Portopulmonary hypertension and the risk of high right ventricular systolic pressure in liver transplant candidates

Abstract

Aim

Portopulmonary hypertension (PoPH) is a rare and serious complication of liver cirrhosis and portal hypertension that can interfere with liver transplantation (LT). We evaluated the prevalence of PoPH and the clinical features of right ventricular systolic pressure (RVSP), which is equivalent to pulmonary artery systolic pressure, in LT candidates.

Methods

This was a single-center retrospective study. A total of 157 Japanese patients with decompensated liver cirrhosis or portal hypertension (76 men, median age = 52 years [range: 18–68 years]) were enrolled. The relationships between RVSP and clinical parameters, and the prevalence of PoPH in LT candidates, were evaluated.

Results

The cardiological parameters were as follows: brain natriuretic peptide (BNP), 39.1 (4.0–780.5) pg/mL; RVSP, 31.2 (16.0–122.4) mmHg; ejection fraction, 58% (28–72%); and mean peak tricuspid regurgitation velocity, 2.3 (1.5–5.3) m/s. The RVSP was significantly higher in females (p = 0.02) and primary biliary cholangitis (PBC) patients (p = 0.01), and was weakly correlated with the BNP level (r = 0.40, p = 0.01). For RVSPs of < 36 and ≥ 36 mmHg, the 5-year survival rates were 36.1% versus 34.1%, and 85.4% versus 85.3%, in non-LT and LT cases, respectively (p = 0.47 and 0.69, respectively). Among six patients with an RVSP ≥ 50 mmHg, three (1.9%) were diagnosed with PoPH and treated with vasodilators.

Conclusions

PoPH was observed in 3 cases (1.9%) in 157 LT candidates. In patients with suspected mild pulmonary hypertension (RVSP, 36 - 50 mmHg), LT was successfully performed.

About the Authors:

Ryoko Hayashi

Roles Data curation, Formal analysis

Affiliation: Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan

Tomomi Kogiso

Roles Conceptualization, Data curation, Investigation, Writing – original draft

* E-mail: [email protected]

Affiliation: Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan

ORCID logo https://orcid.org/0000-0003-1248-4324

Noriko Kikuchi

Roles Supervision

Affiliation: Department of Cardiology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan

Kana Yamamoto

Roles Supervision

Affiliation: Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan

Shinichi Nakamura

Roles Supervision

Affiliation: Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan

Hiroto Egawa

Roles Supervision

Affiliation: Department of surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan

Nobuhisa Hagiwara

Roles Supervision

Affiliation: Department of Cardiology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan

Katsutoshi Tokushige

Roles Conceptualization, Supervision

Affiliation: Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan

Introduction

Portopulmonary hypertension (PoPH) is an uncommon complication of cirrhosis and portal hypertension diagnosed based on concomitant occurrence of pulmonary arterial hypertension (PAH) [1–3]. PoPH was found in 5–15% of PAH cases [4], and 1–6% of patients with portal hypertension have PAH [3, 5–7]. The prevalence of PoPH is 2–6% in liver cirrhosis and liver transplantation (LT) candidates [5–7]. PoPH is defined as a mean pulmonary artery pressure (mPAP) of > 25 mmHg, pulmonary vascular resistance (PVR) of > 120 dyn× s/cm-5, and pulmonary capillary wedged pressure (PCWP) of < 15 mmHg in the presence of portal hypertension [8–10]. Other definitions include a PVR of > 2 or 3 Wood units, as measured by right heart catheterization [10, 11].

