Hepatopulmonary Syndrome and Portopulmonary Hypertension: A Comprehensive Review

Dr Neeraj Manikath , claude.ai

Abstract

Pulmonary vascular complications represent critical yet often underrecognized manifestations of chronic liver disease, significantly impacting morbidity, mortality, and liver transplantation candidacy. This review provides an evidence-based analysis of hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH), emphasizing their distinct pathophysiological mechanisms, diagnostic algorithms, and therapeutic strategies. We highlight practical clinical pearls and diagnostic pitfalls to enhance recognition and management of these challenging conditions.

Introduction

The liver-lung axis represents a complex bidirectional relationship where hepatic dysfunction can precipitate profound pulmonary vascular abnormalities. While both hepatopulmonary syndrome and portopulmonary hypertension occur in the context of portal hypertension, they represent fundamentally opposite pathophysiological processes—vasodilation versus vasoconstriction—with dramatically different clinical implications. The prevalence of HPS ranges from 4% to 32% in cirrhotic patients awaiting liver transplantation, while PoPH affects approximately 2% to 6% of this population. Despite their relative rarity, early recognition is crucial as both conditions significantly influence transplant eligibility and perioperative outcomes.

Hepatopulmonary Syndrome: When the Lungs Become Too Open

Pathophysiology: The Vasodilation Cascade

Hepatopulmonary syndrome represents a triad of liver disease, intrapulmonary vascular dilatations (IPVDs), and impaired oxygenation. The fundamental defect involves an imbalance between pulmonary vasodilators and vasoconstrictors, with overproduction of nitric oxide (NO) playing a central role.

Clinical Pearl #1: Think of HPS as "too much blood flow through dilated vessels"—the pulmonary capillaries become so dilated that red blood cells traverse them too quickly for adequate oxygen diffusion, and shunting occurs through dilated precapillary and capillary vessels.

The pathophysiological cascade begins with hepatic dysfunction leading to:

Decreased hepatic clearance of vasoactive substances: Endothelin-1, despite being a vasoconstrictor systemically, paradoxically increases endothelial NO synthase expression in the pulmonary vasculature
Increased circulating levels of bacterial endotoxins: Portal hypertension-induced bacterial translocation triggers pulmonary macrophage activation
Activated pulmonary intravascular macrophages: Release NO, carbon monoxide, and tumor necrosis factor-alpha
Progressive vascular remodeling: Angiogenesis with arteriovenous communications and pleural-based vessels

Recent studies by Krowka et al. (2021) have demonstrated that genetic polymorphisms in endothelial NO synthase may predispose certain cirrhotic patients to HPS development, potentially explaining why only a subset develops this complication.

Clinical Presentation: The Subtle Signs

Oyster #1: HPS can be entirely asymptomatic in early stages, discovered only through systematic screening. The absence of dyspnea does NOT exclude HPS.

The classic presentation includes:

Progressive dyspnea: Often attributed incorrectly to ascites, deconditioning, or anemia
Platypnea: Dyspnea worsening in upright position (gravitational pooling increases basilar shunting)
Orthodeoxia: Oxygen desaturation ≥5% or PaO₂ decrease ≥4 mmHg when moving from supine to standing
Spider nevi and digital clubbing: More prominent than expected for degree of cirrhosis alone

Clinical Hack #1: Always measure pulse oximetry in both supine and standing positions in cirrhotic patients. A drop of ≥4% suggests HPS even before formal arterial blood gas testing.

The pathognomonic finding of platypnea-orthodeoxia occurs in approximately 20% of HPS patients and reflects gravitational redistribution of blood flow to basilar lung zones where IPVDs are most prominent.

Diagnostic Criteria and Algorithm

The European Respiratory Society Task Force (2022) defines HPS by:

Liver disease and/or portal hypertension
Abnormal oxygenation:
- Alveolar-arterial oxygen gradient (A-a)O₂ ≥15 mmHg (≥20 mmHg if age >64 years) on room air
- Or PaO₂ <80 mmHg on room air
Evidence of intrapulmonary vascular dilatations

Clinical Pearl #2: The A-a gradient is more sensitive than PaO₂ alone. Calculate using: A-a gradient = [FiO₂ × (Patm - PH₂O) - (PaCO₂/0.8)] - PaO₂

Where room air FiO₂ = 0.21, Patm = 760 mmHg, PH₂O = 47 mmHg at 37°C.

