Highlights
1. Overall oxygenation remained stable after PAH-specific therapy in PoPH
Among 107 patients with portopulmonary hypertension (PoPH), initiation of pulmonary arterial hypertension (PAH)-targeted therapy was not associated with a significant overall change in the alveolar-arterial oxygen gradient (A-aDO2) after a median of 4 months. The mean change was -0.92 mmHg (95% CI, -3.2 to +1.3; P=0.42).
2. Individual gas-exchange responses were heterogeneous and appeared hemodynamically linked
Although the cohort-level signal was neutral, changes in oxygenation varied substantially between patients. Baseline A-aDO2 and cardiac output were independently associated with later improvement in A-aDO2, and treatment-related reductions in mean pulmonary arterial pressure (mPAP) together with increases in cardiac output correlated with greater improvement in gas exchange.
3. Coexisting hepatopulmonary syndrome was common at diagnosis
In the prospective cohort, hepatopulmonary syndrome (HPS) was present in 39% of newly diagnosed PoPH patients, underscoring the clinical overlap between pulmonary vascular remodeling and intrapulmonary vascular dilatation in portal hypertension.
4. New intrapulmonary vascular dilatations developed in some patients during treatment
Baseline intrapulmonary vascular dilatations (IPVDs) did not predict subsequent A-aDO2 evolution, but 4 patients developed new IPVDs within the first year after PAH therapy initiation, supporting the need for longitudinal oxygenation and contrast echocardiographic surveillance.
Background
Portopulmonary hypertension is a subtype of pulmonary arterial hypertension that develops in the setting of portal hypertension, most often in advanced liver disease. Clinically, it creates a difficult management intersection between hepatology, pulmonary vascular medicine, and transplant medicine. Patients may have exertional dyspnea, reduced functional capacity, right ventricular strain, and in severe cases, marked barriers to liver transplantation.
A separate but related pulmonary vascular complication of liver disease is hepatopulmonary syndrome, defined by abnormal oxygenation due to intrapulmonary vascular dilatations. HPS typically produces widened A-aDO2 and, in more severe cases, resting hypoxemia. While PoPH and HPS are classically taught as distinct syndromes, they can coexist in the same patient. That overlap raises an important therapeutic question: could PAH-directed vasodilator therapy improve pulmonary hemodynamics while aggravating ventilation-perfusion mismatch or shunting?
This concern is biologically plausible. In PoPH, PAH therapies are used to reduce pulmonary vascular resistance and pulmonary arterial pressure. However, because liver disease can also promote pulmonary vascular dilatation, clinicians have long worried that vasodilator therapy might worsen oxygenation in susceptible patients, particularly those with coexisting IPVDs or HPS. Until now, the effect of PAH therapy on gas exchange in PoPH has remained insufficiently characterized, especially in systematically screened cohorts.
The study by Lacoste-Palasset and colleagues addresses this clinically relevant gap by combining a retrospective assessment of gas-exchange changes after treatment initiation with a prospective evaluation of IPVD prevalence and incident development during follow-up.
Study Design
Overall design
This was a two-part observational study in patients with PoPH.
The first component was a retrospective cohort evaluating the effect of PAH-specific therapy on gas exchange, measured by the alveolar-arterial oxygen gradient. The second component was a prospective cohort in which newly diagnosed patients underwent systematic screening for intrapulmonary vascular dilatations to determine baseline prevalence of HPS/IPVDs and to identify incident IPVDs after treatment initiation.
Population and treatment
The retrospective cohort included 107 patients with PoPH. Seventy percent were male, and mean age was 55 ± 8 years. Baseline mean A-aDO2 was 37.1 ± 13.0 mmHg, indicating substantially abnormal gas exchange at study entry. Initial PAH treatment consisted of oral monotherapy in 83 patients and dual oral therapy in 24 patients.
The prospective cohort included 28 newly diagnosed PoPH patients who underwent systematic screening for IPVDs.
Endpoints
The main retrospective endpoint was change in A-aDO2 after initiation of PAH therapy. Additional analyses examined relationships between gas-exchange changes and clinical or hemodynamic variables, including 6-minute walk distance, WHO/New York Heart Association functional class, mPAP, and cardiac output.