Echocardiography is useful for detecting PoPH [12]. In healthy control subjects, the normal right ventricular systolic pressure (RVSP) is reportedly 28 ± 5 mmHg (range 15–57 mmHg). According to these data, mild pulmonary hypertension can be defined as a pulmonary artery systolic pressure (PASP) of approximately 36–50 mmHg, equivalent to an RVSP of approximately 36–50 mmHg [13, 14]. The clinical signs and symptoms of pulmonary hypertension are pulmonic valve insufficiency, paradoxical septal motion, right ventricular hypertrophy/dilatation, and poor tricuspid annular systolic excursion. Patients with an RVSP of > 50 mmHg according to echocardiography require catheterization [15]. Additionally, in patients with an RVSP ≥ 36 mmHg, when physical findings are consistent with pulmonary hypertension, further evaluation is needed. Colle et al. [5] reported no false-negatives using echocardiography for detecting PoPH; however, it had a poor positive predictive value, so right heart catheterization is recommended for diagnosis.

Female sex and autoimmune liver disease are associated with a higher risk of PoPH (odds ratios [ORs], 4 and 9.8, respectively) [16]. In the pathophysiology of PoPH, increased PVR may occur due to pulmonary vasoconstriction, altered levels of circulating mediators, or shear stress, and can lead to classic vascular remodeling [17, 18]. As mediators, endothelin (ET)-1 thromboxane-B1, interleukin-6 and serotonin have been implicated in the pathophysiology of PoPH [19]. Conversely, vasodilators such as nitric oxide (NO) and prostaglandin I2 (prostacyclin) may be decreased in PoPH, facilitating vascular remodeling and the vasoproliferative response.

Because mild PoPH is not associated with mortality after LT, it worsens the overall prognosis of moderate to severe cases [20]. mPAP < 35 mmHg is required for LT [21, 22] and vasodilatory therapy is improving the mortality rate of LT [10, 22–24]. Ashfaq et al. [25] reported that 12 of 16 (75%) cases had a reduction of mPAP to < 35 mmHg, and 11 successfully underwent deceased donor LT (DDLT). The 1-year survival rate was excellent, at 91%.

PoPH cases have high mPAP and PVR values; we investigated the survival rates and clinical features of high-RVSP LT candidates, as well as the risk factors. Moreover, the prevalence of PoPH was evaluated in Japan.

Methods

Patients and study design

This was a single-center, retrospective observational study conducted between June 2011 and September 2021. A total of 157 Japanese patients with liver cirrhosis or portal hypertension (76 men, 48.4%) considered for LT were enrolled. Cirrhosis or portal hypertension was diagnosed based on imaging and biochemistry results. LT was performed in 88 cases (79 living donor LT [LDLTs] and 9 DDLTs). Of the other 69 cases, 22 were on the waiting list, 14 were not indicated for LT due to malignancy or other complications, and 33 died before LT.

This study was conducted in accordance with the principles of the Declaration of Helsinki and the ethics regulations of Tokyo Women’s Medical University Hospital (TWMU, Tokyo, Japan). The TWMU Institutional Review Board approved the study protocol.

Clinical parameters

The following baseline characteristics of the patients were assessed: age, sex, clinical history, primary hepatic diseases, and complications of cirrhosis (i.e., encephalopathy, esophageal/gastric varices, ascites, and hepatocellular carcinoma [HCC]). Blood samples for biochemistry and hematological data were collected at the time of evaluation for LT. Laboratory tests were performed to determine the serum concentrations of albumin, total bilirubin, aspartate aminotransferase, alanine transaminase, creatinine, and brain natriuretic peptide (BNP), the prothrombin time (PT%) and the PT international normalized ratio. The Child–Turcotte–Pugh (CTP) [26] and Model for End-Stage Liver Disease (MELD) scores [27] were calculated and used for evaluating liver function. For estimation of cardiac function, echocardiography was performed. The ejection fraction (EF) and mean peak tricuspid regurgitation (TR) velocity were also measured. RVSP was determined using the modified Bernoulli equation: RVSP (mmHg) = 4 x TR2+ right atrial pressure estimate (10 mmHg) [7].

Diagnosis of PoPH

All patients underwent echocardiography; however, RVSP could not be measured in 20 cases. In cases with an RVSP ≥ 50 or ≥ 36 mmHg and physical findings consistent with pulmonary hypertension, right heart catheterization was performed (n = 3). Pulmonary hypertension was defined as a resting mPAP > 25 mmHg with pulmonary artery wedge pressure < 15 mmHg and PVR > 3 Wood units, as measured by right heart catheterization [10].

