Liver Research 6 (2022) 10e20

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Liver Research
journal homepage: http://www.keaipublishing.com/en/journals/liver-research

Review Article

Portopulmonary hypertension: Current developments and future

perspectives*
Huawei Xu, Baoquan Cheng, Renren Wang, Mengmeng Ding, Yanjing Gao*
Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong, China

a r t i c l e i n f o a b s t r a c t

Article history: Portopulmonary hypertension (POPH) is a severe pulmonary vascular disease secondary to portal hy-
Received 29 November 2021 pertension and a subset of Group 1 pulmonary hypertension (PH). The pathological changes of POPH are
Received in revised form indistinguishable from other PH phenotypes, including endothelial dysfunction, pulmonary vasocon-
8 February 2022
striction, and vascular remodeling. These changes cause a progressive increase in pulmonary vascular
Accepted 27 February 2022
resistance and afterload of the right ventricle, eventually leading to severe right heart failure. The
prognosis of POPH is extremely poor among untreated patients. POPH is associated with a high risk of
Keywords:
death after liver transplantation (LT), and severe POPH is considered an absolute contraindication for LT.
Portopulmonary hypertension (POPH)
Portal hypertension
However, pulmonary arterial hypertension (PAH)-targeted therapies are administered to patients with
Pulmonary arterial hypertension (PAH) POPH, and aggressive drug treatment significantly optimizes pulmonary hemodynamics and reduces the
Liver transplantation (LT) risk of death. Therefore, early diagnosis, aggressive PAH-targeted therapies, and proper selection of liver
Evaluation transplant candidates are vital to reduce the risk of surgery and improve clinical outcomes. This article
Treatment aims to review the results of previous studies and describe biological mechanisms, epidemiology, po-
tential risk factors, and diagnostic approaches of POPH. Moreover, we introduce recent therapeutic in-
terventions for the early diagnosis of POPH and efficient clinical management decisions.
© 2022 The Third Affiliated Hospital of Sun Yat-sen University. Publishing services by Elsevier B. V. on
behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction altered hemodynamics with complex and diverse complications.

Interestingly, the hemodynamic pattern of POPH differs from those
Portopulmonary hypertension (POPH) was first described by of other complications (Fig. 1).5 Furthermore, POPH diagnosis re-
Mantz and Craige in 1951, and as the name implies, it involves both quires the exclusion of other causes of pulmonary hypertension
the portal and pulmonary circulatory systems.1 POPH is a severe (PH), including pulmonary disease, left heart disease, and connec-
complication of portal hypertension, which occurs with or without tive tissue disease, which complicate diagnosis and jeopardize early
liver diseases.2,3 Since 1998, POPH has been classified as Group 1 intervention. Therefore, improving diagnostic accuracy and efficacy
pulmonary arterial hypertension (PAH), and the clinical classifica- is fundamental for early clinical medical management.
tion and hemodynamic definition of POPH were updated at the 6th The incidence of POPH reported by epidemiological studies
World Symposium on PAH in 2018 (the latest revisions are sum- varies considerably among countries. In Germany, the estimated
marized in Tables 1 and 2).4e7 According to the latest definition, POPH incidence was 1.2 per million adults in 2014, whereas it was
POPH is diagnosed in clinically confirmed portal hypertension and 0.85 per million adults in the United Kingdom (UK) in 2010.8,9 POPH
hemodynamic parameters obtained from right heart catheteriza- poses a mortality threat to patients, with 5-year survival rates of
tion (RHC) that meet the following criteria: mean pulmonary artery 35e68% according to records from national PAH registries.8,10e13
pressure (mPAP) > 20 mmHg, pulmonary vascular resistance Notably, untreated patients are at extremely high risk of death,
(PVR)
3 Wood units (WU), and pulmonary artery wedge pressure with only a 14% 5-year survival rate.14 Fortunately, several studies
(PAWP)  15 mmHg. Patients with advanced liver disease have have shown that PAH-targeted drug therapy applies also to POPH,
and early treatment significantly improves hemodynamics and
increases the survival rate. Critically, sequential therapy with PAH-
*
Edited by Peiling Zhu and Genshu Wang. targeted drugs and liver transplantation (LT) improve or even
* Corresponding author. normalize pulmonary hemodynamics among patients with POPH.
E-mail address: [email protected] (Y. Gao).

https://doi.org/10.1016/j.livres.2022.02.002
2542-5684/© 2022 The Third Affiliated Hospital of Sun Yat-sen University. Publishing services by Elsevier B. V. on behalf of KeAi Communications Co., Ltd. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
H. Xu, B. Cheng, R. Wang et al. Liver Research 6 (2022) 10e20

