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Michael J. Krowka, MD
Professor of Medicine
Vice-Chair, Division of Pulmonary and Critical Care Medicine
Mayo Clinic
Rochester, Minnesota
Introduction
A relationship between the liver and lung was proposed
by the Greek physician Galen (AD c. 126-216), who believed
that venous blood was “concocted in the liver,”
migrated via a tidal motion to the right ventricle of
the heart, and divided into two blood streams, one to
the lungs and one through the heart into the left ventricle.
According to Galen (so say medical historians) the liver
provided “natural spirit” to the body.1 It
wasn’t until the 1500s that these pulmonary vascular
teachings were questioned, and the first accurate description
of the pulmonary circulation evolved from the Spanish
theologian and physician Miguel Servetus.1
Nearly 500 years later we have witnessed both the remarkable
success of orthotopic liver transplantation and a renewed
interest in the seemingly mysterious relationship between
the liver and the lung. Why do some patients with advanced
liver dysfunction develop pulmonary vascular dilatations
leading to severe arterial hypoxemia, which may totally
resolve after liver transplantation (hepatopulmonary syndrome)?
Why do patients with similar liver disorders experience
a pulmonary vasoproliferative and vasoconstrictive process
leading to pulmonary artery hypertension and right heart
failure frequently notreversible by liver transplantation
(portopulmonary hypertension)? Although these pulmonary
vascular consequences of liver disease are relatively
uncommon (up to 4% to 15% of transplant candidates), with
5000 transplants being done annually and another 18,000
patients on the Organ Procurement Transplant Network (OPTN)
liver transplant wait lists, these clinical problems are
no longer trivial.2
Definition of Portopulmonary Hypertension
First described in 1951, the coexistence of pulmonary
arterial hypertension as a consequence of hepatic dysfunction
has been well documented.3,4
The most important cause of increased mean pulmonary artery
pressure (mPAP >25 mm Hg) in the setting of advanced
liver disease remains the pulmonary arterial vasculopathy
known as portopulmonary hypertension.4,5
Vasoconstriction, endothelial and smooth muscle proliferation,
plexogenic arteriopathy, and in situ thrombosis and/or
fibrosis characterize portopulmonary hypertension.6,7
Since a hyperdynamic circulatory state and the increased
blood volume that accompany liver disease may raise mPAP
(in addition to the pulmonary vasculopathy), specific
hemodynamic criteria have evolved to define portopulmonary
hypertension.5,8,9
Pathology and Pathogenesis
It is important to recognize that portopulmonary hypertension
has pulmonary vascular pathology indistinguishable from
that seen in primary pulmonary hypertension.4,10
A spectrum of pathology has been described from autopsy
and lung explant specimens (open lung biopsy has been
rightfully discouraged because of potential complications).
Medial hypertrophy, endothelial and smooth muscle proliferation,
in situ thrombosis, fibrosis, and classic plexogenic arteriopathy
have been noted (Figure
1). Platelet aggregates lodged within
the pulmonary vascular lumen have been reported and may
contribute to acute right heart deterioration in the post
liver transplant period.11,12
The lack of prostacyclin synthase within the pulmonary
endothelium2,8,9 in portopulmonary
hypertension has been documented, suggesting a lack of
vasodilator capability.10
Recently the evolving “signaling” relationship
between angiopoietin-1 and the TIE receptors within the
pulmonary endothelium has received attention; this relationship
in the setting of liver disease needs to be understood.13
To date there has been no relationship documented between
portopulmonary hypertension and mutations in the bone
morphogenetic protein receptor BMPR2 gene, as noted in
other causes of pulmonary arterial hypertension such as
primary pulmonary hypertension.