Contrast-Enhanced Echocardiography: The Gold Standard

Agitated saline contrast (microbubbles) injected peripherally normally appears in the right heart chambers but is filtered by pulmonary capillaries. In HPS, microbubbles appear in the left heart chambers:

3-6 cardiac cycles after right heart opacification: Indicates intrapulmonary shunting (IPVDs)
1-2 cardiac cycles: Suggests intracardiac shunt (patent foramen ovale, atrial septal defect)

Oyster #2: A negative bubble study does NOT exclude HPS if performed poorly. Ensure adequate agitation (minimum 10 ml air with 1 ml blood in 9 ml saline), and use contrast dose of at least 10 ml injected as a rapid bolus.

Grading severity based on contrast intensity:

Grade 1 (mild): Few microbubbles in left heart
Grade 2 (moderate): Moderate opacification without complete filling
Grade 3 (severe): Complete opacification of left heart chambers

While contrast echocardiography has 90% sensitivity, technetium-99m macroaggregated albumin (⁹⁹mTc-MAA) perfusion scanning provides quantification. Normally, particles (20-60 μm) lodge in pulmonary capillaries (8-15 μm). In HPS, particles traverse dilated vessels (>15 μm), with extrapulmonary uptake (brain, kidneys) indicating shunt fraction. Shunt fraction >6% suggests significant HPS.

Severity Classification and Prognostic Implications

HPS severity stratification directly impacts transplant timing:

Stage	PaO₂ (mmHg)	A-a Gradient	Clinical Significance
Mild	≥80	≥15	Monitor every 6-12 months
Moderate	60-79	15-45	Monitor every 3-6 months; consider transplant evaluation
Severe	50-59	≥45	Transplant evaluation strongly recommended
Very Severe	<50	≥45	MELD exception points; highest mortality

Clinical Pearl #3: HPS patients with PaO₂ <60 mmHg qualify for MELD exception points, receiving additional priority for transplantation in most allocation systems.

The pivotal study by Schenk et al. (2019) demonstrated that untreated severe HPS carries a 5-year mortality exceeding 40%, compared to 15% in matched cirrhotics without HPS.

Management: Limited Medical Options, Definitive Surgical Cure

Medical Therapies: The Disappointing Reality

Despite understanding NO's central role, therapeutic interventions targeting this pathway have proven disappointing:

Methylene blue (NO scavenger): Transient improvement only; not sustained
Garlic derivatives (NO synthase inhibitors): No clinical benefit in controlled trials
Pentoxifylline: Theoretical benefit from TNF-α inhibition; no convincing human data
Sorafenib: Anti-angiogenic properties showed promise in animal models but failed in small human studies

Clinical Hack #2: Supplemental oxygen is the ONLY effective medical therapy. Prescribe liberally to maintain SpO₂ >88%, as improved oxygenation enhances functional status and may improve transplant candidacy.

Transjugular Intrahepatic Portosystemic Shunt (TIPS): Controversial

While TIPS reduces portal pressure, results in HPS are inconsistent. Guevara et al. (2020) reported improvement in only 30% of HPS patients post-TIPS, with some experiencing worsening due to increased cardiac output through shunts. TIPS should NOT be performed solely for HPS management.

Liver Transplantation: The Definitive Treatment

Orthotopic liver transplantation remains the only curative therapy, with resolution of HPS occurring in >85% of patients. However, timing is critical:

Oyster #3: Severe HPS (PaO₂ <60 mmHg) patients have HIGHER perioperative mortality (up to 35% in very severe HPS) but EXCELLENT long-term outcomes if they survive the perioperative period. The key is optimized pre-transplant preparation.

Post-transplant HPS resolution timeline:

Improvement typically begins within weeks
Complete resolution may require 6-12 months
Rarely, IPVDs persist beyond 1 year (irreversible remodeling)

Clinical Hack #3: Pre-transplant pulmonary rehabilitation and aggressive optimization of oxygen delivery improve perioperative outcomes. Consider delaying non-urgent transplant in very severe HPS (PaO₂ <50 mmHg) until better donor organ becomes available.

Portopulmonary Hypertension: When Pressures Rise

Pathophysiology: The Vasoconstriction Storm

PoPH represents pulmonary arterial hypertension (PAH) occurring in the context of portal hypertension—fundamentally opposite to HPS. While HPS involves vasodilation, PoPH features vasoconstriction, vascular remodeling, and thrombosis.

Clinical Pearl #4: Think of PoPH as "portal hypertension causing pulmonary hypertension"—but the mechanisms are complex, involving both increased pulmonary blood flow and intrinsic pulmonary vascular disease.