Table 1 Therefore, it is crucial to explore the risk factors for POPH, which
Updated hemodynamic diagnostic criteria for POPH. help clinicians identify high-risk patients much earlier. In this re-
Third WSPH held in 2003a Sixth WSPH held in 2018b view, we describe potential risk factors, pathophysiological mech-
mPAP
25 mmHg mPAP >20 mmHg
anisms, epidemiology, and screening methods of POPH. Moreover,
PAWP 15 mmHg PAWP 15 mmHg we review previously published reports on treatment, highlighting
PVR
3 WU PVR
3 WU the significance of early diagnosis and optimal treatment decisions
Abbreviations: mPAP, mean pulmonary artery pressure; PAWP, pulmonary artery to improve survival outcomes.
wedge pressure; POPH, portopulmonary hypertension; PVR, pulmonary vascular
resistance; WSPH, World Symposium on Pulmonary Hypertension; WU, Wood
2. Pathophysiological mechanisms
units.
a
Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of
pulmonary arterial hypertension. J Am Coll Cardiol. 2004; 43: 40Se47S. https://doi. At present, POPH pathophysiology remains unclear. Inflamma-
org/10.1016/j.jacc.2004.02.032. tion state, oxidative stress, endothelial cell activation, and vasoac-
b
Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and tive substances imbalance are responsible for vascular injury and
updated clinical classification of pulmonary hypertension. Eur Respir J. 2019; 53:
1801913. https://doi.org/10.1183/13993003.01913-2018.
tissue damage occurring in end-stage liver disease and its extra-
hepatic complication.16 Generally, POPH may be linked to the
following pathophysiological changes.
Table 2
Updated clinical classification of Group 1 PAH (quoted from the study by Simonneau
et al.4).
2.1. Proinflammatory state

Group 1 PAH Patients with liver disease develop a proinflammatory state

1.1. Idiopathic PAH induced by hepatic metabolic abnormalities, tissue damage, and
1.2. Heritable PAH abnormal proliferation or dysregulation of the intestinal flora.17,18
1.3. Drug- and toxin-induced PAH
Serum levels of tumor necrosis factor and other proinflammatory
1.4. PAH associated with:
1.4.1. Connective tissue disease cytokines (e.g., interferon-g, interleukin (IL)-1b, and IL-6) are
1.4.2. HIV infection increased.19,20 The sustained inflammatory response contributes to
1.4.3. Portal hypertension pathological angiogenesis, inducing vascular remodeling by
1.4.4. Congenital heart disease directly activating leukocyte aggregation or indirectly promoting
1.4.5. Schistosomiasis
1.5. PAH long-term responders to calcium channel blockers
protease production.21 These proinflammatory factors enhance
1.6. PAH with overt features of venous/capillaries (PVOD/PCH) involvement liver fibrosis and promote endothelial injury by activating hepatic
1.7. Persistent PH of the newborn syndrome stellate cells as well as damaging vascular endothelial and smooth
Abbreviations: HIV, human immunodeficiency virus; PAH, pulmonary arterial hy- muscle cells by inducing an oxidative stress state in vivo.22
pertension; PCH, pulmonary capillary hemangiomatosis; PH, pulmonary hyper- Furthermore, increased intestinal wall permeability and forma-
tension; PVOD, pulmonary veno-occlusive disease. tion of portal-systemic collateral circulation can be found in pa-
tients with advanced liver diseases.23,24 Bacterial microorganisms
from the intestine enter the visceral and systemic circulation
Although most previous randomized controlled studies excluded
through the portal circulation and lymphatic system, thereby
patients with POPH, more prospective randomized clinical trials in
causing endothelial damage.
this specific population are necessary for the future as our under-
standing of POPH improves and guidelines for managing POPH are
published.15 2.2. Hyperdynamic circulatory syndrome
Female sex, autoimmune hepatitis, spontaneous portosystemic
shunts (SPSS), splenectomy, and anemia are underlying risk factors Cirrhotic patients have higher cardiac output (CO) and lower
for POPH. The incidence of POPH is unaffected by the severity of vascular resistance than non-cirrhotic patients.25 Several studies
liver diseases; however, the severity of cirrhosis is an independent have shown that half of the patients with chronic liver disease
prognostic factor influencing the survival of patients with POPH. (CLD) exhibit hyperdynamic circulatory syndrome, characterized
Furthermore, the perioperative and postoperative mortality in LT by high CO and low systemic vascular resistance.26 The hyper-
strongly correlates with the presence and severity of POPH. dynamic circulatory state causes an increased pulmonary blood
volume and contributes to increased pulmonary vascular shear

Fig. 1. Different hemodynamic patterns in patients with advanced liver diseases. Abbreviations: CO, cardiac output; HPS, hepatopulmonary syndrome; mPAP, mean pulmonary
artery pressure; PAWP, pulmonary artery wedge pressure; POPH, portopulmonary hypertension; PVR, pulmonary vascular resistance.

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H. Xu, B. Cheng, R. Wang et al. Liver Research 6 (2022) 10e20