 Epidemiology
Poor correlations with Childs-Turcotte-Pugh severity of
liver disease, levels of liver enzymes, serum total bilirubin,
and splanchnic hemodynamics such as the azygous blood
flow and hepatic venous pressure gradient6,14,16
have been reported. An increased frequency of alcoholic
cirrhosis has been noted.16,17
Noncirrhotic portal hypertension has been associated with
portopulmonary hypertension.17-20
Two retrospective series have documented that surgical
portosystemic shunt procedures preceded the diagnosis
of portopulmonary hypertension in 30% to 76% of patients.16,20
In the pre-liver transplant era, the NIH pulmonary hypertension
registry of 204 patients with primary pulmonary hypertension
classified 17 (8%) of the patients as having cirrhosis-associated
pulmonary hypertension.16 In the current era of liver
transplantation, major transplant centers have reported
the frequency of portopulmonary hypertension to be 4%
to 15%.8,20- 23 Remarkably,
a review of published portopulmonary hypertension cases
through 1999 documented that 65% of diagnoses were first
recognized during the liver transplant procedure.18
Clinical Presentation and Significance
The clinical presentation of portopulmonary hypertension
is subtle; exertional dyspnea is the most common nonspecific
symptom.4,16 Other symptoms
and signs, including fatigue and leg edema, can be easily
confused with those of underlying heart and/or liver disease
so that making the diagnosis requires a high degree of
suspicion. Chest pain and/or pressure and syncope are
usually later manifestations of portopulmonary hypertension.
The chest examination is quite unremarkable except for
the usual cardiac findings of pulmonary hypertension.
In the pre-liver transplant era, survival from a French
series reporting portopulmonary hypertension ranged from
72% mortality within 12 months of diagnosis14 to a US
study from the Cleveland Clinic describing a 6 month (median)/15
month (mean) survival as determined from a literature
review of 78 patents.15 Recent
2-year, single institution survival of portopulmonary
hypertension patients (liver transplant patients excluded)
ranged from 50% to 72%.4,17
The importance of pulmonary hypertension in the setting
of advanced liver disease reflects the high risk of conducting
liver transplantation in such patients.18,19,21
In 43 portopulmonary hypertension patients who underwent
orthotopic liver transplantation, a 35% perioperative
mortality was reported.18
Right heart failure and cardiopulmonary collapse caused
most deaths; intraoperative death occurred in 5 patients.18
In a recent multicenter study, despite excluding 45% of
66 portopulmonary hypertension patients from liver transplantation
consideration due to the severity of the condition, transplant
outcome remained problematic. Transplant hospitalization
mortality was 36%, with all deaths occurring within 18
days of transplant; intraoperative death was reported
in 38%.19
Screening
Routine posteroanterior and lateral chest radiography
and resting electrocardiography are insufficient for portopulmonary
hypertension screening purposes. By the time enlarged
pulmonary arteries and/or cardiomegaly are seen, pulmonary
hemodynamics are markedly abnormal. Likewise, the electrocardiographic
findings of right axis deviation, right bundle branch
block, and t-wave inversions in the precordial leads are
associated with advanced hemodynamic abnormality (mPAP
> 35 mm Hg), and thus these findings are not useful
for detecting early disease.
Transthoracic Doppler echocardiography (DE) is relatively
sensitive in detecting increased right ventricular systolic
pressure (RVsys) as an estimate of pulmonary artery systolic
pressure, as long as the pulmonary valve is normal. However,
DE may not distinguish between causes of increased RVsys
such as seen in the hyperdynamic circulatory state, increased
central volume, and the true pulmonary vasculopathy of
portopulmonary hypertension.4,5,25
DE is the current screening procedure of choice if portopulmonary
hypertension is suspected, 4,5,28
but right heart catheterization is mandatory for the definitive
diagnosis.22-27 However,
although many screened patients have increased RVsys (30
to 50 mm Hg by DE), they do not have increased pulmonary
vascular resistance as determined via right heart catheterization.4,8,23,25
Using the more discriminatory screening criteria RVsys
>50 mm Hg to determine indication for right heart catheterization,
85% to 97% of patients with clinically significant portopulmonary
hypertension (mPAP >35 mm Hg) were identified.23,25
In an unpublished series from the Mayo Clinic (N = 360
over the time period 2001 to 2003), approximately 10%
of all orthotopic liver transplantation candidates had
RVsys >50 mm Hg; 20% had RVsys >40 mm Hg. RVsys
could not be accurately measured in 20%.
