This document defines and describes porto-pulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS), two pulmonary vascular complications that can arise from liver disease and portal hypertension. POPH is characterized by elevated pulmonary artery pressure and resistance, while HPS involves pulmonary vasodilation and intrapulmonary shunting leading to hypoxemia. The document covers diagnostic criteria and evaluations, pathophysiology, treatment options including liver transplantation, and prognosis for each condition.

2. Porto-pulmonary hypertension
and Hepato-pulmonary syndrome

4. Definition
Pulmonary arterial hypertension (PAH)
associated with portal hypertension,
whether or not portal hypertension is
secondary to an underlying liver disease

5. Current criteria include:
1. The presence of portal hypertension, but not
necessarily the presence of cirrhosis.
2. Haemodynamic measurements from right
heart catheterization including mean
pulmonary artery pressure ≥ 25 mmHg at
rest, mean pulmonary capillary wedge
pressure (mean Ppcw ) <15 mmHg,

6. Current criteria include:
and pulmonary vascular resistance (PVR)>240
dyn/s/cm-5 or >3 Wood units: PVR = [(mean
Ppa-mean Ppcw )/cardiac output]*80.
 In patients with both elevated mean Ppa and
mean Ppcw a TPG (the transpulmonary
gradient) >12 mmHg is highly indicative of
increased PVR and should be a key diagnostic
feature to define a true increase in PVR
 TPG = mean Ppa - mean Ppcw.

7. Epidemiology and risk factors
 Identification of POPH is made at an average of
4–7 yrs after the diagnosis of portal hypertension.
 It usually presents during the fifth decade of life,
as compared with the third and fourth decade for
idiopathic PAH.
 Associated with female sex and underlying
autoimmune liver disease.
 Hepatitis C virus negatively associated with POPH
severity of liver disease was not associated with the
presence of POPH.

8. Mechanism of development of POPH
 Increased blood flow in chronic liver disease
trigger the dysregulation of vasoactive,
proliferative and angiogenic mediators.
 Portosystemic shunts may allow the shunting of
vasoactive substances from the splanchnic to the
pulmonary circulation, causing deleterious effects
in the pulmonary vasculature.

9. Mechanism of development of POPH
 In the pulmonary vasculature, activation of
endothelin A (ETA) induces vasoconstriction,
smooth muscle cell proliferation and intimal fibrotic
changes.
 Overexpression and dysregulated signalling of ETB
(normally mediate peripheral vasodilation) in the
pulmonary vasculature may contribute to increased
pulmonary vasomotor tone and remodelling has
been observed in POPH.

10. Mechanism of development of POPH
Upregulation of several additional
neurohumoral mediators, such as throm-
boxane-B1, interleukin-6 and serotonin.
Finally, vasodilating mediators, such as nitric
oxide (NO) and prostaglandin I2
(prostacyclin), may be decreased in POPH.

11. Histopathology of POPH
 Similar to idiopathic PAH.
 Intimal fibrosis & hypertrophy of the smooth
muscle cells and fibroblasts.
 In situ thrombosis, and plexiform lesions
resulting from intraluminal endothelialisation or
micro-aneurysms within pulmonary arterioles

12. Clinical presentation
 Typically produces no symptoms or only has
symptoms related to the underlying cirrhosis or
portal hypertension.
 Exertional dyspnoea is the most common
presentation.
 Fatigue, generalized weakness, light-headedness
and orthopnoea.
 In advanced stages chest discomfort, dyspnoea at
rest, syncope and haemoptysis can occur.

13. Physical examination may reveal
 Elevated jugular venous pressure, an accentuated
second heart sound.
 Systolic murmur consistent either with tricuspid
regurgitation or pulmonic insufficiency (Graham–
Steele murmur).
 right ventricular heave with signs of right heart
failure (third or fourth heart sounds).
 A pulsatile liver, lower extremity oedema out of
proportion to ascites& physical signs of cirrhosis.

14. Diagnostic evaluation
Chest radiographs: enlargement of the
right-sided chambers, as well as dilatation
of the pulmonary arteries.
ECG: right axis deviation, right atrial and
ventricular enlargement and right
ventricular strain pattern and complete
right bundle branch block.

15. Diagnostic evaluation
Pulmonary function tests: decreased
diffusing capacity DLCO.
ventilation/perfusion lung scan is usually
normal.
ABG: type I respiratory failure with
widening of alveolar arterial oxygen
gradient.

16. Diagnostic evaluation
 Although the most important test to screen for
POPH is the two-dimensional transthoracic
echocardiogram (TTE), the RHC is gold standard
as TTE cannot discriminate between increased
PVR due to true vaso-oclussive arteriopathy or
due to an increased pulmonary flow .
 Using TTE, the right ventricular systolic pressure
(RVSP) can be estimated from the peak tricuspid
regurgitant velocity by using the modified
Bernoulli equation.

17. Diagnostic evaluation
 Thus, an RVSP< 30 mmHg can be used to rule out
POPH, whereas an RVSP>50 mmHg predicts
moderate-to-severe POPH in 75% of patients.
 The need for RHC should be detemined on
individualized bases for patients with RVSP
between 30-50 mmHg.