stress.27 Furthermore, patients with decompensated cirrhosis are pulmonary circulation were higher in patients with POPH than
often accompanied by severe water and sodium retention, which those in healthy controls and that MIF levels were closely con-
increases pulmonary blood volume circulation and exacerbates nected with PVR.37 Bone morphogenetic protein 9 (BMP9) is an
PH.28 endothelial cytoprotective factor synthesized mainly by the liver
and improves PH, vascular remodeling, and right ventricular hy-
2.3. Vasoactive substances imbalance pertrophy.38,39 Low BMP9 levels are associated with the production
and development of POPH; BMP9 levels are significantly lower in
Damaged hepatocytes and activated neurohumoral factors in patients with POPH than those in healthy controls and other pa-
liver diseases increase the serum levels of vasoconstrictors, tients with classified PH.40 Furthermore, several animal model
including 5-hydroxytryptamine, endothelin-1, thromboxane A2, trials have demonstrated that exogenous BMP9 supplementation
norepinephrine and angiotensin II, and IL-1 and IL-6.29,30 By can protect pulmonary vascular endothelial cells from damage and
contrast, there is a decrease in the serum levels of vasodilators, such slow the disease progression.41 These recent findings appear to
as prostaglandins and nitric oxide (NO). These vasoactive sub- provide significant insights into the pathogenesis of POPH and
stances directly enter the pulmonary circulation via portosystemic provide new approaches for the clinical treatment of POPH. Future
shunts, causing excessive pulmonary vasoconstriction and endo- drug development and multicenter prospective drug clinical trials
thelial and periarterial smooth muscle remodeling, thereby are necessary to test the safety and efficacy used in patients with
constantly increasing the pulmonary artery pressure.31,32 POPH.

2.4. Oxidative stress 3. POPH epidemiology

Oxidative stress levels are increased in patients with POPH, The prevalence of POPH significantly varies across countries,
causing hepatocyte mortality and stellate cell activation, which which may be due to regional disparities in demography, medical
promote the release of proinflammatory cellular mediators in vivo, care levels, degrees of economic and cultural development,
ultimately causing tissue and endothelial damage.33 Consequently, comprehensive management of POPH, as well as differences in the
reducing oxidative stress may be a therapeutic target for POPH etiology and severity of underlying liver diseases.42,43 In Western
prevention. countries, alcoholic liver disease is the leading cause of cirrhosis,
whereas hepatitis B is the most common cause in Asian coun-
2.5. Genetic susceptibility tries.44,45 POPH accounts for 2e17.6% of all PAH cases
(Table 3),9,12,13,46e48 affecting 2e10% of patients with portal hy-
Notably, not all patients with portal hypertension develop pertension and 2e10% of patients awaiting LT.46,49e52 Since the
POPH; therefore, genetic susceptibility may be implicated in the recent definition has been proposed, POPH prevalence needs to be
mechanism of POPH. Al-Naamani et al.34 reported that high levels reassessed. Atsukawa et al.53 recently performed RHC on 186 pa-
of estradiol and aromatase gene variants were associated with tients with portal hypertension and discovered a POPH prevalence
increased risk of POPH, suggesting that estrogen and its metabolites of 3.3% based on the recent definition; however, this percentage
may play a role in POPH pathogenesis. POPH development is was reduced to 1.1% based on the old definition. The updated
associated with single nucleotide polymorphisms in the estrogen definition allows for more high-risk patients to undergo RHC,
receptor 1, aromatase, calcium-binding protein A4, phosphodies- reducing the rate of missed screening and reflecting a more realistic
terase 5, and angiopoietin 1 genes.35 These findings provide in- prevalence.
sights into the search for novel therapeutic targets for POPH.
4. Risk and prognosis
2.6. Cell factor
Although several studies have demonstrated that the severity
Macrophage migration inhibitory factor (MIF) is a vasocon- of liver disease and portal pressure are not associated with the
strictor factor expressed in several organs throughout the body. It is presence and severity of POPH,53,54 a few studies have found that
associated with pulmonary artery smooth muscle cell proliferation the severity of liver diseases is a vital predictor of mortality risk
and is involved in autoimmune liver disease pathogenesis.36 One in patients with POPH.10,12 Perioperative mortality in LT is
prospective study found that MIF levels in both the systemic and significantly correlated with the presence and severity of POPH.55

Table 3
Prevalence of POPH in the PAH population in different national PAH registries.

Authors (year) Period of observation Diagnostic criteria Nation Prevalence rate

46
Humbert et al. (2006) 2002.10e2003.10 mPAP >25 mmHg and PCWP 15 mmHg France 10.4%
(70/674)
47
Chazova et al. (2020) 2012.1e2019.1 mPAP
25 mmHg, PAWP 15 mmHg, and PVR
3 WU Russia 1.8%
(9/487)
Lazaro Salvador et al.13 (2021) 1998.1e2017.12 mPAP
25 mmHg at rest, PCWP or LVEDP 15 mmHg, and PVR
3 WU Spain 10.7%
(237/2224)
Badesch et al.48 (2010) 2006.3e2007.9 mPAP >25 mmHg at rest or > 30 mmHg with exercise, PCWP or American 10.6%
LVEDP 18 mmHg and PVR
240 dyn $ s $ cm5 (136/1280)
12
Savale et al. (2020) 2007.1e2017.1 mPAP
25 mmHg, PAWP 15 mmHg, and PVR >3 WU France 17.6%
(742/4225)
9
Hoeper et al. (2016) 2014.1e2014.12 mPAP
25 mmHg and PAWP 15 mmHg at rest Germany 4.5%
(78/1752)

Abbreviations: LVEDP, left ventricular end-diastolic pressure; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PAWP, pulmonary artery wedge
pressure; PCWP, pulmonary capillary wedge pressure; POPH, portopulmonary hypertension; PVR, pulmonary vascular resistance; WU, Wood units.

