European Journal of Cardiovascular Medicine

Portopulmonary hypertension (PoPH) is a distinct form of pulmonary arterial hypertension (PAH) that occurs in association with portal hypertension, with or without chronic liver disease. It is characterized by increased pulmonary vascular resistance, leading to elevated pulmonary artery pressures and eventual right heart dysfunction. Clinically, patients with PoPH may present with exertional dyspnea, fatigue, chest pain, and syncope, reflecting the progressive nature of pulmonary hypertension (1). The reported prevalence of PoPH in cirrhotic patients varies between 0.25% and 4%, depending on diagnostic criteria and study populations (2). The condition remains a significant challenge in patients with chronic liver disease, particularly those being evaluated for liver transplantation, as severe pulmonary hypertension increases perioperative mortality.

Despite significant advances in the understanding of PoPH, several research gaps persist. The precise pathophysiological mechanisms linking portal hypertension to pulmonary vascular remodeling remain incompletely understood. Current evidence suggests that an imbalance in vasoactive mediators, including increased levels of endothelin-1 and decreased nitric oxide bioavailability, contributes to pulmonary vasoconstriction and vascular proliferation (3). However, the interplay between liver dysfunction and pulmonary endothelial injury requires further elucidation. Moreover, the influence of different liver disease etiologies, such as viral hepatitis, non-alcoholic fatty liver disease (NAFLD), and alcohol-related cirrhosis, on the development of PoPH is not well-defined. Understanding whether certain liver diseases predispose patients to PoPH more than others could inform targeted screening and management strategies.

Several previous studies have explored the hemodynamic benefits of vasomodulator therapy, particularly phosphodiesterase-5 inhibitors and endothelin receptor antagonists, in PoPH patients. These therapies have been shown to improve pulmonary hemodynamics, potentially rendering some patients eligible for liver transplantation (4). A systematic review and meta-analysis reported improved outcomes in PoPH patients who received vasomodulators prior to liver transplantation, highlighting the role of pharmacologic therapy in optimizing candidates for surgery (5). Additionally, recent studies suggest that a subset of patients with PoPH can achieve improved long-term survival with a combination of vasomodulator therapy and liver transplantation, though careful patient selection remains critical.

The aim of this study is to characterize the clinical features and determine the prevalence of PoPH in patients with chronic liver disease. By identifying specific clinical characteristics and assessing the frequency of PoPH in this population, the study seeks to enhance early recognition and diagnosis. Additionally, the research aims to address existing gaps by exploring the pathophysiological mechanisms underlying PoPH and evaluating the influence of different liver disease etiologies on its development. Insights gained from this study could contribute to the development of targeted screening protocols and therapeutic interventions, ultimately improving patient outcomes.

This prospective observational study was conducted at the Department of General Medicine in collaboration with and Respiratory Medicine, Dr. N Y Tasgaonkar Institute of Medical Science over a period of two years, from January 2023 to January 2025. The study includes 100 patients diagnosed with chronic liver disease (CLD), with or without portal hypertension, who are attending the outpatient department (OPD) and inpatient department (IPD) of General Medicine and Respiratory Medicine.

Inclusion Criteria

• Adults aged ≥18 years with a confirmed diagnosis of chronic liver disease (CLD), based on clinical, biochemical, imaging, and/or histopathological findings.
• Patients with portal hypertension diagnosed based on clinical features, imaging, or endoscopic evidence of esophageal varices.
• Patients who underwent echocardiography and right heart catheterization (if indicated) for pulmonary hypertension assessment.

Exclusion Criteria

• Patients with pre-existing pulmonary hypertension due to causes other than PoPH (e.g., chronic thromboembolic pulmonary hypertension, primary pulmonary hypertension).
• Patients with severe cardiac disease unrelated to PoPH, such as ischemic heart disease or valvular heart disease.
• Patients with chronic kidney disease (CKD) stage 4 or 5 or severe systemic illnesses that could confound the study results.
• Patients who are pregnant or lactating.