Endoscopic grading of esophageal varices

Endoscopic grading of esophageal varices was based on the guidelines of the Japanese Research Society for Portal Hypertension [28]. Esophageal varix was classified as follows: F1, small straight varix; F2, enlarged tortuous varix occupying less than one-third of the lumen; and F3, large coil-shaped varix occupying more than one-third of the lumen.

Follow-up and outcomes

The patients were hospitalized and evaluated for LT. After discharge, patients were followed up every 1–2 months at the outpatient clinic, when blood samples were obtained. Prognosis was evaluated in terms of survival time. The observation periods were from the date of LT or hospitalization for LT to death, and the time of censoring (July 2021).

Statistical analysis

Data are medians with minimum and maximum values. The significance of differences between the RVSP < 36 and ≥ 36 mmHg groups was assessed by the Mann–Whitney U test, χ2 test, or Wilcoxon rank sum test using SPSS software (version 25; SPSS Inc., Chicago, IL). Multivariate regression analysis was performed to compare the groups. Factors highly significant in univariate analyses were subjected to multivariate analysis. The following factors were used to estimate ORs and 95% confidence intervals (CIs): sex, presence of varices, BNP, and EF. Mean peak TR velocity was not included due to collinearity. The survival rate was subjected to Kaplan–Meier analysis. Subgroup analysis was performed by stratifying non-LT and LT patients according to RVSP level (< 36 versus [vs.] ≥ 36 mmHg). Differences between groups were analyzed by log-rank test and p < 0.05 was taken to indicate statistical significance.

Results

Baseline characteristics of cirrhotic candidates for LT

The median age of the 157 patients was 52 (range: 18–68) years, and 76 (48.4%) were male (Table 1). The primary liver diseases were viral hepatitis (hepatitis C, 27 cases; hepatitis B, 8 cases), alcoholic liver disease/nonalcoholic fatty liver disease (25/24 cases), autoimmune hepatitis (AIH, 4 cases), primary biliary cholangitis (PBC, 20 cases), primary sclerosing cholangitis (16 cases), biliary atresia (12 cases), Wilson’s disease (3 cases), Budd-Chiari syndrome (4 cases), and others (14 cases, including 1 of extrahepatic portal vein obstruction). With regard to complications of liver cirrhosis, hepatic encephalopathy (36 cases, 22.9%), esophageal/gastric varices (108 cases, 75.0%), portal thrombosis (25 cases, 15.9%), and HCC (25 cases, 15.9%) were all observed.

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Table 1. Baseline characteristics of the patients.

https://doi.org/10.1371/journal.pone.0267125.t001

Cardiac parameters of LT candidates

The cirrhotic patients had a median BNP of 39.1 (4.0–780.5) pg/mL. According to echocardiography, the EF was 58% (28–72%), the mean peak TR velocity was 2.3 (1.5–5.3) m/s, and the RVSP was 31.2 (16–122.4) mmHg. An RVSP of ≥ 50 mmHg was observed in 6 cases, and 36–49 mmHg in 26 cases (Fig 1). The RVSP was significantly higher in females compared to males (Fig 2A). RVSP and BNP were weakly correlated (r = 0.40, p = 0.01, Fig 2B). The RVSP tended to be elevated in PBC patients among several background liver diseases (Wilcoxon rank sum test; p = 0.07, Fig 2C). The RVSP was higher in patients without esophageal/gastric varices (p = 0.04, Fig 2D). (Frequency distribution of each parameter of liver and cardiac function was shown in S1 Fig).

[Figure omitted. See PDF.]

Fig 1. Flow-chart of the LT candidates.