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H. Xu, B. Cheng, R. Wang et al. Liver Research 6 (2022) 10e20

As POPH severity progresses, the right heart structure and func- 5. POPH evaluation
tion are significantly impaired, and the prognosis of patients
becomes worse. Krowka et al.56 revealed that POPH increased 5.1. Clinical presentation
cardiopulmonary-related mortality among patients with liver
transplant; moreover, they observed the significant increase in The clinical symptoms of POPH are insignificant and do not
mPAP, PVR, and transpulmonary gradient before LT was associ- differ from other PAH phenotypes within Group 1. At the time of
ated with poor postoperative prognosis. Le Pavec et al.10 found initial diagnosis, 60% of patients have no apparent clinical symp-
that the presence and severity of cirrhosis, as well as the low toms.66 Dyspnea is the most prevalent manifestation, and other
cardiac index (CI), were independent prognostic factors influ- clinical symptoms include chest tightness and pain, cough, he-
encing survival in patients with POPH. Further, another study moptysis, peripheral edema, and syncope.67 Physical examination
found that the severity of cirrhosis was highly associated with the may reveal signs of right heart failure (RHF), such as jugular vein
risk of death in patients with POPH on the waiting list of LT.57 By dilatation, generalized edema, ascites, and a systolic murmur in the
contrast, a study from the UK reported that POPH-related survival tricuspid valve auscultation area.68,69 Electrocardiography may
was unrelated to the severity of cirrhosis.8 These differences in present increased P-wave amplitude and negative T-wave on limb
the studies may be attributed to the etiology and severity of leads, rightward deviation of the electrical axis, and right bundle
involved cirrhotic patients. branch conduction block.70 Chest X-ray may show enlarged heart
Female sex and autoimmune hepatitis have been recognized as shadow and dilated main pulmonary artery.71 Pulmonary function
independent risk factors for POPH.54 Recently, DuBrock et al.58 tests may reveal decreased pulmonary diffusion function. Arterial
analyzed the impact of gender differences on the presentation blood gases mostly demonstrate mild or moderate hypoxemia.72
and prognosis of POPH. They found that, unlike males, female pa- Furthermore, decreased exercise tolerance and shortened 6-
tients exhibited a lower model for end-stage liver disease (MELD) minute walking distance (6MWD) are found among patients with
score (12.1 ± 4.2 vs. 13.8 ± 4.9, P ¼ 0.01), higher baseline PVR POPH. More than half of the patients with POPH are in New York
(610.6 ± 366.6 dyn $ s $ cm5 vs. 461.0 ± 185.3 dyn $ s $ cm5, P < Heart Association (NYHA) functional class (FC) IIIeIV and WHO FC
0.001), and were more likely to suffer from autoimmune liver dis- IIeIII.10,13,47 However, due to the complexity of CLD and its com-
eases. Although overall survival rates were similar in female and plications, which can easily overlap with the clinical symptoms of
male patients, females under the age of 50 years had a poorer POPH, it is challenging for clinicians to identify patients with POPH
survival rate after age stratification. One possible explanation is based on their clinical symptoms.
that estrogen and its metabolites may worsen hemodynamics and
increase the risk of death in patients with POPH. A case-control 5.2. TTE
study also showed that estrogen levels and estrogen metabolizing
enzyme gene variants (CYP19A1) were associated with POPH TTE is an excellent noninvasive, highly sensitive screening tool
development.34 Therefore, additional studies are necessary to for POPH. POPH is associated with right heart insufficiency, which
investigate the relationship between sex hormone levels and he- significantly affects the survival prognosis of patients with POPH.
modynamic changes, as well as the impact on POPH morbidity and TTE screening reveals structural changes, such as right ventricular
survival. enlargement and hypertrophy, and hemodynamic changes, such as
SPSS are prevalent in patients with advanced cirrhosis.59 elevated RVSP and right atrial pressure. However, controversy still
Several studies have shown that patients with POPH had a exists over the optimal cutoff values of hemodynamic parameters.
higher SPSS prevalence, and patients with moderate to severe The Mayo Clinic recommends systolic pulmonary artery pressure
POPH were more likely to develop portosystemic shunts than (sPAP) > 50 mmHg as the threshold for TTE screening, with a
those with mild POPH.60 Patients with portal hypertension are at positive predictive value (PPV) and a negative predictive value
a higher risk of developing POPH after splenectomy. Furthermore, (NPV) of 74% and 97%, respectively, for detecting moderate and
patients with POPH who underwent splenectomy have a worse severe POPH.50 In a recent meta-analysis, Korbitz et al.73 showed
prognosis than those who did not.61 In a subgroup analysis of 141 that the sensitivity of screening gradually decreased when the
patients with POPH, Segraves et al.62 discovered that after sple- estimated pulmonary artery systolic pressure (ePASP) threshold
nectomy, patients exhibited higher right ventricular systolic increased from 35 to 45 mmHg. However, sensitivities of the three
pressure (RVSP) than those with unresected spleens. Therefore, groups (ePASP >35e40 mmHg, ePASP >40e50 mmHg, and ePASP
clinicians should prioritize early transthoracic echocardiography >45e50 mmHg) were 0.91, 0.85, and 0.62, respectively, with no
(TTE) screening among patients with portal hypertension un- statistical difference between subgroups.73 Colle et al.3 reported
dergoing splenectomy. The risk of portal vein thrombosis (PVT) is that the PPV and NPV of sPAP >30 mmHg for POPH screening were
increased after splenectomy.63 PVT incidence is higher in patients 59% and 100%, respectively. Raevens et al.55 found that only 7 of 74
with POPH than those without (50.0% vs. 16.7%, P ¼ 0.04); patients with TTE-estimated sPAP >30 mmHg met the diagnostic
however, PVT is not an independent risk factor for POPH.64 PVT criteria for RHC, with a sensitivity and specificity of 100% and 54%,
may be involved in POPH development, and its mechanistic role respectively. When 38 mmHg was used as a threshold, the area
in POPH development needs to be further investigated. Some under the curve was 0.974, with a sensitivity and specificity of 100%
studies have shown that low hemoglobin concentration was a and 82%, respectively. Interestingly, with the introduction of right
risk factor for POPH, possibly due to increased CO in the presence ventricular dilatation (defined as RVEDD >3.3 cm), the specificity
of anemia.43,65 Several studies have found a relationship between increased from 82% to 93%.55 However, Cotton et al.74 used the
ascites and poor prognosis of POPH, which may indirectly reflect threshold of sPAP >50 mmHg and reported a PPV and an NPV of
the effect of poorer liver function and fluid retention on pulmo- 37.5% and 91.9%, respectively.
nary hemodynamics.13 According to one study, high creatinine Considering the updated diagnostic criteria for POPH, the cutoff
and low oxygen partial pressure were linked to POPH develop- values for TTE-estimated hemodynamic indices may no longer be
ment.43 However, these findings are still controversial, and applicable. Future studies are still necessary to explore and estab-
additional research is needed to explore the role of these factors lish the optimal cutoff values of hemodynamic indices for more
in POPH development and progression. patients with POPH to undergo an effective early screening.