Methodology

1. Clinical and Demographic Data Collection:
   • Demographic details: age, sex, BMI, smoking/alcohol history, comorbidities.
   • Liver disease etiology: Alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), viral hepatitis (HBV, HCV), autoimmune liver disease, etc.
   • Severity assessment using Child-Pugh score and MELD score.
2. Pulmonary Hypertension Evaluation:
   • Transthoracic echocardiography (TTE) to assess pulmonary artery pressure (PAP).
   • Right heart catheterization (RHC) in patients with echocardiographic suspicion of pulmonary hypertension (mean PAP ≥25 mmHg at rest).
   • Pulmonary function tests (PFT) to rule out other respiratory causes of dyspnea.
   • Six-minute walk test (6MWT) to assess exercise tolerance.
3. Laboratory Investigations:
   • Complete blood count (CBC), liver function tests (LFT), renal function tests (RFT), prothrombin time (PT/INR).
   • Arterial blood gas (ABG) analysis.
   • NT-proBNP levels to assess cardiac function.
   • Viral markers (HBsAg, Anti-HCV) for etiology classification.
4. Imaging:
   • Ultrasound abdomen with Doppler to assess portal hypertension and liver morphology.
   • CT/MRI abdomen (if indicated) for further liver and vascular assessment.
   • Chest X-ray and High-resolution CT (HRCT) of the thorax in selected cases with suspected interstitial lung disease or pulmonary embolism.
5. Classification and Outcome Measures:
   • Patients diagnosed with PoPH based on ESC/ERS guidelines will be categorized according to hemodynamic severity (mild, moderate, severe).
   • Primary outcome: Prevalence of PoPH in chronic liver disease patients.
   • Secondary outcomes: Association of PoPH with liver disease severity, clinical presentation, and pulmonary function parameters.

Statistical Analysis

Data was entered and analyzed using SPSS version 26.0. Continuous variables were expressed as mean ± standard deviation (SD) or median (IQR) based on distribution. Whereas, categorical variables were expressed as percentages. Chi-square test was used for categorical variables, and Student’s t-test or Mann-Whitney U test for continuous variables. Multivariate logistic regression analysis were performed to identify independent predictors of PoPH in CLD patients. A p-value <0.05 was considered statistically significant.

Ethical Considerations

The study protocol has been approved by the Institutional Ethics Committee of Dr. N Y Tasgaonkar Institute of Medical Science. Informed consent will be obtained from all participants before enrollment. Confidentiality of patient data will be maintained as per Good Clinical Practice (GCP) guidelines.

Table 1: Baseline Characteristics of the Study Population

Table 1 presents the baseline characteristics of the study population, including demographic and clinical parameters. The mean age of participants was 53.42 ± 9.13 years, with a predominantly male population (75%). The mean BMI was 28.18 ± 5.48 kg/m², indicating an overweight population on average. Nearly 47% had a history of smoking, and 53% reported alcohol use. Comorbidities were present in 50% of participants, suggesting a significant burden of associated health conditions among CLD patients.

Table 2: Liver Disease Severity Scores

Table 2 summarizes the liver disease severity scores in the study population. The mean Child-Pugh score was 8.63 ± 2.14, reflecting moderate liver dysfunction in most patients. The mean MELD score was 14.50 ± 5.21, indicating a moderate risk of liver-related complications and mortality.

Figure 1: Combined Baseline Characteristics and Liver Disease Severity Scores

Figure 1 shows a comprehensive overview of the baseline characteristics along with liver disease severity scores of the study population. The mean age was 53.42 ± 9.13 years, with a predominantly male cohort (75%). The mean BMI of 28.18 ± 5.48 kg/m² indicates an overweight population. Smoking (47%) and alcohol use (53%) were common among participants, while 50% had comorbid conditions. The Child-Pugh score (8.63 ± 2.14) and MELD score (14.50 ± 5.21) suggest moderate liver dysfunction, which may contribute to complications such as portopulmonary hypertension.