Overall, 157 patients underwent LT for end-stage liver disease. According to cardiography, 105, 26, and 6 cases had RVSPs of < 36, 36–49, and ≥ 50 mmHg, respectively. LT was performed in 88 cases (9 cases of DDLT and 79 of LDLT). Three cases (1.9%) were diagnosed with PoPH. LT, liver transplantation; PAH, pulmonary arterial hypertension; PoPH, portopulmonary hypertension.

https://doi.org/10.1371/journal.pone.0267125.g001

[Figure omitted. See PDF.]

Fig 2. RVSP by sex, BNP, liver disease, and esophageal/gastric varices in LT candidates.

(a) Sex, (b) BNP, (c) liver disease, and (d) esophageal/gastric varices. The RVSP was significantly higher in females compared to males (p = 0.03) (a). RVSP and the BNP level were weakly correlated (r = 0.40, p = 0.01) (b). The RVSP tended to be higher in PBC patients (p = 0.07) (c)*. The RVSP was significantly higher in patients without esophageal/gastric varices (p = 0.04) (d)*. *Wilcoxon rank sum test. AIH, autoimmune hepatitis; ALD, alcoholic liver disease; BA, biliary atresia; BNP, brain natriuretic peptide; EIS, endoscopic injection sclerotherapy; EVL, endoscopic variceal ligation; HBV, hepatitis B virus; HCV, hepatitis C virus; LT, liver transplantation; NASH, nonalcoholic steatohepatitis; PBC, primary sclerosing cholangitis; PSC, primary sclerosing cholangitis; RVSP, right ventricular systolic pressure.

https://doi.org/10.1371/journal.pone.0267125.g002

Comparison of clinical features by RVSP level in LT candidates

Among LT candidates with RVSPs of < 36 and ≥ 36 mmHg, female sex (p = 0.02) and the prevalence of PBC were significantly increased (p = 0.01), while the cardiac parameters BNP (p < 0.01), EF (p = 0.01), and mean peak TR velocity (p < 0.01) were significantly increased in patients with an RVSP ≥ 36 mmHg (Table 1). Esophageal/gastric varices was negatively associated with an RVSP ≥ 36 mmHg. The results of a multivariate analysis of the risk of RVSP ≥ 36 mmHg are shown in Table 2. The cardiac parameters were positive predictors (EF; OR, 1.23, 95% CI, 1.028–1.471, p = 0.02 and BNP; OR, 1.01, 95% CI, 1.003–1.017, p = 0 .04) and esophageal/gastric varices was an independent negative predictor of an RVSP ≥ 36 mmHg (OR, 0.21, 95% CI, 0.070–0.611, p = 0.04).

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Table 2. Predictors of an RVSP ≥ 36 mmHg.

https://doi.org/10.1371/journal.pone.0267125.t002

Survival rates of LT candidates according to RVSP

The survival rates of cirrhotic LT candidates by Kaplan–Meier analysis are shown in Fig 3. The 5- and 10-year survival rates of cirrhotic LT candidates were 66.5% and 64.6%, respectively (Fig 3A). Prognosis was significantly poorer in patients without than with LT (p < 0.01). In a sub-analysis stratified by RVSP (< 36 vs. ≥ 36 mmHg) in LT and non-LT cases, the survival rates were similar. In non-LT cases, the 5-year survival rates were 36.1% and 34.1% in patients with RVSP values of < 36 and ≥ 36 mmHg, respectively (p = 0.47, Fig 3B). In LT cases, the respective rates were 85.4% and 85.3%, and did not differ by RVSP value (< 36 vs. ≥ 36 mmHg; p = 0.69, Fig 3C).

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Fig 3. Mortality rates of cirrhotic LT candidates.