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H. Xu, B. Cheng, R. Wang et al. Liver Research 6 (2022) 10e20

5.3. Chest computed tomography (CT) help clinicians effectively identify high-risk patients during the
early stages of disease progression and execute early intervention
Patients with POPH show dilated main pulmonary artery on of risk factors to improve prognosis.
chest CT. A meta-analysis from China showed that the sensitivity
and specificity of CT-based detection of main pulmonary artery 6. POPH treatment
diameter (mPA-D) for diagnosing PH were 79% and 83%, respec-
tively.75 A recent retrospective study attempted to assess the 6.1. General supportive therapy
feasibility of screening for POPH with mPA-D and the ratio of the
mPA-D to the ascending aortic diameter (aAo-D). Based on CT Anticoagulation is not recommended for patients with POPH
findings, suspicious POPH was defined as mPA-D
29 mm or mPA- owing to the risk of gastrointestinal bleeding.84 Beta-blockers have
D/aAo-D
1.0, whereas mPA-D
33 mm was classified as probable negative chronotropic effects and may worsen pulmonary hemo-
POPH. The authors found that a portal venous system shunt of dynamics. Several studies have shown that discontinuing beta-

5 mm and a higher inferior vena cava minimum diameter were blockers improved exercise capacity and resting pulmonary he-
independent predictors of suspicious POPH (P < 0.05). However, no modynamics in patients with moderate to severe POPH.85
independent predictors related to probable POPH were found.76 CT Accordingly, beta-blockers are not recommended to patients with
may help clinicians select high-risk patients with POPH prior to POPH, and other treatments, including endoscopic variceal ligation,
echocardiography. However, this study lacks further validation of may be considered. Furthermore, calcium channel blockers are not
echocardiography and RHC and does not provide the sensitivity and recommended for patients with POPH since they may increase the
specificity of CT screening indicators. Additional larger prospective risk of hepatic venous pressure gradients as well as water and so-
studies are still necessary to analyze the potential of CT in POPH dium retention.86 Patients with severe POPH are prone to devel-
screening. oping peripheral edema; therefore, diuretic treatments may be
used accordingly.
5.4. Cardiac magnetic resonance imaging (CMR) Hypoxemia promotes pulmonary vasoconstriction, increases
PVR, and exacerbates PH. Therefore, oxygen therapy can be
CMR is the gold standard for assessing right ventricular struc- administered to patients with POPH with severe hypoxemia
ture and function.77 CMR accurately estimates right ventricular (PaO2 < 60 mmHg) at rest.72 Transjugular intrahepatic portosys-
volume and right ventricular ejection fraction (RVEF), calculates temic shunt (TIPS) increases preload and worsens RHF after the
biventricular extracellular volume, and assesses myocardial fibrosis procedure. Therefore, current guidelines recommend that TIPS be
by late gadolinium-chelation enhancement.78 Studies have shown preceded by a comprehensive risk assessment and should be
that enlarged right ventricular volumes and reduced RVEF were avoided in patients with severe POPH.15,87
associated with poorer survival outcomes in patients with PAH.79,80
CMR overcomes the load-dependent and sound window limita- 6.2. PAH-targeted therapy
tions of echocardiography and can predict clinical deterioration in
patients with PAH. However, the high cost, long examination time, Although few randomized controlled studies on patients with
and low availability limit its use as a screening tool for routine POPH are available, several uncontrolled studies and case series
examination and follow-up assessment of clinical deterioration risk have reported that PAH-targeted drugs can be a treatment alter-
among patients with PAH. Right heart function is a significant factor native, thereby increasing the safety of LT and improving the sur-
affecting the clinical prognosis of patients with PAH. As an excellent vival outcomes of patients.88e92 A recent study from the Spanish
noninvasive screening tool, it is necessary to further evaluate the PAH Registry (REHAP) showed that patients with POPH who
role of CMR in clinical risk stratification and disease prognosis received PAH-targeted therapy exhibited significantly higher sur-
assessment of patients with POPH. vival rates than those who did not.13 The overall survival rates at 1,
3, and 5 years were 81.1%, 66.4%, and 49.8%, respectively, in the
5.5. RHC treated group compared with 53.3%, 35.5%, and 17.8%, respectively,
in the untreated group (P < 0.001).
Elevated CO, PAWP, and PVR can increase the mPAP.81 Statisti- A meta-analysis of 26 studies evaluated the effect of PAH-
cally, 20e50% of cirrhotic patients have mild PH, which can cause targeted therapy on hemodynamics and exercise capacity among
an increased mPAP with a normal PVR. However, this particular patients with POPH.93 Subgroup analysis revealed significant im-
hemodynamic alteration caused by hyperdynamic circulation does provements in pulmonary hemodynamics and exercise capacity
not affect the risk of death in LT.82 Although TTE is the effective among patients with POPH who received drugs with LT. The esti-
method for POPH screening, RHC is crucial in confirming the mated overall mortality rates were 62%, 33%, and 36% for 38 un-
diagnosis. Therefore, all patients suspected of having underlying treated patients, 290 patients treated with PAH-targeted therapy,
POPH should undergo screening using TTE, and all high-risk pa- and 40 patients treated with LT, respectively. By contrast, the
tients meeting the current screening thresholds should undergo mortality rate was 20% in 113 patients who received sequential
RHC. However, since the clinical signs of POPH are nonspecific and treatment with drugs and LT. Notably, nearly half of the patients
RHC is an intrusive test with the risk of hemorrhage, infection, and treated with sequential therapy stopped taking drugs after LT.
venous embolism, a considerable delay between the earliest Legros et al.94 reported that oral pulmonary vasoactive drugs
appearance of clinical signs and the final diagnosis exists. In a significantly improved the hemodynamic status of patients with
prospective cohort study, Cartin-Ceba et al.83 found that the median POPH, and oral therapy was well tolerated by patients. The 5-year
time between portal hypertension diagnosis and POPH diagnosis survival rate was 35% for patients who received pharmaco-
was 2.3 (interquartile range: 0.6e3.0) years. therapy, whereas it increased to 53% for those who received drug
Because POPH is a major cause of mortality, early identification therapy combined with LT.94 These findings suggest that pulmo-
of potential patients with POPH is crucial for disease progression nary vasoactive drugs combined with LT appear to be the most
and survival outcomes. More prospective cohort studies should be effective POPH treatment. However, whether cirrhotic or non-
conducted in the future to explore the diagnosis of pre-POPH and cirrhotic patients who do not yet meet the criteria for LT should
identify high-risk factors driving POPH development. These will undergo LT remains unclear. A large number of prospective
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H. Xu, B. Cheng, R. Wang et al. Liver Research 6 (2022) 10e20

