably, this testing should be performed in addi-
tion to hepatic hemodynamic assessment in the hepatic
catheter laboratory. Also, pulmonary function testing
including arterial blood gas analysis, thoracic CT scan,
pulmonary angiography and/or ventilation–perfusion
scan, assessment of autoantibodies (ANA, ANCA,…), and
HIV status are recommended [
100
,
101
].
Therapy
Several case series reported effects of medical therapy
of PPHTN. Currently, there is a lack of randomized con-
trolled studies. Patients that suffer from NYHA II dyspnea
or higher despite optimized therapy of portal hyperten-
sion, should receive medical therapy [
101
] (II-2). This
could include:
• Prostaglandin-derivates (Epoprostenol, Iloprost,…)
improved pulmonary hemodynamics and exercise ca-
pacity [
112
–
116
] (II-2).
• Case series using endothelin receptor antagonists
(Bosentan, Ambrisentan) reported improved pulmo-
nary hemodynamics without adverse events on the
hepatic function [
117
–
120
] (II-2).
• Sildenafil improved pulmonary hemodynamics in a
small uncontrolled cohort [
118
] (II-2).
• Long term oxygen therapy (LTOT) is recommended in
patients with PaO
2
< 60 mmHg [
101
] (III).
• Beta-blocking agents have deleterious effects on he-
modynamics and exercise capacity in patients with
PPHTN and should be strictly avoided [
121
] (II-2).
• Calcium channel blockers are not recommended as
they may increase HVPG [
101
] (III).
• Systemic anticoagulation cannot be recommended
for all patients because of the lack of data and because
it may increase the risk of bleeding. Administration
should be performed after individualized evaluation
of the risk-benefit ratio [
101
] (III).
• TIPS is not recommended in PPHTN as it may increase
the risk of right heart decompensation [
101
] (III).
• Liver transplantation is an effective treatment option
of PPHTN. However, patients must be stratified ac-
cording to severity of PPHTN [
101
] (II-2):
1. Patients with mild PPHTN (PAPm < 35 mmHg,
good cardiac function) should proceed to liver
transplantation.
2. Patients with moderate PPHTN (PAPm ≥ 35 mmHg–
45 mmHg, good cardiac function) should receive
vasodilator therapy prior to liver transplantation.
3. Liver transplantation is contraindicated in patients
with severe PPHTN (PAPm ≥ 45 mmHg). These
patients should be considered for medical therapy
of PPHTN, only.
Hepatopulmonary syndrome
Definition
Hepatopulmonary syndrome (HPS) is the most common
hepatopulmonary vascular disorder in patients with liver
cirrhosis with a prevalence of 20–30 % [
122
,
123
] (II-2). It
is defined as gas exchange abnormality as a consequence
of liver disease due to intrapulmonary vascular dilatation
and shunting [
101
].
Diagnostic criteria of HPS are:
1. Presence of liver disease.
2. Gas exchange abnormality (alveolar arterial oxygen
tension difference (AaDO
2
) ≥ 15 mmHg or AaDO
2
≥ 20 mmHg in patients for patients aged > 64 years,
respectively.
3. Positive contrast-enhanced echocardiography (intra-
pulmonary shunting is defined as detection of micro-
bubbles in the left atrium 4–6 heartbeats after the ini-
tial appearance in the right side of the heart).