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Drs. Sulica and DePalo, the ACCP Evidence-Based
Clinical Practice Guidelines offer a lengthy discussion
of the complexities of portopulmonary hypertension and
suggestions with regard to therapy. However, based on
the small sample size of most clinical studies, no formal
recommendations are made with regard to the therapeutic
approach to this entity. How do you address it?
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 Roxana
Sulica, MD
Instructor of Medicine
Mount Sinai Pulmonary Hypertension Program
Mount Sinai School of Medicine
New York, New York
 Louis
R. DePalo, MD
Assistant Professor of Medicine
Mount Sinai Pulmonary Hypertension Program
Mount Sinai School of Medicine
New York, New York
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Let us first offer some background on this entity. Portopulmonary
hypertension is a subtype of PAH defined by an elevated
pulmonary artery pressure and increased pulmonary vascular
resistance in association with porto-systemic shunts.
In patients with end-stage liver disease, it must be distinguished
from increased pulmonary artery pressure due to hyperdynamic
circulatory states or to fluid overload. Patients with
portopulmonary hypertension have a particular hemodynamic
profile characterized by a higher cardiac output compared
to patients with idiopathic PAH
with a similar degree of pulmonary pressure elevation.
Cardiopulmonary complications and right ventricular failure
are the main cause of death in approximately two thirds
of patients with portopulmonary hypertension. The pathophysiology
and pathological findings are similar to other categories
of PAH, thereby allowing similar therapies to be used.
However, the presence of liver disease modifies most treatment
considerations, explaining why portopulmonary hypertension
patients have been excluded from multicenter PAH
treatment trials and the consequent lack of evidence-based
recommendations.
Moderate-to-severe pulmonary hypertension significantly
increases the mortality of orthotopic liver transplantation.
The estimated prevalence of portopulmonary hypertension
in patients presenting for liver transplantation is 10%
to 15%.
While in the typical PAH patient, the primary goal of
therapy is right ventricular functional improvement, for
portopulmonary hypertension patients, rapid reduction
in pulmonary pressure is also important for transplant
eligibility. During evaluation for orthotopic liver transplantation,
the main objective is to reduce and keep mean pulmonary
arterial pressure <35 mm Hg and pulmonary vascular
resistance <240 dyne sec cm-5. The degree of right
ventricular dysfunction is also important for surgical
outcome; therefore, echocardiography with dobutamine stress
test and fluid
challenge are employed preoperatively to determine the
right ventricular reserve. Follow-up with echocardiography
and right-heart catheterization is performed every 6 months
in patients with portopulmonary hypertension on the liver
transplant waiting list to assure maintenance of hemodynamic
eligibility. Therapeutic choices in patients with portopulmonary
hypertension depend not only on consideration of liver
transplantation, but also on other aspects of the disease.
Most information regarding the treatment options in portopulmonary
hypertension comes from case series and case reports.
How does the diagnosis of portopulmonary hypertension
affect your treatment decision compared with patients
with other causes of PAH? Which drugs do you use?
Continuous intravenous epoprostenol has led to improved
pulmonary hemodynamics in several case series of patients
with portopulmonary hypertension, leading to successful
transplantation in these patients. Epoprostenol has been
also used in patients who developed de novo portopulmonary
hypertension after liver transplantation. Long-term administration
of epoprostenol results in augmentation of cardiac output
in idiopathic PAH and adjustments in the epoprostenol
rate are tailored to avoid the drug-induced high flow
state. Since CO is elevated at baseline in patients with
portopulmonary hypertension, further increases related
to therapy can prove deleterious and difficult to interpret
and manage. In patients with portopulmonary hypertension,
specific adverse effects of prostacyclin therapy have
been described, including thrombocytopenia and pancytopenia,
either from splenomegaly and hypersplenism (which are
potentially worsened by therapy) or related to an autoimmune
phenomenon. The continuous monitoring of blood cell
counts is critically important in the follow-up of these
patients to avoid bleeding complications or overwhelming
infections.
Epoprostenol administration is cumbersome and requires
a serious commitment. Patients must be able to reconstitute
their own drug and to follow strict administration recommendations.
These skills can be compromised in patients
with fluctuating mental status from hepatic encephalopathy
and appropriate family and social support is an important
consideration before initiation of epoprostenol therapy.
Epoprostenol is reserved for patients with more severe
portopulmonary
hypertension.
Treprostinil is a prostacyclin analogue with a longer
halflife compared to epoprostenol, thereby allowing subcutaneous
administration by continuous infusion. Advantages over
epoprostenol include easier administration and avoidance
of line sepsis and of rebound pulmonary hypertension in
cases of abrupt drug discontinuation. Although the landmark
treprostinil trial in PAH did not include portopulmonary
hypertension patients, a large retrospective series of
portopulmonary hypertension patients demonstrated hemodynamic,
functional, and survival benefit (compared to historical
controls) at 8-month follow-up. There were no instances
of significant effect of treprostinil on liver function
tests or on platelet counts. Control of pain and reactions
at the infusion site related to treprostinil administration
remains a difficult problem. Although various local measures
are employed, some patients require systemic pain management
(including opioids). This can be associated with increased
complications in patients with advanced liver disease.