randomized controlled trials are still needed to investigate the in- reduction in pulmonary flow resistance from baseline levels;
dications for LT in patients with POPH and the optimal timing of however, no major changes were observed in WHO FC or 6MWD.
interface between targeted drug therapy and LT. Macitentan is well tolerated by patients with POPH with no
Current pharmacologic treatments of patients with POPH hepatotoxicity. The most frequently observed adverse effects
comprise four major drug classes, including prostacyclins and their included peripheral edema (26%), headache (16%), and anemia (5%).
analogs causing vasodilation, phosphodiesterase 5 inhibitors However, the Portico study excluded patients with severe liver
(PDE5i) inhibiting apoptosis, endothelin receptor antagonists injury (defined as Child C or MELD score
19) and was unable to
blocking endothelin A and B receptor pathways, and soluble gua- determine whether macitentan is effective in the treatment of se-
nylate cyclase stimulators regulating NO function. vere liver disease. Furthermore, the relatively short follow-up
period did not allow for an assessment of long-term prognostic
6.2.1. Prostacyclin and its analogs impacts of macitentan in patients with POPH.
Prostacyclin is a vasodilator with an antiplatelet aggregation According to case reports and small-sample studies, ambri-
effect with analogs that promotes visceral vasodilation while sentan is a selective endothelin receptor A antagonist that reduces
simultaneously inhibiting vascular proliferation. Previous clinical PVR and mPAP and increases 6MWD without causing liver dam-
studies with small samples sizes and case reports indicated that age.109 A prospective multicenter open-label clinical study evalu-
prostacyclin analogs, including intravenous epoprostenol, intrave- ated the efficacy of ambrisentan in patients with POPH and found
nous treprostinil, and inhaled iloprost, significantly improved that 23 patients showed significant improvements in hemody-
pulmonary hemodynamic indices and survival outcomes in pa- namics and WHO FC after 24 weeks of ambrisentan mono-
tients with POPH.91,95e98 Notably, splenomegaly was observed in therapy.110 Furthermore, ambrisentan had no liver toxicity, and the
patients with POPH who received continuous intravenous epo- most common drug-related adverse health events included edema
prostenol therapy. Moreover, leukocytopenia and thrombocyto- (38.7%) and headache (22.5%); however, the risk of water and so-
penia were observed during blood routine examination.99 dium retention could be mitigated by adjusting diuretic therapy.
Additionally, prostacyclin causes adverse effects, including skin However, this clinical study also excluded severe cirrhotic patients
flushing, headache, and hypotension, and inhibits platelet aggre- (Child C); therefore, the efficacy and safety of ambrisentan in pa-
gation, thereby increasing the hemorrhagic risk.100,101 More tients with severe liver diseases remain unclear, and further studies
importantly, because intravenous injection and inhalation are are required to address these issues.
inconvenient to operate, and intravenous injection carries the risk
of infection and bleeding, widespread clinical application is 6.2.4. sGC stimulator
hampered. Riociguat, an sGC stimulator that promotes NO elevation, causes
pulmonary vasodilation and has been approved for PAH treat-
6.2.2. PDE5i ment.111 A PATENT-1 randomized placebo-controlled study found
Sildenafil is a pulmonary vasoactive drug with excellent efficacy that 11 patients with POPH administered with riociguat oral
in PAH treatment.102 It acts on the NO-soluble guanylate cyclase treatment (2.5 mg per day) demonstrated significant improve-
(sGC)-cyclic guanosine monophosphate (cGMP) signal transduction ments in 6MWD and WHO FC at 12 weeks, and their PVR levels
pathway, inhibits cGMP breakdown by phosphodiesterase, and were remarkably lower than the baseline levels.112 The safety and
reduces PVR and pulmonary arterial pressure. Small retrospective overall tolerability of the drug were favorable, with peripheral
studies and case reports indicated that patients with POPH respond edema and headache being the most common adverse effects.