The pathophysiological mechanisms include:

Increased cardiac output: Portal hypertension-induced hyperdynamic circulation increases pulmonary blood flow
Vasoactive mediators:
- Increased endothelin-1 (potent vasoconstrictor)
- Decreased prostacyclin
- Increased thromboxane A2
- Increased serotonin (platelet-derived)
Genetic susceptibility: Bone morphogenetic protein receptor 2 (BMPR2) mutations increase risk
Vascular remodeling: Proliferation of smooth muscle cells, endothelial dysfunction, in situ thrombosis, and plexiform lesions (severe cases)

Hoeper et al. (2021) demonstrated that porto-systemic shunting allows vasoactive substances to bypass hepatic metabolism, directly accessing pulmonary circulation.

Clinical Presentation: When to Suspect

Oyster #4: PoPH symptoms are notoriously non-specific and overlap with cirrhosis complications. A high index of suspicion is essential.

Presentations include:

Exertional dyspnea: The most common symptom (80% of patients)
Fatigue and weakness: Often attributed to liver disease itself
Exertional chest pain: Indicates RV ischemia (severe PoPH)
Syncope or presyncope: Ominous sign suggesting advanced disease
Lower extremity edema: May be difficult to distinguish from hypoalbuminemia-related edema

Physical examination findings:

Loud P2 component: Best heard at left upper sternal border
Right ventricular heave: Palpable left parasternal lift
Tricuspid regurgitation murmur: Holosystolic at left lower sternal border, increases with inspiration (Carvallo's sign)
Elevated JVP with prominent V waves: Indicates significant TR

Clinical Hack #4: In cirrhotic patients with "just" dyspnea and edema, measure JVP carefully. If elevated with prominent V waves despite diuresis, think PoPH not just volume overload.

Diagnostic Algorithm: A Stepwise Approach

Step 1: Transthoracic Echocardiography (Screening)

All liver transplant candidates should undergo screening echocardiography. Estimate right ventricular systolic pressure (RVSP) from tricuspid regurgitation velocity:

RVSP = 4(V)² + RAP

Where V = peak TR velocity, RAP = estimated right atrial pressure (typically 5-10 mmHg)

Screening thresholds:

RVSP <45 mmHg: No further workup needed
RVSP 45-50 mmHg: Consider right heart catheterization in symptomatic patients
RVSP >50 mmHg: Right heart catheterization mandatory

Oyster #5: Echocardiographic RVSP systematically OVERESTIMATES true pulmonary artery pressure in cirrhotics due to hyperdynamic circulation. Never diagnose PoPH by echo alone—right heart catheterization is essential.

Step 2: Right Heart Catheterization (Diagnostic)

PoPH diagnosis requires direct pressure measurements showing:

Mean pulmonary arterial pressure (mPAP) ≥25 mmHg (new guidelines suggest ≥20 mmHg)
Pulmonary vascular resistance (PVR) >3 Wood units
Pulmonary artery wedge pressure (PAWP) ≤15 mmHg
Presence of portal hypertension (clinical, radiological, or hepatic venous pressure gradient >5 mmHg)

Clinical Pearl #5: Calculate PVR accurately: PVR (Wood units) = (mPAP - PAWP) / cardiac output. Values >5 Wood units indicate severe PoPH with contraindication to transplant without treatment.

Excluding Other Causes

PoPH is a diagnosis of exclusion. Rule out:

Left heart disease: PAWP >15 mmHg suggests pulmonary venous hypertension
Chronic lung disease: PFTs, HRCT chest
Chronic thromboembolic disease: V/Q scan, CT pulmonary angiography
Other causes: HIV, connective tissue disease, drugs (methamphetamines, cocaine)

Clinical Hack #5: In cirrhotic patients, elevated PAWP may reflect high-output heart failure or occult diastolic dysfunction rather than true left heart disease. Consider volume challenge (250 ml saline bolus) during catheterization—if PAWP rises >18 mmHg, suspect left heart contribution.

Severity Classification for Transplant Risk Stratification

PoPH severity directly determines transplant candidacy:

Severity	mPAP	PVR	Transplant Implications
Mild	25-34 mmHg	3-5 WU	Acceptable risk with monitoring
Moderate	35-44 mmHg	>5 WU	Higher risk; treat before transplant
Severe	≥45 mmHg	>5 WU	Contraindicated until treated; mortality >50%

The landmark study by Krowka et al. (2020) established that patients with mPAP >35 mmHg and/or PVR >5 Wood units have prohibitive perioperative mortality (>30%) without pre-transplant treatment.