Right Heart Catheterization
Right heart catheterization is necessary to explicitly delineate
the pulmonary hemodynamic patterns that exist in t he
setting of hepatic dysfunction. In patients with advanced
liver disease, increased pulmonary artery pressures can
be found as a result of multiple underlying causes, including
the high flow hyperdynamic state, excess volume, and the
vasoproliferation and vasoconstriction pulmonary vasculopathy
associated with portopulmonary hypertension (Figure
2). The current portopulmonary hypertension
diagnostic criteria recently endorsed by the European Respiratory
Society-European Association for Study of the Liver (ERS-EASL)
task force on pulmonary-hepatic vascular disorders are summarized
in
Table
1—Current Diagnostic Criteria for Portopulmonary Hypertension.
• Portal hypertension (ie, ascites, esophagogastric
varices, splenomegaly)
• Mean pulmonary artery pressure >25 mm Hg
• Pulmonary capillary wedge pressure <15 mm Hg
• Pulmonary vascular resistance >240 dynes.s.cm-5
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Table 1.4-6,18,19,28
Consensus regarding “normal” pulmonary vascular
resistance in the setting of advance liver disease varies.28
It is well documented that a reduced pulmonary vascular
resistance exists in association with the hyperdynamic
high-flow circulatory state in such patients.8,10,16,28
It is useful to describe evidence- based, clinically significant
hemodynamic cutoffs as well as respect textbook-listed
lower limits of normal in such patients. Data from the
ERS-EASL task force on at least 200 patients with portopulmonary
hypertension suggest that pulmonary vascular resistance
>240 dyne.s.cm-5 is distinctly abnormal; it is always
associated with mPAP >25 mm Hg, and it poses increased
risk of right heart failure in the setting of liver transplantation.28
A subgroup of liver disease patients with 120 < pulmonary
vascular resistance <240 dynes.s.cm-5 and increased
pulmonary capillary wedge pressure are of interest.8,19
If these patients have increased transpulmonary gradients
(mPAP -
PCWP >15 mm Hg), they should be considered to have
mild portopulmonary hypertension and treated as such.
The natural history of this subgroup is unclear and careful
follow-up is required. It is also recognized that selected
hemodynamic data (cardiac output and pulmonary vascular
resistance) should be reported as indices that reflect
body surface area in this subgroup. Rapid volume infusion
during right heart catheterization (1.0 liter of saline
over 10 minutes) has been suggested as a means to identify
patients susceptible to ventricular failure during liver
allograft reperfusion.29
The clinical implications and/or benefits of vasoactive
testing during right heart catheterization in the setting
of portopulmonary hypertension are unclear, sincethe use
of calcium channel blockers in this group of patients
could theoretically worsen portal hypertension.
Other Pulmonary Studies
Although pulmonary function abnormalities are not specific
for portopulmonary hypertension, arterial hypoxemia (mean
PaO2 = 76+9; range, 53 to 97 mm Hg) was reported in 80%
of patients with moderate to severe disease.26 Increased
alveolararterial oxygen gradient and significant accentuation
of respiratory alkalosis compared with cirrhotic patients
without portopulmonary hypertension have been reported.9
Reduced diffusing capacity is frequent,8,16
but nonspecific. In order to consider other possible causes
of pulmonary hypertension in the setting of liver disease,
recommended diagnostic assessments are summarized in the
accompanying portopulmonary hypertension algorithm.
Conclusion
Recognition of the unique clinical associations and characteristics
of portopulmonary hypertension has evolved rapidly over
the last 15 to 20 years as a result of advances in medical
therapies and implications for orthotopic liver transplantation
(both cadaveric and living donor). Further understanding
of the natural history and pathophysiology of portopulmonary
hypertension is essential as our potential therapeutic
interventions expand.
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