What is portopulmonary syndrome?

Portopulmonary Syndrome: Definition, Diagnosis, and Management

Portopulmonary hypertension (POPH) is a form of pulmonary arterial hypertension that develops in patients with portal hypertension, characterized by increased pulmonary vascular resistance and pulmonary arterial pressure in the setting of liver disease with portal hypertension. 1

Definition and Pathophysiology

Portopulmonary hypertension is one of two major pulmonary vascular complications that can occur in patients with chronic liver disease:

• Portopulmonary hypertension (POPH): A subset of Group 1 pulmonary arterial hypertension (PAH) that develops in the setting of portal hypertension 1

  • Characterized by increased pulmonary vascular resistance
  • Requires the presence of portal hypertension (with or without cirrhosis) 1
  • Plexiform lesions similar to those in idiopathic PAH are often found 1

• Hepatopulmonary syndrome: The other major pulmonary vascular complication 1

  • Characterized by hypoxemia due to intrapulmonary shunting
  • Presents with low oxygen saturations and orthodeoxia (lower oxygen saturations when standing)
  • Different pathophysiology and treatment approach than POPH 1

The pathophysiology of POPH involves:

• Portal hypertension allowing vasoconstrictive and vasoproliferative substances to bypass liver clearance via portosystemic shunts 1
• Serotonin from intestinal enterochromaffin cells may be one of these substances 1
• Duration of portal hypertension may increase risk of developing POPH 1

Epidemiology

• Prevalence of POPH among liver transplant candidates is approximately 2-9% 2
• POPH represented 8% of cases in the NIH registry of pulmonary arterial hypertension 1
• Surgical portosystemic shunts increase the risk of developing POPH 1
• Can occur in both cirrhotic and non-cirrhotic portal hypertension 3

Clinical Presentation and Diagnosis

The clinical presentation may be:

• Indistinguishable from idiopathic PAH 1
• Include a combination of symptoms from both PAH and underlying liver disease 1

Diagnostic approach:

1. Echocardiographic screening is recommended in:

   • Symptomatic patients with liver disease 1
   • Candidates for liver transplantation 1

2. Right heart catheterization (RHC) is essential for:

   • Confirming diagnosis in all cases with elevated pulmonary pressures on echocardiography 1
   • Determining hemodynamic parameters crucial for prognosis and treatment decisions 1

Hemodynamic findings in POPH compared to idiopathic PAH:

• Higher cardiac output 1
• Lower systemic vascular resistance 1
• Lower pulmonary vascular resistance 1
• Later-stage disease may show hemodynamics more similar to idiopathic PAH 1

Diagnostic criteria for portal hypertension during RHC:

• Hepatic venous pressure gradient >10 mmHg (normal is <5 mmHg) 1

Treatment

Treatment of POPH should follow the same algorithm as other forms of PAH, with adaptations for liver disease and its complications. 1

Key treatment components:

1. Supportive care:

   • Supplemental oxygen to maintain saturations >90% 1
   • Diuretic therapy to control volume overload, edema, and ascites 1

2. Pharmacologic therapy:

   • Anticoagulation is NOT recommended in patients with increased bleeding risk 1
   • Beta-blockers (often used for portal hypertension) may worsen hemodynamics and exercise capacity in POPH 1
   • For mild-to-moderate PH, assess acute vasoreactivity in the catheterization laboratory 1
   • If positive vasoreactivity, cautious introduction of calcium channel blockers may be considered 1
   • High-dose calcium channel antagonists should be avoided as they may precipitate hepatic failure 1
   • Epoprostenol has shown benefit in case reports and small series 1
   • Bosentan and sildenafil may provide beneficial effects in selected patients 1
   • Careful monitoring is required with endothelin receptor antagonists due to potential hepatotoxicity 1

3. Liver transplantation considerations:

   • Significant PAH substantially increases risk with liver transplantation 1
   • PAH is a contraindication to liver transplantation if mean PAP is >35 mmHg and/or PVR is >250 dynes.s.cm⁻⁵ 1
   • PAH-specific therapy may improve hemodynamics prior to transplantation 1
   • Some patients may improve after liver transplantation, particularly those with high cardiac output pre-transplantation 1
   • Others may experience worsening of PAH after transplantation 1
   • Combined liver-lung or liver-heart-lung transplantation may be considered in selected patients 1

Prognosis

• Untreated POPH has poor prognosis 3
• Long-term survival is generally poor 2
• Some retrospective studies suggest better survival rates compared to idiopathic PAH, though this is debated 1
• Severe POPH with right ventricular failure despite therapy is associated with poor outcomes after liver transplantation 2

Important Considerations and Pitfalls

• Do not confuse POPH with hepatopulmonary syndrome, which has different pathophysiology, presentation, and treatment 1
• Thorough evaluation is needed to exclude other causes of PAH (thromboembolic disease, congenital heart disease, collagen vascular disease) 1
• Patients with POPH should be managed by a multidisciplinary team including hepatologists and pulmonary hypertension specialists 3
• The post-liver transplantation course of POPH is unpredictable; some patients improve while others worsen 4
• Careful monitoring is required if endothelin receptor antagonist treatment is initiated due to potential hepatotoxicity 1