(a) All patients and patients with RVSPs of < 36 and ≥ 36 mmHg (b) without LT and (c) with LT. The 5- and 10-year survival rates in cirrhotic LT candidates were 66.5% and 64.6%, respectively (a). About survival rate according to RVSP in LT and non-LT cases, in non-LT cases, the 5-year survival rates were 36.1% and 34.1% in those with RVSPs of < 36 and ≥ 36 mmHg, respectively (p = 0.47) (b). In LT cases, the 5-year survival rates were 85.4% and 85.3% in those with RVSPs of < 36 and ≥ 36 mmHg, respectively (p = 0.69) (c). LT, liver transplantation; RVSP, right ventricular systolic pressure.

https://doi.org/10.1371/journal.pone.0267125.g003

Incidence of PoPH among LT candidates

Among 6 patients with an RVSP ≥ 50 mmHg, 3 (1.9%) were diagnosed with a PoPH complication by right heart catheterization at the time of considering LT (Table 3). PoPH cases had a significantly lower MELD score 10 than non-PoPH cases (17, p < 0.01). CTP score was not significantly different (PoPH 6 vs. non-PoPH 11, p = 0.13). Among three patients with PoPH, one of CTP class B-C died of progressive liver failure despite treatment for PoPH with tadalafil (a phosphodiesterase 5 [PDE5] blocker). The other two patients immediately started macitentan (ET receptor blocker), tadalafil, and/or selexipag (prostacyclin receptor agonist); as a result, mPAP was decreased and they were considered for LT. Among other 3 cases with an RVSP ≥ 50 mmHg, one case of Alagille syndrome was complicated by congenital aortic stenosis, pulmonary artery stenosis, spina bifida, and spinal canal stenosis. Congenital aortic and pulmonary artery stenosis increased the RVSP, resulting in pulmonary hypertension without symptom. This case was unlike PoPH; his EF was preserved and he underwent successful LT. In the other two patients with alcoholic liver disease and PBC, RVSP was increased by pleural effusion and ascites. After management with diuretic drugs, RVSP was decreased and LT was performed successfully.

[Figure omitted. See PDF.]

Table 3. Characteristics of patients with PoPH.

https://doi.org/10.1371/journal.pone.0267125.t003

Discussion

The results revealed three cases (1.9%) of PoPH among LT candidates. The survival rates were not significantly different between patients with an RVSP < 36 and ≥ 36 mmHg suspected of having mild pulmonary hypertension, and the outcomes of LT were favorable. RVSP was increased in females and PBC patients, and weakly correlated with the BNP level.

LT candidates require comprehensive cardiopulmonary assessments, and all patients underwent screening echocardiography. Among the candidates for DDLT, 8.2% (101 of 1,235) had an RVSP > 50 mmHg according to echocardiography [7]. Among them, 90 had an mPAP > 25 mmHg and 66 had PAH, for a PoPH prevalence of 5.3% (66/1,235). Among the LT candidates, six cases (3.8%) had an RVSP of ≥ 50 mmHg and PoPH was observed in three cases.

Cardiac parameters including EF, peak TR velocity, and BNP were correlated with RVSP. Therefore, the measurement of serum BNP might be useful information for detecting PoPH. Yoshimaru et al. [29] reported that patients with PoPH had a significantly higher BNP level, which was predictive of asymptomatic PoPH; the optimal cutoff value was 29.1 pg/mL. In this study, median level of BNP was 39.1 pg/mL and it was 90.8 pg/mL in cases with RVSP ≥36. In terms of prognosis, there was no significant difference in the survival rate according to a BNP level (S2 Fig).

Patients with an RVSP ≥ 36 were more likely to be female, to have PBC and to have higher values for the cardiac parameters of BNP, EF, and mean peak TR velocity than those with an RVSP < 36. Kawut SM et al. [16] reported that female sex and autoimmune liver disease, especially PBC, were associated with pathogenesis of PoPH. Our RVSP data suggested their hypothesis. Esophageal varices was reported in 155 of 168 (92.3%) cases and in all patients with a mPAP > 20 [30]. In this study, esophageal/gastric varices were present in 108 cases (75.0%). The RVSP was lower in those cases compared to patients without variceal varices (p = 0.04). We speculate that RVSP can be increased by large shunts in the absence of esophageal/gastric varices; however, further analysis is needed.