well to sildenafil. Sildenafil monotherapy and dual therapy com- Furthermore, hypotension occurred more frequently in the rioci-
bined with inhaled iloprost improved pulmonary hemodynamics guat group than that in the placebo group, indicating that riociguat
and WHO FC and were well tolerated by patients with no may be an appropriate treatment option for patients with POPH
hepatotoxicity.103e105 with moderate to severe hypertension. Nevertheless, larger pro-
spective studies with a larger sample size are necessary to inves-
6.2.3. Endothelin receptor antagonists tigate the efficacy of riociguat in POPH. Furthermore, a recent
Bosentan, macitentan, and ambrisentan are endothelin receptor multicenter randomized controlled trial compared the efficacy and
antagonists that act on the therapeutic target of PAH and are drug safety of PDE5i treatment and switching to riociguat treatment in
options for PAH treatment. According to several retrospective patients with PAH. The study found that the riociguat group
studies, bosentan is a nonselective endothelin receptor A and B showed more significant improvements in exercise capacity
antagonist that significantly reduces PVR, improves prognosis, and (6WMD), WHO FC, and serum NT-proBNP concentrations than the
can be well tolerated by patients with POPH.106 Savale et al.107 re- PDE5i group (sildenafil or tadalafil) at 24 weeks. Moreover, the
ported that, unlike baseline levels, patients treated with bosentan riociguat group was less likely to experience clinical adverse
performed well at short-term (5 ± 2 months) and long-term events.113 Therefore, riociguat oral therapy seems to be a better
(35 ± 16 months) follow-up, with remarkable improvements in drug option for patients who are not well treated with PDE5i.
hemodynamics and activity endurance. Although a considerable
rise in liver enzymes (>three-fold the upper limit of normal) was 6.2.5. Combination therapy
observed in seven patients, they were normalized within 3 months Several randomized drug clinical studies have demonstrated
after drug reduction or withdrawal in six patients. This indicates that dual-targeted drug therapy reduces the risk of death in pa-
the significance of regular monitoring of liver function during drug tients with PAH better than single-drug oral therapy.114e116
administration. Although studies have shown that PAH-specific drug triple ther-
A Portico study, which was the first randomized controlled trial apy lowered PVR more than monotherapy or dual therapy, patients
of PAH-targeted drugs specifically targeting this specific population with POPH were excluded.117,118 Some case report studies have
of patients with POPH, recently investigated the therapeutic effi- shown improvements in hemodynamics and clinical parameter
cacy of macitentan in patients with POPH with mild to moderate among patients with POPH who received combination drug
liver disease.108 After 12 weeks, the macitentan group (n ¼ 43) therapy.119e121 However, due to the small-sample size and lack of
showed significant improvements in pulmonary hemodynamics long-term follow-up data, the safety and efficacy of combination
compared with the control group (n ¼ 42), resulting in a 35% drugs in patients with POPH remain poorly understood; therefore,
15
H. Xu, B. Cheng, R. Wang et al. Liver Research 6 (2022) 10e20

it is not currently recommended as the first option of therapy combined with LT. Several studies have described the long-
pharmacotherapy.122 term outcome of POPH after LT. Through a long-term post-LT
follow-up (median time, 7.8 years) of 488 patients with POPH,
6.3. LT Khaderi et al.125 found that the patients had a good long-term
prognosis with an overall survival rate of 85.7%. Moreover, pa-
The European Respiratory Society Task Force classifies POPH tients with moderate to severe POPH who responded well to
severity into three levels based on mPAP measured by RHC at rest vasodilator therapy could be safely treated with LT.125 A study that
(in the presence of increased PVR): mild (25  mPAP <35 mmHg), examined data from the French Pulmonary Hypertension Registry
moderate (35  mPAP <45 mmHg), and severe (mPAP over a 10-year period found that patients with POPH who under-