Figure 2: Distribution of Liver Disease Etiology in the Study Population

Figure 2 presents the distribution of liver disease etiology among the study population. Alcoholic Liver Disease (46%) was the most prevalent cause, followed by Non-Alcoholic Fatty Liver Disease (28%). Hepatitis B (12%) and Hepatitis C (9%) accounted for a smaller proportion, while Autoimmune Liver Disease (5%) was the least common. This distribution aligns with global trends, where alcohol-related and metabolic-associated liver disease are the leading contributors to chronic liver disease

Table 3: Laboratory Abnormalities in the Study Population

Table 3 presents the key laboratory abnormalities observed in the study population. Elevated total bilirubin (>1.2 mg/dL) was the most common abnormality (70 individuals), reflecting significant liver dysfunction. Elevated NT-proBNP (>300 pg/mL) was found in 57 individuals, indicating possible cardiac involvement. Low hemoglobin (<12 g/dL) was noted in 39 patients, suggesting anemia, which is common in chronic liver disease. Prolonged PT/INR (>1.3) in 45 individuals indicates impaired liver synthetic function. Additionally, HBsAg positivity (12 cases) and Anti-HCV positivity (9 cases) highlight the proportion of patients with viral hepatitis as an underlying etiology.

Table 4: Pulmonary Hypertension and Functional Impairment in the Study Population

Table 4 presents pulmonary hypertension and functional impairment indicators in the study population. 29% of individuals had pulmonary arterial pressure (PAP) ≥ 25 mmHg, indicating pulmonary hypertension, which is consistent with portopulmonary hypertension (PoPH) in chronic liver disease. Reduced pulmonary function (FEV1 < 70%) was observed in 15% of patients, suggesting obstructive or restrictive lung disease, while 20% had a 6-minute walk test (6MWT) distance < 350m, reflecting diminished exercise tolerance.

Table 5: Imaging Findings in the Study Population

Table 5 summarizes the key imaging findings among the study population. Portal hypertension was detected in 74% of patients via ultrasound, confirming its high prevalence in chronic liver disease. CT/MRI abnormalities were present in 60% of cases, likely indicating structural liver or vascular changes. Chest X-ray abnormalities (77%) and HRCT abnormalities (80%) suggest significant pulmonary involvement, which may be associated with portopulmonary hypertension or other lung complications in chronic liver disease.

Table 6: Distribution of PoPH Severity in the Study Population

The table 6 shows the distribution of portopulmonary hypertension (PoPH) severity among the study participants. 54% of patients had mild PoPH, while 8% had moderate PoPH, and no cases of severe PoPH were observed. Additionally, 38% of patients did not have PoPH. The predominance of mild PoPH in this cohort suggests early-stage pulmonary vascular involvement in chronic liver disease. The absence of severe cases may reflect early diagnosis and intervention or selection bias in the study population.

Table 7: Chi-Square Test Results for Categorical Variables

Table 7 (Chi-Square Test for Categorical Variables), sex (p = 0.041), smoking history (p = 0.032), presence of comorbidities (p = 0.023), pulmonary hypertension (PAP ≥ 25 mmHg, p = 0.011), impaired pulmonary function (FEV1 < 70%, p = 0.028), and reduced exercise tolerance (6MWT Distance < 350m, p = 0.008) were all significantly associated with PoPH. This indicates that male sex, smoking, the presence of comorbid conditions, and pulmonary dysfunction contribute to an increased risk of PoPH. However, alcohol history (p = 0.368) did not show a significant association, suggesting that alcohol consumption alone may not be a direct risk factor for PoPH.

Table 8: Statistical Tests for Continuous Variables

In Table 8 (Statistical Tests for Continuous Variables), all examined parameters were significantly associated with PoPH. Age (p = 0.045), BMI (p = 0.002), Child-Pugh Score (p = 0.015), and MELD Score (p = 0.041) all demonstrated statistical significance, indicating that older age, higher BMI, and more severe liver disease contribute to the development of PoPH. Among these, BMI and liver disease severity (as measured by Child-Pugh and MELD scores) showed the strongest associations, suggesting that obesity and worsening liver function may promote pulmonary vascular changes leading to PoPH.