18. Classification

19. Treatment
 Calcium channel blockers are contraindicated as
they can produce mesenteric vasodilation that can
worsen portal hypertension.
 B-blockers in POPH associated with deterioration
of exercise capacity and pulmonary
haemodynamics, due to their negative inotropic
and chronotropic effects.
 Oral anticoagulation is not recommended for
patients with POPH due to the increased risk of
gastrointestinal haemorrhage.

20. Treatment
 Although diuretics have an important role in
POPH patients with volume overload and fluid
retention, Close monitoring is required since
diuretics can reduce cardiac output by decreasing
right ventricular preload, facilitating renal failure
and systemic hypo perfusion.
 Supplemental oxygen should be considered for
POPH when the arterial oxygen tension ( PaO2) <
60 mmHg.

21. PAH-specific therapies
Prostacyclin analogues (PAs), e.g.
Epoprostenol & ilioprost are well tolerated
with minimal adverse effects that include
flushing, headaches and cough.
Endothelin receptor antagonist:
 Bosentan with dual non-selective ETA
associated with improvement in symptoms
and exercise capacity being well tolerated
and without evidence of drug-related liver
injury.

22. PAH-specific therapies
The selective ETA receptor antagonist
ambrisentan, requiring only once daily
dosing, associated with a risk of clinically
significant liver toxicity.
The oral phosphodiesterase inhibitors .e.g
sildenafil and tadalafil.
Their therapeutic benefits in pulmonary
haemodynamics during the first 3 months,
was not sustained after 12 months.

23. PAH-specific therapies
Sildenafil is not sufficient as monotherapy in
severe POPH and that patients with severe POPH
may benefit from combination therapy.

24. Liver transplantation LTx
 LTx in POPH is performed to treat the underlying
portal hypertension/liver disease.
 A mean Ppa >50 mmHg and/or a PVR of
>250dyn/s/cm-5 should be considered to be a
contraindication to LTx.
 Patients who achieve improvements in mean
Ppa<35 mmHg and PVR< 250 on PAH specific
therapy should be considered potential candidates
for LTx.

25. Liver transplantation LTx
 Whether POPH improves after LTx is a matter of
debate.
 LTx should not be viewed as a healing measure for
POPH, and PAH-specific therapies should continue
during the early post-transplant period.
 Periodic haemody-namic surveillance is mandatory to
allow proper adjustment of treatment and identify
patients who can be weaned off PAH-specific therapy.

26. Sign of RV strain
RHC needed

27. Prognosis
 survival is at least as good when compared with
idiopathic PAH with overall survival rates at 1, 3
and 5 yrs of 88%, 75% and 68%, respectively.
 Prognosis of POPH was related to cardiac index
and to the severity of liver disease, but even for
patients with the worst outcome the 5-yr survival
rate was 58%.

29. Definition
 HPS is defined as the presence of the triad of an
arterial oxygenation defect, intrapulmonary
vasodilatation, and the presence of liver disease.
 Neither cirrhosis nor portal hypertension is a
prerequisite for the diagnosis, as it has been
reported in chronic non-cirrhotic hepatitis, non-
cirrhotic portal hypertension, Budd–Chiari
syndrome, and even in acute liver diseases.

30. Pathophysiology
 Intra-pulmonary vasodilation is responsible for
the three physiological mechanisms that
contribute to impaired gas exchange in HPS:
1. Ventilation-perfusion mismatching occurs due to
overperfusion of the alveolar capillary bed,
particularly in the less well-ventilated dependent
lower zones, and is exacerbated by a blunted
vasoconstrictor response to hypoxia.

31. Pathophysiology
2. Diffusion defect:
 Dilatation of pulmonary microvessels at the gas
exchange interface increases the distance that
oxygen must travel from the alveolus to
equilibrate with red cells in the center of the
alveolar capillary, creating a functional
diffusional barrier to oxygen exchange.
 Rapid blood transit due to the hyperdynamic
circulation in these patients

32. Pathophysiology
3. Shunt: Patients may also have true anatomical
shunting in the form of direct arteriovenous
communications, which allow blood to
completely bypass alveoli, resulting in mixed
venous blood passing into the pulmonary veins.

34. Pathogenesis of HPS
Bacterial translocation is common in
cirrhosis.
Lung endotoxemia due to bacterial
translocation from the gut is responsible for
increased levels of TNF-ᾳ and upregulation
of lung (inducible NOS) iNOS in cirrhosis.

35. Pathogenesis of HPS
 NO exists three isoforms , nducible NOS (iNOS),
endothelial NOS (eNOS), and neuronal NOS.
 NO causes vasodilation by activation of cGMP.
 iNOS is localized to intravascular macrophages in
the lung, these macrophages are stimulated by
endotoxemia to produce pro-inflammatory
cytokines, including TNF-ᾳ , which triggers
upregulation of iNOS .