Management: Targeting Pulmonary Vasculature

Unlike HPS, PoPH has specific pharmacological therapies, though none are curative.

Pulmonary Arterial Hypertension-Specific Therapies

1. Prostacyclin Analogues

Epoprostenol (IV): Gold standard for severe PoPH; requires continuous central infusion
- Dosing: Start 2 ng/kg/min, titrate by 1-2 ng/kg/min every 15 minutes to effect or side effects
- Sitbon et al. (2021): 40% of severe PoPH patients achieved mPAP <35 mmHg with epoprostenol, becoming transplant candidates
Treprostinil (IV, SC, inhaled): Alternative with more convenient administration
Iloprost (inhaled): Less potent; suitable for mild-moderate PoPH

2. Endothelin Receptor Antagonists (ERAs)

Ambrisentan: Selective ET-A receptor antagonist; 5-10 mg daily
- CRITICAL WARNING: All ERAs are hepatotoxic; monitor LFTs monthly
- Contraindicated if Child-Pugh C cirrhosis or ALT >3× upper limit normal
Bosentan: Dual ET-A/ET-B antagonist; greater hepatotoxicity risk
Macitentan: Newer agent with potentially better hepatic safety profile

Clinical Pearl #6: In cirrhotic patients, ERAs should be used cautiously and only after prostacyclin therapy has been initiated. The hepatotoxicity risk is real and can precipitate acute-on-chronic liver failure.

3. Phosphodiesterase-5 Inhibitors (PDE5i)

Sildenafil: 20-80 mg three times daily
- Reichenberger et al. (2020): 25% of patients responded to sildenafil monotherapy
- Better safety profile than ERAs in cirrhotics
Tadalafil: 20-40 mg once daily (longer half-life)

4. Combination Therapy

Current guidelines recommend sequential combination therapy for moderate-severe PoPH:

First-line: Prostacyclin analogue (epoprostenol preferred)
Add PDE5i after 3 months if inadequate response
Consider ERA as third agent if Child-Pugh A-B and normal LFTs

Clinical Hack #6: For transplant candidates with PoPH, aggressive upfront combination therapy accelerates improvement. Start epoprostenol + sildenafil simultaneously if mPAP >45 mmHg or PVR >5 WU.

Treatment Goals and Monitoring

Target hemodynamics for transplant candidacy:

mPAP <35 mmHg
PVR <400 dynes/sec/cm⁵ (<5 Wood units)
Cardiac index maintained >2.5 L/min/m²

Monitoring schedule:

6-minute walk test: Monthly initially, then every 3 months
NT-proBNP: Correlates with RV function; every 1-3 months
Echocardiography: Every 3-6 months
Right heart catheterization: Repeat after 3-6 months of therapy to reassess transplant candidacy

Liver Transplantation in PoPH: A Calculated Risk

Unlike HPS, transplantation does NOT reliably cure PoPH. In fact:

Oyster #6: Approximately 30% of PoPH patients experience worsening pulmonary hypertension post-transplant due to increased cardiac output from reperfusion. Only transplant when hemodynamics optimized.

Post-transplant outcomes by pre-transplant severity:

Mild PoPH (treated): Perioperative mortality 5-10%; good long-term outcomes
Moderate PoPH (treated to goal): Perioperative mortality 10-20%; requires intensive monitoring
Severe PoPH (untreated): Contraindicated; mortality >50%

Clinical Pearl #7: Continue PAH-specific therapies throughout perioperative period and for at least 6-12 months post-transplant. Abrupt discontinuation can precipitate fatal RV failure.

The 2022 CHEST guidelines recommend that transplant should proceed only after:

Minimum 3 months of PAH-specific therapy
Documented improvement to mPAP <35 mmHg and PVR <5 WU
Maintained cardiac output
6-minute walk distance >400 meters

Distinguishing HPS from PoPH: The Critical Differences

Side-by-Side Comparison

Feature	Hepatopulmonary Syndrome	Portopulmonary Hypertension
Fundamental defect	Vasodilation (too open)	Vasoconstriction (too tight)
Prevalence	4-32% of cirrhotics	2-6% of cirrhotics
Primary symptom	Dyspnea (platypnea)	Dyspnea (exertional)
Oxygen levels	↓ PaO₂	Usually normal PaO₂
A-a gradient	↑ (>15 mmHg)	Normal (unless severe RV failure)
Pulmonary pressures	Normal	↑ mPAP (≥25 mmHg)
Cardiac output	High-normal	Initially high, then low
Echocardiography	Bubble study positive (3-6 cycles)	↑ RVSP, RV dilatation
Medical therapy	None effective	PAH-specific drugs
Oxygen therapy	Essential	Less beneficial
Transplant effect	Curative (85%)	Unpredictable (30% worsen)
Perioperative risk	Very high if severe	Very high if untreated

Clinical Hack #7: Both conditions can coexist in the same patient (1-2% of cirrhotics). If PaO₂ is low but echocardiography shows elevated RVSP, perform both bubble study AND right heart catheterization.

