What is the likely diagnosis in a 45‑year‑old man with alcohol‑related liver disease and portal hypertension who has dyspnea that worsens when supine (orthodeoxia), an alveolar‑arterial oxygen gradient of 17 mm Hg, a normal left‑ventricular ejection fraction (55 %), and delayed microbubble appearance in the left heart after five cardiac cycles on contrast echocardiography?

Hepatopulmonary Syndrome

The likely diagnosis is hepatopulmonary syndrome (HPS), confirmed by the triad of alcohol-related liver disease with portal hypertension, an elevated alveolar-arterial oxygen gradient (17 mmHg, above the normal 4-8 mmHg threshold), and delayed microbubble appearance in the left heart after five cardiac cycles on contrast echocardiography, which definitively demonstrates intrapulmonary vascular dilatations. 1

Diagnostic Confirmation

The clinical presentation meets all three diagnostic criteria established by the European Association for the Study of Liver Diseases for HPS 1:

• Liver disease with portal hypertension: Alcohol-related liver disease with documented portal hypertension 1
• Arterial hypoxemia: Alveolar-arterial oxygen gradient of 17 mmHg exceeds the diagnostic threshold of ≥15 mmHg for patients under 65 years 1
• Intrapulmonary vascular dilatations: Delayed microbubble opacification of the left heart chambers occurring 3-6 cardiac cycles after right atrial passage on contrast echocardiography is pathognomonic for HPS 1

Key Distinguishing Features

The timing of microbubble appearance is critical for diagnosis. Microbubbles appearing after 3-6 cardiac cycles indicate intrapulmonary vascular dilatations characteristic of HPS, distinguishing it from intracardiac shunts where bubbles would appear within 1-3 cycles 1. The five-cycle delay in this patient confirms pulmonary rather than cardiac shunting.

Orthodeoxia (worsening dyspnea when moving from supine to upright position) is a classic clinical feature of HPS, occurring in approximately 88% of patients, and results from gravitational redistribution of blood flow to dilated basilar pulmonary vessels 2, 1.

The preserved left ventricular ejection fraction (55%) excludes cardiac causes of dyspnea and is typical for HPS, where systolic function remains normal despite the pulmonary vascular abnormalities 1.

Severity Classification and Prognosis

Based on the diagnostic workup, this patient requires arterial blood gas analysis to determine HPS severity 3:

• Mild HPS: PaO2 ≥80 mmHg
• Moderate HPS: PaO2 60-79 mmHg
• Severe HPS: PaO2 50-59 mmHg
• Very severe HPS: PaO2 <50 mmHg 3

The prognosis without liver transplantation is poor, with five-year survival of only 23% in HPS patients compared to 63% in matched cirrhotic patients without HPS 1, 3. Patients with severe HPS (PaO2 <50 mmHg) have a median survival of less than 12 months without transplantation 1, 3.

Management Algorithm

Immediate liver transplantation evaluation is mandatory, as this is the only definitive treatment that reverses HPS and improves mortality 4, 3:

1. Perform arterial blood gas analysis every 6 months to monitor progression, as hypoxemia worsens progressively 4
2. Initiate liver transplant evaluation immediately rather than waiting for severe hypoxemia to develop, as mortality is nearly double compared to cirrhotic patients without HPS 4
3. Provide supplemental oxygen therapy for symptomatic relief while awaiting transplantation, particularly during physical activity 1, 4
4. Obtain MELD exception points to prioritize transplantation before PaO2 falls below 50 mmHg, as this threshold is associated with significantly increased post-transplant mortality 4, 3

Critical Pitfalls to Avoid

Do not delay transplant evaluation even if liver function appears relatively preserved, as HPS severity does not correlate with liver disease severity and can progress independently 1. Substantial deterioration in PaO2 can occur despite clinically stable hepatic dysfunction 2.

Do not attempt medical management as definitive therapy, as no established medical therapy exists for HPS and spontaneous resolution is uncommon 1, 4. Trials with pentoxifylline, beta-blockers, and other agents have been uniformly unsuccessful 1.

Do not wait until PaO2 falls below 44-50 mmHg to pursue transplantation, as patients with PaO2 <50 mmHg who lack reversibility to 100% oxygen have increased risk of irreversible respiratory failure post-transplant and higher perioperative mortality 1, 4.

Avoid using TIPS routinely for HPS treatment, as there is insufficient evidence and potential to worsen pulmonary vasodilation 4.

Post-Transplant Considerations

Respiratory function may temporarily worsen in the first days after liver transplantation due to the surgical procedure itself, and complete improvement may take months 1, 4. However, liver transplantation results in complete reversal or significant improvement in more than 85% of patients with severe hypoxemia, with five-year survival improving from 67% to 88% 4.