Patients receiving treprostinil have been successfully
activated for orthotopic liver transplantation.
What about endothelin receptor antagonists?
Clinical trials with endothelin receptor antagonists in
patients with PAH have demonstrated beneficial effect
on symptoms, WHO functional class, hemodynamics, and right
ventricular function. An important advantage of these
drugs is oral administration. Because of the potential
for liver toxicity, endothelin receptor antagonists are
currently not recommended for portopulmonary hypertension.
Although there is no formal recommendation from the ACCP,
the document emphasizes that “most experts would
likely recommend avoiding the oral endothelin antagonist
bosentan in this population.” Approximately 10% of
the PAH patients treated with bosentan have developed
reversible elevations in hepatic transaminases, but no
cases of fulminant liver injury were reported in clinical
trials or postmarketing. Of note, recent case reports
have demonstrated the safe use of bosentan in portopulmonary
hypertension.
Is sildenafil an option in this disease?
The theoretical lack of hepatotoxicity and the ease of
oral administration render sildenafil treatment an attractive
potential therapeutic alternative in patients with portopulmonary
hypertension, particularly in light of the data in PAH
presented at the ACCP meeting in October. However, both
sildenafil plasma levels and duration of action are altered
in the presence of advanced liver disease and the optimal
dosing regimen is not established in portopulmonary hypertension.
How about conventional therapy with anticoagulation,
diuretics, and calcium-channel blockers?
As with the above therapies, there are no randomized
controlled trials in patients with portopulmonary hypertension
with conventional therapies. Warfarin anticoagulation
is recommended by experts in patients with PAH to counteract
insitu thrombosis. The role of anticoagulation in portopulmonary
hypertension is unknown and potentially hazardous given
the already present increased risk of bleeding. It is
not recommended in portopulmonary hypertension. In a select
group of idiopathic PAH patients who demonstrate acute
vasoreactivity during vasodilator administration, oral
calcium-channel blocker therapy is associated with long-term
benefit. There are no studies on calcium-channel blockade
in portopulmonary hypertension, but experts advocate the
role of a vasodilator trial in portopulmonary hypertension
evaluation as a guide to the vasoactive perioperative
management of orthotopic liver transplantation. The ACCP
suggests that in vasodilator responders calcium-channel
blockers are appropriate to consider, but that high-dose
challenges should probably be avoided. Diuretics are used
to avoid fluid overload states and oxygen supplementation
is given to keep the arterial oxygen saturation >90%.
In conclusion, current recommendations for portopulmonary
hypertension therapy are scarce and incomplete and mainly
based on expert opinion with moderate strength of recommendation
(E/B). Severity of the disease and impact on the outcome
of liver transplantation should serve as strong motivators
for future treatment trials in this particular group of
PAH patients. I offer a few selected references on this
topic.1-7
References
1. Swanson KL, McGoon MD, Krowka MJ. Survival
in Portopulmonary
hypertension with the use of intravenous epoprostenol.
Am J Respir Crit Care Med. 2003;167:A693.
2. Krowka MJ, Frantz RP, McGoon MD, et al. Improvement
in pulmonary
hemodynamics during intravenous epoprostenol (prostacyclin):
a study of 15 patients with moderate to severe portopulmonary
hypertension. Hepatology. 1999;30:641-8.
3. Sulica R, Emre S, Poon M. Medical management of porto-pulmonary
hypertension and right ventricular failure prior to living-related
liver transplantation. Congest Heart Fail. 2004;10:192-4.
4. Kuo PC, Johnson LB, Plotkin JS, et al. Continuous intravenous
infusion of epoprostenol for the treatment of portopulmonary
hypertension. Transplantation. 1997;63:604-6.
5. Benza RL, Tallaj JA, Rayburn BK, et al. Safety and
efficacy of treprostinil in cirrhosis-related pulmonary
arterial hypertension. Presented at the 54th Annual Meeting
of the American Association for the Study of Liver Diseases;
Boston, Massachusetts, 2003.
6. Clift PF, Townend JN, Bramhall S, Isaac JL. Successful
treatment of severe portopulmonary hypertension after
liver transplantation by bosentan. Transplantation. 2004;77:1774-5.
7. Halank M, Miehlke S, Hoeffken G, et al. Use of oral
endothelin receptor antagonist bosentan in the treatment
of portopulmonary hypertension. Transplantation. 2004;77:1774-5.
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