Review

Portopulmonary hypertension: A focused review for the internist

Mamta S. Chhabria, MD, Leela Krishna Teja Boppana, MD, Gaurav Manek, MD and Adriano R. Tonelli, MD, MSc
Cleveland Clinic Journal of Medicine October 2023, 90 (10) 632-639; DOI: https://doi.org/10.3949/ccjm.90a.23023

Article Figures & Data

Figures

  • Figure 1
    Figure 1

    Mechanism of action of pulmonary hypertension medications.

    cGMP = cyclic guanosine monophosphate; GMP = guanosine monophosphate; PDE-5 = phosphodiesterase type 5; sGC = soluble guanylyl cyclase

Tables

  • TABLE 1

    Features suggesting portopulmonary hypertension in patients with cirrhosis

    History
    Dyspnea, fatigue, chest pain
    Syncope, presyncope
    Weight gain
    Lower-extremity swelling
    Ascites
    Clinical evidence of portal hypertension, eg, variceal hemorrhage, portal gastropathy, hepatic hydrothorax, ascites
    Physical examination
    Jugular vein distention
    Wide, split second heart sound, with loud pulmonic component
    Tricuspid regurgitation murmur
    Parasternal heave
    Hepatomegaly, pedal edema, ascites
    Signs of cirrhosis: spider angiomata, jaundice, gynecomastia, caput medusa, palmar erythema, ascites, hepatosplenomegaly
    Imaging and electrocardiography
    Computed tomography: main pulmonary artery-to-ascending-aorta ratio ≥ 1, dilation of right atrium and ventricle
    Electrocardiography: signs of right ventricular strain, right axis deviation, right atrial abnormality (P pulmonale), incomplete or complete right bundle branch block
    Hepatic vein catheterization diagnostic of portal hypertension: hepatic venous pressure gradient ≥ 6 mm Hg
    Echocardiography
    Enlarged right atrial area (> 18 cm2)
    Reduced right ventricular fractional area change (< 35%)
    Flattened interventricular septum
    D-shaped left ventricle
    Right ventricular/left ventricular basal diameter > 1
    Peak tricuspid regurgitation jet velocity > 2.8 m/s
    Right ventricular systolic pressure ≥ 45 mm Hg
    Decreased tricuspid annular plane systolic ejection (< 18 mm)
    Pulmonic insufficiency
    Pulmonary artery diameter ≥ 25 mm
    Inferior vena cava diameter > 21 mm with decreased respirophasic variation
  • TABLE 2

    Pulmonary hemodynamic patterns in patients with liver disease

    Embedded Image

    • ↑= elevated; ↑↑= very elevated; ↔ = normal; ↔↓ = normal or low

  • TABLE 3

    Trials of treatment of portopulmonary hypertension

    Portopulmonary Hypertension Treatment WIth Macitentan—a Randomized Clinical Trial (PORTICO)27
    Design: Multicenter, randomized, double-blind, placebo-controlled trial of macitentan 10 mg by mouth once daily (n = 43) vs placebo (n = 42) for 12 weeks.
    Inclusion and exclusion criteria: Adults age ≥ 18 with portopulmonary hypertension, 6-minute walking distance ≥ 50 m, pulmonary vascular resistance > 320 dynes·sec·cm−5; excluded patients with Model for End-stage Liver Disease score ≥ 19 or Child-Pugh class C liver disease.
    Results: 35% reduction in pulmonary vascular resistance in macitentan group compared with placebo.
    Comments: No hepatic safety concerns; more adverse effects (such as peripheral edema) in the macitentan group.
    Subgroup analysis from Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1) and PATENT-233–35
    Design: Multicenter, randomized, double-blind, placebo-controlled trial of riociguat up to 2.5 mg 3 times daily vs placebo for 12 weeks in 443 patients with pulmonary arterial hypertension (PATENT-1), of whom 13 had portopulmonary hypertension, with open-label extension in 396 patients who had no side effects (PATENT-2).
    Inclusion criteria. Adults age ≥ 18, pulmonary arterial hypertension due to any cause, never treated or treated with endothelin receptor antagonist or prostacyclin analogue (except intravenous).
    Results: Improvement in 6-minute walking distance (+ 48 meters with riociguat compared with +3 meters with placebo) Secondary end point: Improvement in World Health Organization functional class
    Sustained effect noted at the end of 2 years in PATENT-2.
    Comments: No hepatic safety concerns, but dose adjustment needed; peripheral edema and headache were common adverse effects.
    Open-label trial of ambrisentan36
    Design: Open-label comparison of ambrisentan 5 mg once daily (titrated up to 10 mg once daily at or after week 4 if tolerated) for 24 weeks (n = 23), followed by long-term extension for 24–28 weeks (n = 19).
    Inclusion criteria: Adults age ≥ 18 with portopulmonary hypertension, Child-Pugh class A or B, alanine aminotransferase and aspartate aminotransferase levels less than 5 times the upper limit of normal.
    Results: No change in 6-minute walking distance, improvement in pulmonary vascular resistance (7.1 ± 5 vs 3.8 ± 1.8 WU, P < .001). Secondary end points: improvement in World Health Organization functional class, right atrial pressure, mean pulmonary artery pressure, and cardiac index.
    Comments: Peripheral edema and headaches were common side effects.
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