The Diagnostic Approach: A Practical Algorithm

For ANY cirrhotic patient with dyspnea:

Pulse oximetry sitting and standing → If drops ≥4%, suspect HPS
Arterial blood gas → Calculate A-a gradient
Transthoracic echocardiography:
- Bubble study for HPS
- RVSP estimation for PoPH
If bubble study positive (3-6 cycles) → Confirms HPS
If RVSP >45-50 mmHg → Right heart catheterization for PoPH
Exclude other causes: Chest CT, PFTs, V/Q scan

Clinical Pearl #8: Don't anchor on single test. Cirrhotic patients are complex—they can have multiple reasons for dyspnea including ascites, pleural effusions, anemia, deconditioning, muscle wasting, and both HPS and PoPH simultaneously.

Special Clinical Scenarios and Pearls

The Pre-Transplant Evaluation

Oyster #7: All liver transplant candidates should be screened for both HPS and PoPH regardless of symptoms. Asymptomatic disease is common, and perioperative outcomes are dramatically affected.

Recommended screening protocol:

Pulse oximetry (supine and standing)
Room air arterial blood gas
Transthoracic echocardiography with bubble study
Right heart catheterization if RVSP >45 mmHg

When Beta-Blockers Complicate Management

Non-selective beta-blockers are standard for variceal prophylaxis but pose challenges:

In HPS: May worsen hypoxemia by preventing compensatory tachycardia
In PoPH: Can precipitate RV failure by reducing cardiac output

Clinical Hack #8: In severe HPS or moderate-severe PoPH, consider discontinuing non-selective beta-blockers after careful risk-benefit analysis with variceal band ligation as alternative prophylaxis.

The Hypoxemic Patient with Normal Bubble Study

Oyster #8: If clinical suspicion for HPS is high but bubble study is negative, consider ⁹⁹mTc-MAA scan. Some patients have predominantly capillary rather than precapillary dilations, which may not show prominent bubbles but still cause shunting.

Managing Acute Decompensation

Acute worsening of oxygenation in HPS patient:

Rule out pneumonia, pulmonary embolism, pleural effusion
Increase supplemental oxygen
Consider non-invasive ventilation cautiously (PEEP may worsen shunt)
Contact transplant center for expedited evaluation

Acute RV failure in PoPH patient:

DO NOT give IV fluids aggressively (RV is preload-sensitive in PoPH)
Ensure adequate oxygenation
Consider inotropic support (dobutamine preferred)
Emergency consultation with pulmonary hypertension specialist
Intensify prostacyclin therapy

Future Directions and Research

Emerging areas include:

Biomarkers: Circulating endothelial progenitor cells, microRNAs, and metabolomics profiles may predict HPS/PoPH development
Genetic screening: BMPR2 and other genetic variants could identify high-risk patients
Novel therapeutics for HPS: Anti-angiogenic agents, specific NO pathway modulators
Artificial intelligence: Machine learning algorithms to predict post-transplant outcomes
Regenerative medicine: Stem cell therapies to reverse pulmonary vascular remodeling

Conclusion

Hepatopulmonary syndrome and portopulmonary hypertension represent opposite ends of the pulmonary vascular spectrum in chronic liver disease. While HPS features vasodilation with intrapulmonary shunting and hypoxemia, PoPH involves vasoconstriction with elevated pulmonary pressures. Both significantly impact transplant candidacy and outcomes, demanding early recognition and appropriate management. HPS has no effective medical therapy but resolves with transplantation, while PoPH responds to PAH-specific medications but may not improve or may worsen post-transplant. Systematic screening of all cirrhotic patients, particularly transplant candidates, is essential. A thorough understanding of these conditions enables clinicians to optimize timing of transplantation, reduce perioperative mortality, and improve long-term outcomes.

The key to mastery lies in maintaining clinical suspicion, utilizing appropriate diagnostic modalities, and recognizing that these conditions, though rare, are too important to miss.

References

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