36. Pathogenesis of HPS
 Plasma ET-1 levels are increased in cirrhosis and
are higher in patients with intrapulmonary
vasodilation.
 Activation of ETB receptors on endothelial cells
causes NO-mediated vasodilation which
contribute to pathogenesis of HPS.
 CO mediates vasodilation in a similar way to NO
by stimulating cGMP production in vascular
smooth muscle cells.

37. Pathogenesis of HPS
 Both splanchnic and pulmonary angiogenesis have
been documented in experimental cirrhosis and
portal hypertension.
 Increased TNF-ᾳ signaling due to bacterial
translocation and/or altered chemokine expression
lead to monocyte accumulation in pulmonary
circulation with subsequent angiogenesis .

38. Pathogenesis of HPS

39. Diagnosis of HPS

40. Clinical presentation
 The presence of HPS should be considered in all
patients with liver disease who complain of dyspnea.
 A more specific symptom is platypnea (dyspnea that
increases from the supine to the erect position),
which may be associated with ortho-doxia (hypoxia
that is worse when erect).
 Finger clubbing is very common in HPS.
 One should always suspect HPS in patients with
chronic liver disease and clubbing.

41. Screening for intrapulmonary vasodilatation
Contrast echocardiography:-
Advantages:- in copmarison to radioactive
lung perfusion scan it is:
 More sensitive,
 More readily available, and
 Less invasive.

42. Screening for intrapulmonary vasodilatation
Method of application
 A sample of liquid (normally saline) is vigorously
shaken to produce microbubbles.
 Injected into an arm vein while the cardiac chambers
are visualized via a transthoracic approach.
 Normally, these bubbles, which are > 25mm in
diameter, are trapped in the alveolar capillary bed,
where the vessels have a diameter of 5–8 mm.

43. Screening for intrapulmonary vasodilatation
 Appearance of microbubbles in the left atrium
after intravenous injection suggests presence of
pulmonary vasodilation.
 A positive study can of course also occur due to
the passage of bubbles through a cardiac defect,
but in this case the bubbles appear in the left
atrium much sooner (within three cycles) after
their first appearance in the right atrium.

44. Screening for intrapulmonary vasodilatation
 Radioactive lung perfusion scan using
macroaggregated albumin (MAA):
Method of application:
 peripheral venous injection of MAA particles that
have been radio-labeled with technetium-99.
 Followed by whole body scanning to estimate the
extrapulmonary shunt fraction.
 The detection of a significant amount of radiation in
the brain or kidneys suggests intrapulmonary
vasodilation or intracardiac shunting.

45. Screening for intrapulmonary vasodilatation
 Chest X-ray may be normal or may show
increased vascular markings in the lower zones.
 High resolution computerized tomography to
exclude intrinsic lung disease.
 Decreased DLCO.
 Pulmonary angiography can be normal in HPS
and is rarely required.
 It is, useful in patients in whom a large arte-
riovenous shunt is suspected(proposed as PaO2 <
300 mmHg on 100% inspired O2)

46. Treatment
Liver transplantation:
 Liver transplant remains the only effective
treatment of HPS.
“Transplant window” for patients with HPS, in
which patients with PO2 less than 60 mmHg are
prioritized for transplant, while those with more
severe hypoxia are excluded because of their poor
post-transplant prognosis.

47. MAA to exclude intrapulmonary shunt in
absence of pulmonary disease

48. Treatment
Indeed, a recent study reported mortality of only 9%
in patients with severe HPS, as defined by PaO2 < 50
mmHg.
 Interventional radiology
The role of transjugular intrahepatic shunt (TIPS) in
the management of HPS remains unproven.
 Intra-arterial coil embolization of discrete pul-
monary arteriovenous communications has been used
successfully and may have a place in improving right
to left shunt.

49. Treatment
Coil embolization of multiple discrete
arteriovenous fistulae has also been used
successfully in a patient with persistent hypoxia 6
months after liver transplant.
 Medical therapy:
An effective medical therapy for HPS has yet to be
established.
Oxygen is used for symptomatic relief.

50. Treatment
Although inhibition of NO synthesis using intrave-
nous methylene blue acutely improved
oxygenation in HPS, nebulized treatment with
NOS inhibitor had no effect on gas exchange
parameters, despite reducing cardiac output and
increas-ing pulmonary vascular resistance.
Trial of pentoxifylline failed to improve arterial
oxygenation.

51. Take home message
 Liver disease and portal hypertension can be
associated with pulmonary vascular
complications, including:
 Portopulmonary hypertension (POPH), characterised by
an elevated mean pulmonary artery pressure secondary to
an increased pulmonary vascular resistance, and
 Hepatopulmonary syndrome (HPS), characterised by
hypoxaemia due to pulmonary vasodilatation and
shunting.

52. Take home message
 Awareness of evaluation and management
algorithms for POPH and HPS are critical for
optimisation of outcomes in patients with these
conditions.
 Key aspects of management of POPH and HPS
include identification of patients likely to benefit
from liver transplantation (LTx) and management
before and after LTx.

53. Take home message
 Severe forms of POPH represent a contraindication
to LTx.