45 mmHg).123 POPH is a primary risk factor for poor prognosis in went LT had better long-term outcomes than those who received
LT. Krowka et al.56 revealed that the severity of POPH was correlated pharmacotherapy.12 Furthermore, approximately half of the pa-
with post-LT survival, and patients with mild POPH had a good tients who experienced early PAH-targeted drug therapy and suc-
prognosis with zero mortality, whereas patients with severe POPH cessful LT safely stopped taking drugs after LT.93
had a mortality rate of up to 100%. Therefore, a pre-LT hemody- POPH directly affects mortality in patients with POPH by
namic evaluation is vital for patients with POPH. According to the contributing to progressive RHF. Furthermore, the presence of
International Liver Transplant Society Practice Guidelines, an mPAP POPH and severe hemodynamic alterations prolong the waiting
of
45 mmHg is considered an absolute contraindication for LT.15 time for LT in patients with advanced liver disease, thereby indi-
Based on this international guideline, patients with POPH who do rectly affecting mortality. Higher PVR prior to LT is related to a high
not meet the criteria for safe LT must be administered PAH-targeted risk of mortality after LT.126 Statistically, patients mostly die from
drug therapy. Patients with good response to targeted drug therapy intraoperative hemodynamic deterioration, severe RHF, graft
(mPAP <35 mmHg or mPAP 35e50 mmHg, 3 WU < PVR <4 WU) dysfunction, severe liver disease and its complications, and infec-
and strong right ventricular function can undergo LT.124 tion during the perioperative and postoperative periods of LT.127,128
Swanson et al.14 reported that the 5-year survival rate was only Therefore, early therapeutic intervention, comprehensive preop-
14% for untreated patients with POPH, 45% for those treated with erative risk assessment, and good postoperative care are essential
targeted drugs, and 67% for those subjected to PAH-targeted for patients with POPH.

Fig. 2. Algorithm for screening and hemodynamic treatment in LT candidates and symptomatic patients. Abbreviations: LT, liver transplantation; MELD, model for end-stage
liver disease; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PAWP, pulmonary artery wedge pressure; PH, pulmonary hypertension; PVR, pul-
monary vascular resistance; RHC, right heart catheterization; sPAP, systolic pulmonary artery pressure; TTE, transthoracic echocardiography; WU, Wood units.

16
H. Xu, B. Cheng, R. Wang et al. Liver Research 6 (2022) 10e20

Considering the significance of POPH risk stratification for the 8. Conclusion

preoperative evaluation of LT as well as the goal of targeted drug
therapy, the algorithm for screening and hemodynamic therapy POPH is a pulmonary vascular disease caused by portal hyper-
based on the practice guidelines presented by the International tension (with or without underlying liver disease), and it can affect
Liver Transplantation Association in 2016 is summarized in Fig. 2.15 multiple organ systems. We recommend that multidisciplinary
Salgia et al.129 reported that the 3-year survival rate for patients clinicians should be involved in the optimal management of POPH.
with POPH on the liver transplant waiting list was 75.6%. Due to the Moreover, clinicians must focus on risk factors that influence the
high risk of death for patients on the liver transplant waiting list development and prognosis of POPH, identify high-risk patients
and the potential benefits of receiving PAH-targeted drug therapy early, and provide targeted interventions to delay disease pro-
and LT, in 2006, the United Network for Organ Sharing proposed the gression. A large number of future trials are needed to assess the
MELD exception policy.130 Patients with POPH with adequate he- impact of diverse treatment approaches on patient prognosis and
modynamic response to PAH-targeted drug therapy (mPAP guide clinicians in selecting targeted treatment options and LT
<35 mmHg and PVR <400 dyn $ s $ cm5) qualify for the MELD candidates, including those responding well to treatment although
exception, which shortens the time spent on the liver transplant without indications for LT.
waiting list. Patients must undergo RHC every 3 months to ensure a
continued effective response to PAH-targeted drug therapy and Authors’ contributions
minimize risk during the LT and perioperative periods.
H. Xu wrote and revised the manuscript and drew figures. B.
7. Perspectives Cheng, R. Wang, M. Ding and Y. Gao checked the manuscript. All
authors approved the manuscript.
POPH is secondary to portal hypertension, and most patients
with POPH have a history of liver diseases, which readily influence Declaration of competing interest
blood flow systems in multiple organs. Cirrhosis is currently the
11th leading cause of death worldwide, with approximately 2 The authors declare that they have no conflicts of interest.
million individuals dying each year from CLDs. Based on the current
high global prevalence of cirrhosis, the prevalence may be under- Acknowledgements
estimated. Consequently, further research into the prevalence of
POPH and the reasons for the differences in prevalence among This work was supported by the Key Research and Development
different regions is necessary. Program of Shandong Province of China (NO.2019GSF108254).
In the current state of PAH management, the survival rate of
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