Before the availability of PAH-specific therapies, LT was usually contraindicated because a large amount of blood flows into the right heart from the grafted liver, elevating the right cardiac pressure and PAP level [20, 22]. Advanced treatments for PAH have significantly improved survival [10, 22, 23]. The 5-year survival rates with PAH-specific therapy and LT, no therapy, and only medical therapy were 76%, 14%, and 45%, respectively [31]. The combination of PAH-specific therapy and LT yielded favorable outcomes. In our study, the 5-year survival rate was 86.8% in patients with an RVSP < 36 mmHg and 82.8% in those with an RVSP ≥ 36 mmHg. We performed LT in patients with a high RVSP, among whom 3 had an RVSP ≥ 50 and 16 an RVSP of 36–49. The mild to moderate RVSP cases underwent successful LT. In Japan, we must rely on LDLT due to a lack of available organs; moreover, the pressure on the portal vein might be increased by small-sized grafts. However, the surgical results were satisfactory in end-stage liver disease patients. Therefore, LT should be considered after or during ongoing treatment for PAH.

PoPH was diagnosed in three of our patients (1.9%, Table 3), a lower rate than in studies from Western countries [7]. Atsukawa et al. [30] reported that 1.1% of Japanese patients had PoPH, similar to our study. The PoPH cases were all female, and all had complicated autoimmune liver disease or extrahepatic portal vein obstruction (EHO). As the MELD score was poorly correlated with pulmonary hemodynamics [7], it was not related to the RVSP, similar to the CTP score. Actually, our PoPH cases showed a significantly lower MELD score and a tendency toward a decreased CTP score (one patient was CTP class B-C). These findings are comparable with a prior study [30]. We reported previously that two PoPH patients died due to severe liver and respiratory conditions, while two others survived for > 5–10 years after being treated with several drugs for PAH [32]. It was reported that the main causes of death in PoPH were complications of liver disease, particularly in patients with advanced cirrhosis [22]. In contrast, in patients with mild cirrhosis, the causes were PAH and hepatic or extrahepatic cancers. In the REVEAL registry of the United States, 5-year survival rates were significantly lower in patients with PoPH compared to idiopathic PAH (IPAH) (40% vs. 64%) [4]. Khaderi et al. [33] reported that, in patients with severe PoPH (7/488 cases), LT is feasible after reducing mPAP, and the survival rate after LT was 85.7% (median follow-up = 7.8 years). LT is indicated if mPAP can be controlled by vasodilators. Treatments for PAH might not be universally effective and the majority of PAH drugs are contraindication in liver cirrhosis with CTP class C. Therefore, it is important to diagnose PoPH at early stage of liver cirrhosis and LT should be considered in PoPH cases before progression to end-stage of liver cirrhosis. To diagnose PoPH at an early stage, screening by echocardiography should be performed for patients with liver cirrhosis or portal hypertension.

This study had several limitations. First, it was retrospective and involved a single center. Furthermore, not all patients underwent cardiac catheterization and we did not measure hepatic vein pressure. A prospective study of the outcomes of PoPH patients is needed.

In conclusion, the RVSP was increased in female and PBC patients. In the patients who underwent LT, survival was not associated with mild-moderate RVSP and the outcomes were favorable. PoPH cases had an RVSP of ≥ 50 mmHg; complications of PoPH should be screened by echocardiography in patients with portal hypertension being considered for LT.

Supporting information

S1 Fig. Frequency distribution of each parameter of liver and cardiac function.

a) BNP, b) CTP score, c) MELD score, d) EF, e) RVSP, f) peak TR velocity, and g) LA diameter. BNP, brain natriuretic peptide; CTP, Child–Turcotte–Pugh; EF, ejection fraction; LA, left atrium; MELD, model for end-stage liver disease; RVSP, right ventricular systolic pressure; TR, tricuspid regurgitation.

https://doi.org/10.1371/journal.pone.0267125.s001

(TIF)

S2 Fig. About survival rate according to BNP level in LT and non-LT cases, there was no significant difference in the survival rate according to a BNP level.

