What are the diagnostic criteria for hepatopulmonary syndrome in a patient with liver disease, particularly cirrhosis, presenting with dyspnea, platypnea, and orthodeoxia?

Diagnosis of Hepatopulmonary Syndrome

Hepatopulmonary syndrome is diagnosed when all three criteria are met: (1) hypoxemia with PaO2 <80 mmHg or alveolar-arterial oxygen gradient ≥15 mmHg (≥20 mmHg if age >65 years) on room air, (2) evidence of intrapulmonary vascular dilatations by contrast-enhanced echocardiography or lung perfusion scanning showing >6% shunt fraction, and (3) presence of liver disease or portal hypertension. 1

Essential Diagnostic Components

1. Arterial Oxygenation Assessment

• Arterial blood gas analysis is mandatory, measuring PaO2 and calculating the alveolar-arterial oxygen gradient using the formula: P(A-a)O2 = (FIO2 [Patm–PH2O] - [PaCO2/0.8]) - PaO2 1
• Hypoxemia is defined as PaO2 <80 mmHg or P(A-a)O2 ≥15 mmHg in ambient air (≥20 mmHg in patients older than 65 years) 1
• Pulse oximetry in the upright position showing SpO2 <96% is highly sensitive for screening and should be performed routinely 2
• Orthodeoxia (decreased oxygenation when upright) occurs because intrapulmonary vascular dilatations predominate in lung bases, worsening shunt with gravitational blood flow redistribution 3

2. Demonstration of Intrapulmonary Vascular Dilatations

Contrast-enhanced transthoracic echocardiography is the most sensitive first-line test, showing microbubble opacification of the left heart chambers three to six cardiac cycles after right atrial passage 1, 2. This delayed appearance (beyond 3-6 beats) distinguishes intrapulmonary shunting from intracardiac shunts, which appear within 1-3 beats.

Alternative confirmatory tests include:

• Technetium-99m macroaggregated albumin lung perfusion scan demonstrating shunt fraction >6% to the brain 1, 2
• Cardiac catheterization demonstrating severe intrapulmonary vascular dilatations (reserved for unclear cases) 1

3. Presence of Liver Disease or Portal Hypertension

HPS occurs most commonly with:

• Hepatic portal hypertension with underlying cirrhosis 1
• Pre-hepatic or hepatic portal hypertension without cirrhosis 1
• Less commonly: acute liver failure, chronic hepatitis, or congenital portosystemic shunts 1

Critical caveat: Severe liver dysfunction is NOT required for HPS development—it can occur with non-cirrhotic portal hypertension, portal vein thrombosis, or congenital hepatic fibrosis 1.

Clinical Presentation Features

Look specifically for:

• Dyspnea (most common symptom) 4, 5
• Platypnea (dyspnea worsening when upright) 4, 5, 6
• Orthodeoxia (oxygen desaturation when upright, improving when supine) 4, 6
• Digital clubbing (present in many cases) 4, 5
• Cyanosis or acrocyanosis 4
• Spider angiomata (significantly more common in HPS patients) 5

Severity Classification

HPS severity is stratified by PaO2 levels, which has major prognostic and transplant listing implications 2:

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

Prognostic significance: Median survival without liver transplantation in severe HPS (PaO2 <50 mmHg) is less than 12 months in adults 1, 2. Five-year survival is only 23% in untransplanted HPS patients versus 63% in matched cirrhotic patients without HPS 2, 3.

Screening Recommendations

All patients with portal hypertension (cirrhotic or non-cirrhotic) or congenital/acquired portosystemic shunts should undergo regular screening with room air pulse oximetry in the upright position 1, 2. This is particularly important for transplant candidates, as HPS confers MELD exception points for transplant prioritization 2.

Common Diagnostic Pitfalls

• Failing to test in the upright position: Orthodeoxia and platypnea are hallmark features that will be missed if only supine measurements are obtained 3, 6
• Assuming normal liver function excludes HPS: Portal hypertension alone, even without cirrhosis, can cause HPS 1
• Confusing timing on bubble study: Intracardiac shunts appear within 1-3 beats; intrapulmonary shunts appear after 3-6 beats 1
• Not considering HPS in acute presentations: While typically diagnosed during transplant evaluation, HPS can present acutely with severe hypoxemia and may be the initial manifestation of previously unrecognized cirrhosis 7