In the prospective cohort, key outcomes were the prevalence of HPS at baseline, the influence of baseline IPVDs on subsequent gas exchange, and the incidence of new IPVDs during follow-up.
Key Findings
Neutral overall effect on gas exchange
The central message is reassuring: PAH-specific therapy was not associated with overall worsening of oxygenation in PoPH. After a median follow-up of 4 months, the mean A-aDO2 change was -0.92 mmHg, with a 95% confidence interval spanning -3.2 to +1.3 mmHg, and the result was not statistically significant (P=0.42). At a practical level, this means that initiating PAH therapy did not, on average, produce a clinically meaningful deterioration in gas exchange.
This finding matters because many clinicians have approached PAH vasodilator therapy cautiously in PoPH patients with baseline oxygenation abnormalities. The study suggests that such concern should not automatically preclude treatment when there is a hemodynamic indication.
Marked interindividual variability
The absence of an average deleterious effect should not be misread as uniform safety at the individual level. Gas-exchange responses varied widely. Some patients improved, some remained stable, and others worsened. That heterogeneity is one of the most clinically important aspects of the report because it implies that bedside monitoring remains essential even when population-level data are reassuring.
Notably, changes in A-aDO2 were not associated with changes in 6-minute walk distance or WHO/NYHA functional class. This dissociation suggests that symptomatic or exercise gains from pulmonary vascular treatment do not necessarily mirror oxygenation changes, and vice versa. A patient may walk farther because of improved hemodynamics while still experiencing no measurable improvement in gas exchange.
Hemodynamic correlates of oxygenation change
The most informative mechanistic signal in the study is the relationship between oxygenation and hemodynamics. Baseline A-aDO2 and cardiac output independently predicted later improvement in A-aDO2. In addition, treatment-induced reductions in mPAP and increases in cardiac output correlated with greater improvement in gas exchange.
This pattern is biologically coherent. PoPH can impair oxygenation through several pathways, including reduced mixed venous oxygen content from circulatory dysfunction, abnormal pulmonary perfusion distribution, and coexistence of HPS-related shunting. If therapy improves right-sided hemodynamics and systemic oxygen delivery, some patients may experience better alveolar-arterial oxygen transfer despite receiving vasodilators. In other words, improved flow and pressure relationships may offset or exceed any tendency toward worsened perfusion mismatch.
The association with baseline cardiac output is especially interesting in a portal hypertension population, where hyperdynamic circulation is common. It raises the possibility that the balance between pulmonary vasoconstriction, vascular remodeling, and hyperdynamic flow state influences whether gas exchange improves or deteriorates after therapy.
High baseline prevalence of HPS in newly diagnosed PoPH
In the prospective cohort, HPS was present in 39% of newly diagnosed PoPH patients. This is a strikingly high prevalence and reinforces the concept that PoPH and HPS are not mutually exclusive syndromes. Rather, they may represent different pulmonary vascular expressions of portal hypertension that can overlap in the same individual.
For clinicians, this has immediate implications. A PoPH diagnosis should not end the investigation of abnormal oxygenation. If dyspnea or desaturation seems disproportionate to hemodynamic severity, concomitant HPS should remain firmly in the differential diagnosis.
Baseline IPVDs did not predict subsequent A-aDO2 evolution
Patients with IPVDs at baseline did not show a distinctly different trajectory of A-aDO2 over time. This is useful because it argues against a simple deterministic model in which pre-existing IPVDs inevitably lead to worsening oxygenation once PAH therapy begins. The interaction appears more complex and likely depends on the net effect of treatment on pulmonary vascular resistance, cardiac output, and intrapulmonary blood flow distribution.
Incident IPVDs during follow-up
Even so, the prospective data also provide a cautionary note: 4 patients developed new IPVDs within the first year after PAH therapy initiation. The study does not prove causality, and progression of portal hypertension-related vascular disease could itself explain these events. Still, the observation is clinically important. It means that a stable baseline bubble study or absence of HPS at diagnosis does not guarantee that intrapulmonary vascular abnormalities will not emerge later.
This finding supports ongoing monitoring of oxygenation parameters and consideration of repeat contrast echocardiographic assessment when symptoms, saturation, or transplant status change.