BNP, brain natriuretic peptide; LT, liver transplantation.

https://doi.org/10.1371/journal.pone.0267125.s002

(TIF)

Acknowledgments

We are grateful to Dr. Etsuko Hashimoto of Seibu Railway Company Health Support Center for supervision; we also thank Dr. Makiko Taniai, Dr. Kazuhisa Kodama, Dr. Yuichi Ikarashi, Dr. Takaomi Sagawa, Dr. Yuri Ogasawara, and Dr. Kentaro Horiuchi of the Institute of Gastroenterology, Department of Internal Medicine, Tokyo Women’s Medical University for patient care.

Citation: Hayashi R, Kogiso T, Kikuchi N, Yamamoto K, Nakamura S, Egawa H, et al. (2022) Portopulmonary hypertension and the risk of high right ventricular systolic pressure in liver transplant candidates. PLoS ONE 17(4): e0267125. https://doi.org/10.1371/journal.pone.0267125

References

1. Lebrec D, Capron JP, Dhumeaux D, Benhamou JP. Pulmonary hypertension complicating portal hypertension. Am Rev Respir Dis. 1979;120(4):849–56. pmid:159649

2. McDonnell PJ, Toye PA, Hutchins GM. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis. 1983;127(4):437–41. pmid:6838050

3. Hadengue A, Benhayoun MK, Lebrec D, Benhamou JP. Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology. 1991;100(2):520–8. pmid:1985048

4. Krowka MJ, Miller DP, Barst RJ, Taichman D, Dweik RA, Badesch DB, et al. Portopulmonary hypertension: a report from the US-based REVEAL Registry. Chest. 2012;141(4):906–15. pmid:21778257

5. Colle IO, Moreau R, Godinho E, Belghiti J, Ettori F, Cohen-Solal A, et al. Diagnosis of portopulmonary hypertension in candidates for liver transplantation: a prospective study. Hepatology. 2003;37(2):401–9. pmid:12540791

6. Kawut SM, Taichman DB, Ahya VN, Kaplan S, Archer-Chicko CL, Kimmel SE, et al. Hemodynamics and survival of patients with portopulmonary hypertension. Liver Transpl. 2005;11(9):1107–11. pmid:16123953

7. Krowka MJ, Swanson KL, Frantz RP, McGoon MD, Wiesner RH. Portopulmonary hypertension: Results from a 10-year screening algorithm. Hepatology. 2006;44(6):1502–10. pmid:17133488

8. Mandell MS. Critical care issues: portopulmonary hypertension. Liver Transpl. 2000;6(4 Suppl 1):S36–43. pmid:10915190

9. Simonneau G, Galiè N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):5S–12S. pmid:15194173

10. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67–119. pmid:26320113

11. Badesch DB, Champion HC, Gomez Sanchez MA, Hoeper MM, Loyd JE, Manes A, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S55–S66. pmid:19555859

12. Korbitz PM, Gallagher JP, Samant H, Singh S, Jophlin L, Ingviya T, et al. Performance of echocardiography for detection of portopulmonary hypertension among liver transplant candidates: Meta-analysis. Clin Transplant. 2020;34(11):e13995. pmid:32485008

13. Galiè N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J. 2004;25(24):2243–78. pmid:15589643

14. Foocharoen C, Nanagara R, Kiatchoosakun S, Suwannaroj S, Mahakkanukrauh A. Prognostic factors of mortality and 2-year survival analysis of systemic sclerosis with pulmonary arterial hypertension in Thailand. Int J Rheum Dis. 2011;14(3):282–9. pmid:21816025

15. Medarov BI, Chopra A, Judson MA. Clinical aspects of portopulmonary hypertension. Respir Med. 2014;108(7):943–54. pmid:24816204

16. Kawut SM, Krowka MJ, Trotter JF, Roberts KE, Benza RL, Badesch DB, et al. Clinical risk factors for portopulmonary hypertension. Hepatology. 2008;48(1):196–203. pmid:18537192