This study aimed to evaluate the prevalence and clinical features of portopulmonary hypertension (PoPH) in patients with chronic liver disease (CLD) and to explore associations between PoPH and various clinical parameters.

In our cohort, the prevalence of PoPH was 29%, with 29 individuals exhibiting a pulmonary artery pressure (PAP) ≥ 25 mmHg. This prevalence is notably higher than figures reported in previous studies, which have ranged from 1.7% to 10% among cirrhotic patients (7). The elevated prevalence in our study may be attributed to differences in patient selection, diagnostic criteria, or regional variations.

The mean age of participants was 53.42 years, and 75% were male. The average BMI was 28.18 kg/m², and statistical analysis revealed a significant association between higher BMI and PoPH (p = 0.002), suggesting that obesity is a strong risk factor for developing PoPH in CLD patients. This finding aligns with existing literature that identifies obesity as a potential risk factor for pulmonary hypertension (8).

Contrary to earlier findings (9), our study found a significant association between male sex (p = 0.041), smoking history (p = 0.032), and comorbidities (p = 0.023) with PoPH. These results suggest that male patients, smokers, and individuals with multiple comorbid conditions may be at a heightened risk of developing PoPH. Additionally, PAP ≥ 25 mmHg (p = 0.011), impaired pulmonary function (FEV1 < 70%, p = 0.028), and reduced exercise tolerance (6MWT < 350m, p = 0.008) were significantly associated with PoPH. This indicates that worsening lung function and decreased physical capacity contribute to the progression of PoPH. However, alcohol history (p = 0.368) was not significantly associated with PoPH, suggesting that alcohol consumption alone may not directly contribute to its pathogenesis.

The mean Child-Pugh and MELD scores were 8.63 and 14.50, respectively. Statistical analysis showed that higher Child-Pugh scores were significantly associated with PoPH (p = 0.015), indicating that more severe liver dysfunction increases the likelihood of PoPH development. The MELD Score was also significantly associated with PoPH (p = 0.041), reinforcing the impact of liver disease severity on pulmonary vascular changes. These findings suggest that both Child-Pugh and MELD scores should be considered in PoPH risk stratification, as opposed to earlier studies that found no clear correlation (10).

The distribution of liver disease etiologies in our study showed Alcoholic Liver Disease (46%), Non-Alcoholic Fatty Liver Disease (28%), Hepatitis B Virus (12%), Hepatitis C Virus (9%), and Autoimmune Liver Disease (5%). While previous studies have suggested a higher prevalence of PoPH in patients with autoimmune liver diseases, our study did not find a significant association between disease etiology and PoPH development (11).

Among laboratory parameters, 39% of patients had hemoglobin levels <12 g/dL, and elevated NT-proBNP (>300 pg/mL) was observed in 57% of cases. These findings suggest a potential role of anemia and cardiac dysfunction in the pathophysiology of PoPH, warranting further investigation. Additionally, imaging studies revealed portal hypertension on ultrasound in 74% of patients, abnormal CT/MRI findings in 60%, abnormal chest X-ray in 77%, and abnormal HRCT findings in 80%. These imaging findings shows the systemic involvement of CLD, but no direct correlation with PoPH was observed in our study (12).

Based on hemodynamic measurements, 54% of patients were classified with mild PoPH, 8% with moderate, and none with severe PoPH which are in align with earlier studies (13). The predominance of mild cases suggests early-stage pulmonary vascular involvement in CLD patients, while the absence of severe cases may reflect early diagnosis and intervention or selection bias in our study population.

Our study shows a higher prevalence of PoPH (29%) in CLD patients than previously reported, with significant associations between PoPH and higher BMI, male sex, smoking history, comorbidities, and advanced liver disease (Child-Pugh and MELD scores). Additionally, lung function impairment (FEV1 < 70%) and reduced exercise tolerance (6MWT < 350m) were significantly linked to PoPH, reinforcing the need for comprehensive cardiopulmonary evaluation in high-risk CLD patients. These findings shows the importance of regular screening for PoPH in CLD patients, particularly those with obesity and advanced liver disease. Early identification and management are essential to improving outcomes in this population. Future studies should focus on longitudinal assessments and potential therapeutic interventions to prevent PoPH progression.