Clinical Interpretation
This study helps refine a practical treatment message for PoPH. First, PAH-targeted therapy should not be assumed to worsen gas exchange on average. That is encouraging, particularly because these therapies are often necessary to improve hemodynamics, symptoms, and transplant eligibility. Second, oxygenation responses are individualized and linked to hemodynamic context, so serial assessment remains necessary. Third, coexistence of HPS is common, and incident IPVDs may develop during follow-up.
From a translational standpoint, the findings fit with the complex pulmonary vascular biology of portal hypertension. PoPH reflects pulmonary arterial vasculopathy with elevated resistance, whereas HPS reflects diffuse precapillary and capillary dilatation causing shunt-like physiology. A patient may carry elements of both processes. PAH therapy may improve right ventricular-pulmonary arterial coupling and pulmonary perfusion efficiency in some cases, yet evolving liver-related vascular signaling may still permit later development of IPVDs.
For multidisciplinary teams, the results argue for integrated management rather than siloed decision-making. Hepatologists, pulmonary hypertension specialists, and transplant physicians should jointly interpret oxygenation trends, hemodynamics, and imaging findings when planning treatment escalation or transplant evaluation.
Strengths and Limitations
Strengths
The study addresses a clinically important but understudied issue. Its dual-cohort design is a major strength: the retrospective analysis offers a larger treatment dataset, while the prospective cohort adds systematic screening for IPVDs rather than relying on incidental detection. The inclusion of hemodynamic correlates also provides mechanistic insight beyond a simple before-and-after oxygenation comparison.
Limitations
Several caveats should shape interpretation. The retrospective component is vulnerable to selection bias, incomplete data capture, and unmeasured confounding. The follow-up interval for the primary gas-exchange analysis was relatively short, with a median of 4 months, which may underestimate delayed pulmonary vascular changes. The prospective cohort was small, limiting precision around prevalence and incidence estimates for HPS and incident IPVDs. Details on specific PAH drug classes, dosing strategies, and differential effects of monotherapy versus dual therapy were limited in the abstract. Finally, the observational design precludes firm causal conclusions regarding incident IPVDs after treatment initiation.
Implications for Practice
Several practical points emerge. Baseline evaluation in PoPH should include careful oxygenation assessment, ideally with arterial blood gases when clinically indicated, because A-aDO2 abnormalities may be substantial even without severe resting hypoxemia. Screening for HPS or IPVDs should be considered, especially in patients with unexplained desaturation, platypnea-orthodeoxia, or symptoms disproportionate to pulmonary hemodynamics.
Once PAH therapy is initiated, clinicians can be reassured that oxygenation will not necessarily worsen. However, serial follow-up remains important because aggregate stability does not exclude patient-level deterioration. Monitoring should include symptom review, pulse oximetry, and repeat blood gas or imaging assessment when clinically warranted. If new oxygenation abnormalities arise, incident HPS/IPVDs should be considered rather than attributing dyspnea solely to progression of pulmonary hypertension.
For liver transplant programs, the study is also relevant. PoPH management increasingly aims not only to improve symptoms but also to optimize transplant candidacy. Understanding that PAH therapy is broadly neutral for gas exchange, while recognizing the possibility of evolving IPVDs, may improve pre-transplant surveillance strategies.
Funding and ClinicalTrials.gov
Funding information and any ClinicalTrials.gov registration number were not provided in the abstract or citation details supplied here. Readers should consult the full Chest publication for complete disclosures, funding sources, and protocol information.
Conclusion
The study by Lacoste-Palasset and colleagues provides an important evidence update for the management of portopulmonary hypertension. PAH-specific therapy did not worsen gas exchange overall, which should reassure clinicians treating hemodynamically significant PoPH. At the same time, the wide interindividual variability in A-aDO2 response shows that oxygenation cannot be inferred from hemodynamic improvement alone. The high prevalence of coexisting HPS and the appearance of new IPVDs in some patients further emphasize that pulmonary vascular disease in portal hypertension is dynamic and multidimensional.
The most clinically useful takeaway is a balanced one: treat PoPH when indicated, but monitor oxygenation longitudinally and remain alert to evolving intrapulmonary vascular abnormalities. Future studies should define whether particular PAH drug classes, liver disease phenotypes, or baseline hemodynamic profiles identify patients most likely to improve or worsen from a gas-exchange perspective.
References
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