17. Benjaminov FS, Prentice M, Sniderman KW, Siu S, Liu P, Wong F. Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut. 2003;52(9):1355–62. pmid:12912870

18. Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet. 2004;363(9419):1461–8. pmid:15121411

19. Humbert M, Guignabert C, Bonnet S, Dorfmüller P, Klinger JR, Nicolls MR, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J. 2019;53(1). pmid:30545970

20. Ramsay MA, Simpson BR, Nguyen AT, Ramsay KJ, East C, Klintmalm GB. Severe pulmonary hypertension in liver transplant candidates. Liver Transpl Surg. 1997;3(5):494–500. pmid:9346791

21. Krowka MJ, Fallon MB, Kawut SM, Fuhrmann V, Heimbach JK, Ramsay MA, et al. International Liver Transplant Society Practice Guidelines: Diagnosis and Management of Hepatopulmonary Syndrome and Portopulmonary Hypertension. Transplantation. 2016;100(7):1440–52. pmid:27326810

22. Savale L, Guimas M, Ebstein N, Fertin M, Jevnikar M, Renard S, et al. Portopulmonary hypertension in the current era of pulmonary hypertension management. J Hepatol. 2020;73(1):130–9. pmid:32145258

23. Hoeper MM, Kramer T, Pan Z, Eichstaedt CA, Spiesshoefer J, Benjamin N, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J. 2017;50(2). pmid:28775047

24. DuBrock HM, Runo JR, Sadd CJ, Burger CD, Cartin-Ceba R, Rosen CB, et al. Outcomes of Liver Transplantation in Treated Portopulmonary Hypertension Patients With a Mean Pulmonary Arterial Pressure ≥35 mm Hg. Transplant Direct. 2020;6(12):e630. pmid:33204828

25. Ashfaq M, Chinnakotla S, Rogers L, Ausloos K, Saadeh S, Klintmalm GB, et al. The impact of treatment of portopulmonary hypertension on survival following liver transplantation. Am J Transplant. 2007;7(5):1258–64. pmid:17286619

26. Cholongitas E, Papatheodoridis GV, Vangeli M, Terreni N, Patch D, Burroughs AK. Systematic review: The model for end-stage liver disease—should it replace Child-Pugh’s classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther. 2005;22(11–12):1079–89. pmid:16305721

27. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000;31(4):864–71. pmid:10733541

28. Tajiri T, Yoshida H, Obara K, Onji M, Kage M, Kitano S, et al. General rules for recording endoscopic findings of esophagogastric varices (2nd edition). Dig Endosc. 2010;22(1):1–9. pmid:20078657

29. Yoshimaru K, Matsuura T, Takahashi Y, Yanagi Y, Nagata H, Ohga S, et al. The efficacy of serum brain natriuretic peptide for the early detection of portopulmonary hypertension in biliary atresia patients before liver transplantation. Pediatr Transplant. 2018;22(5):e13203. pmid:29733490

30. Atsukawa M, Tsubota A, Hatano M, Kondo C, Shioda K, Ohno H, et al. Prevalence and characteristics of portopulmonary hypertension in cirrhotic patients who underwent both hepatic vein and pulmonary artery catheterization. Hepatol Res. 2020;50(11):1244–54. pmid:32822521

31. Swanson KL, Wiesner RH, Nyberg SL, Rosen CB, Krowka MJ. Survival in portopulmonary hypertension: Mayo Clinic experience categorized by treatment subgroups. Am J Transplant. 2008;8(11):2445–53. pmid:18782292

32. Kodama K Serizawa N, Hashimoto E, et al. Current Status of Portopulmonary Hypertension and Hepatopulmonary Syndrome. EC Gastroenterology and Digestive System 2020:63–9.

33. Khaderi S, Khan R, Safdar Z, Stribling R, Vierling JM, Goss JA, et al. Long-term follow-up of portopulmonary hypertension patients after liver transplantation. Liver Transpl. 2014;20(6):724–7. pmid:24648168