1. Saleemi S. Portopulmonary hypertension. Ann Thorac Med. 2010 Jan;5(1):5-9. doi: 10.4103/1817-1737.58953. PMID: 20351954; PMCID: PMC2841810.
2. Soulaidopoulos S, Cholongitas E, Giannakoulas G, Vlachou M, Goulis I. Review article: Update on current and emergent data on hepatopulmonary syndrome. World J Gastroenterol. 2018 Mar 28;24(12):1285-1298. doi: 10.3748/wjg.v24.i12.1285. PMID: 29599604; PMCID: PMC5871824.
3. Ramsay M. Portopulmonary hypertension and right heart failure in patients with cirrhosis. Curr Opin Anaesthesiol. 2010 Apr;23(2):145-50. doi: 10.1097/ACO.0b013e32833725c4. PMID: 20124995.
4. Deroo R, Trépo E, Holvoet T, De Pauw M, Geerts A, Verhelst X, Colle I, Van Vlierberghe H, Fallon MB, Raevens S. Vasomodulators and Liver Transplantation for Portopulmonary Hypertension: Evidence From a Systematic Review and Meta-Analysis. Hepatology. 2020 Nov;72(5):1701-1716. doi: 10.1002/hep.31164. Epub 2020 Oct 19. PMID: 32017176.
5. Fritz JS, Fallon MB, Kawut SM. Pulmonary vascular complications of liver disease. Am J Respir Crit Care Med. 2013 Jan 15;187(2):133-43. doi: 10.1164/rccm.201209-1583CI. Epub 2012 Nov 15. PMID: 23155142; PMCID: PMC3570657.
6. Gupta A, Pradhan A, Mehrotra S, Misra R, Usman K, Kumar A, Pandey S. Prevalence and Clinical Features of Portopulmonary Hypertension in Patients With Hepatic Cirrhosis: An Echocardiographic Study. Cureus. 2022 May 13;14(5):e24957. doi: 10.7759/cureus.24957. PMID: 35698719; PMCID: PMC9188673.
7. Jasso-Baltazar, Erick A et al. “Portopulmonary Hypertension: An Updated Review.” Transplantation direct 9,8 e1517. 21 Jul. 2023, doi:10.1097/TXD.0000000000001517
8. Shao, Yueming et al. “Prevalence and Associated Factors of Portopulmonary Hypertension in Patients with Portal Hypertension: A Case-Control Study.” BioMed research international 2021 5595614. 20 Apr. 2021, doi:10.1155/2021/5595614
9. Chhabria MS, Boppana LK, Manek G, Tonelli AR. Portopulmonary hypertension: A focused review for the internist. Cleve Clin J Med. 2023 Oct 2;90(10):632-9.
10. Chen HS, Xing SR, Xu WG, Yang F, Qi XL, Wang LM, Yang CQ. Portopulmonary hypertension in cirrhotic patients: prevalence, clinical features and risk factors. Experimental and Therapeutic Medicine. 2013 Mar 1;5(3):819-24.
11. Raevens S, Geerts A, Van Steenkiste C, Verhelst X, Van Vlierberghe H, Colle I. Hepatopulmonary syndrome and portopulmonary hypertension: recent knowledge in pathogenesis and overview of clinical assessment. Liver Int. 2015 Jun;35(6):1646-60. doi: 10.1111/liv.12791. Epub 2015 Feb 16. PMID: 25627425.
12. Thomas C, Glinskii V, de Jesus Perez V, Sahay S. Portopulmonary hypertension: from bench to bedside. Frontiers in Medicine. 2020 Nov 3;7:569413.
13. Shao Y, Yin X, Qin T, Zhang R, Zhang Y, Wen X. Prevalence and Associated Factors of Portopulmonary Hypertension in Patients with Portal Hypertension: A Case-Control Study. Biomed Res Int. 2021 Apr 20;2021:5595614. doi: 10.1155/2021/5595614. PMID: 33987440; PMCID: PMC8079202.