Hepatopulmonary Syndrome

AUTHOR: Kathleen Doo, MD, MHPE

Definition

Hepatopulmonary syndrome (HPS) is defined by the presence of (1) liver disease (usually chronic), (2) reduced arterial oxygenation, and (3) evidence of intrapulmonary vascular dilations (IPVDs).¹

Synonym

HPS

ICD-10CM CODE
K76.81		Hepatopulmonary syndrome

Epidemiology & Demographics

Prevalence

4% to 47% of patients with cirrhosis;² the wide range is due to lack of diagnostic criteria.

Risk Factors

HPS occurs with any degree or etiology of liver disease but is more prevalent in patients with established cirrhosis and portal hypertension.

Genetics

New data suggest that polymorphisms in genes involved in the regulation of angiogenesis are associated with increased HPS risk.³

Physical Findings & Clinical Presentation

Dyspnea
Platypnea: Increased dyspnea when sitting upright and relieved when supine
Orthodeoxia: Decreased PaO₂ (by more than 4 mm Hg) when sitting upright and improved when supine
Increased spider nevi (spider angiomata)
Signs of severe hypoxemia (e.g., cyanosis and clubbing of the digits)
Table E1 describes a severity grading for HPS

TABLE E1 Grading of Severity of Hepatopulmonary Syndrome ∗

Stage	Alveolar-Arterial Po₂ Difference	Arterial Partial Pressure of Oxygen
Mild	≥15 mm Hg or >20 mm Hg if age >64 yr	≥80 mm Hg
Moderate	≥15 mm Hg or >20 mm Hg if age >64 yr	<80 to ≥60 mm Hg
Severe	≥15 mm Hg or >20 mm Hg if age >64 yr	<60 to ≥50 mm Hg
Very severe	≥15 mm Hg or >20 mm Hg if age >64 yr	<50 mm Hg

^∗All with positive contrast-enhanced echocardiography, breathing room air at rest and at sea level. From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Etiology

Dilation of intrapulmonary arterioles and dilated vascular channels between pulmonary arteries and veins leads to a ventilation-perfusion mismatch and right-to-left shunting. Research shows that nitric oxide (NO) plays a role in vasodilation.⁴ The relationship of vasodilation to liver disease is unclear. Fig. E1 illustrates a proposed pathophysiology of hepatopulmonary syndrome. In some patients, intrapulmonary shunting via dilated intrapulmonary vessels and pulmonary and pleural-based arteriovenous malformations can develop, resulting in worse hypoxemia and a blunted response to supplemental oxygen. A diffusion limitation has been postulated to be due to a “diffusion-perfusion defect” for oxygen in dilated pulmonary capillaries (Fig. E2). New areas of research include endothelin-1, which is produced by proliferating cholangiocytes, pulmonary angiogenesis, and opiate receptors’ influence on NO production.

Figure E1 Proposed Pathophysiology of Hepatopulmonary Syndrome

Enos, Endothelial Nitric Oxide Synthase; Et1, Endothelin-1; Ho-1, Heme Oxygenase; Inos, Inducible Nitric Oxide Synthase; Tgf-, Transforming Growth Factor-; VEGF, Vascular Endothelial Growth Factor.

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

Figure E2 Mechanisms of Arterial Hypoxemia in Hepatopulmonary Syndrome in a Two-Compartment Gas Exchange Model

(A) In the homogeneous lung of a healthy individual, with uniform alveolar ventilation and pulmonary blood flow, the capillary ranges between 8 and 15 μm in diameter, and oxygen diffuses properly into the capillary while ventilation-perfusion is well balanced. (B) In hepatopulmonary syndrome, where many capillaries are dilated and blood flow is nonuniform, alveolar ventilation-to-pulmonary perfusion mismatch emerges as the predominant mechanism at any clinical stage, either with or without the presence of intrapulmonary shunt and coexistent with oxygen diffusion limitation into the center of the dilated capillaries in the most advanced stages.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Diagnosis ⬆ ⬇

Differential Diagnosis

Portopulmonary hypertension (Table E2)
Cavopulmonary anastomosis
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
Chronic lung disease (e.g., chronic obstructive pulmonary disease [COPD] or pulmonary fibrosis) with coexisting liver disease

TABLE E2 Comparison of Clinical Features of Hepatopulmonary Syndrome and Portopulmonary Hypertension

	Hepatopulmonary Syndrome	Portopulmonary Hypertension
Symptoms	Dyspnea, platypnea, fatigue	Dyspnea, fatigue, lower extremity edema, abdominal distention
Physical exam findings	Clubbing, cyanosis, spider angiomata, orthodeoxia	Jugular venous distention, prominent pulmonic component of the second heart sound, tricuspid regurgitation murmur, ascites, lower extremity edema
Prevalence	5%-32%	5%-6%
Gas exchange	Elevated alveolar-arterial Po₂ difference with mild to severe hypoxemia	Normal or mild hypoxemia
Contrast-enhanced transthoracic echocardiogram	Intrapulmonary vasodilation (late appearance of microbubbles in the left-sided chambers)	Elevated right ventricular systolic pressure and/or right ventricular dilation or dysfunction
Pathology	Precapillary and capillary vasodilation	Plexiform lesions, intimal thickening, smooth muscle proliferation and in situ thrombosis
Medical treatment	Supportive	Pulmonary arterial hypertension-targeted therapy
Effect of liver transplantation	Resolution of hypoxemia	Variable outcomes

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Workup

Diagnosis should be suspected in patients with cirrhosis who develop hypoxemia in the absence of other causes (e.g., COPD, thromboembolism).
Workup includes lab testing and imaging studies (see following), but diagnosis is based on clinical findings.

Laboratory Tests

Arterial blood gas while breathing room air, both supine and upright; PaO₂ <80 mm Hg in the absence of an alternative cause or A-a gradient ≥15 mm Hg (or ≥20 mm Hg in those ≥65 yr old).
Pulmonary function tests will show nonspecific reduction in DLCO.

Imaging Studies

Transthoracic contrast echocardiography (“bubble study”) (Fig. E3) is the most effective screening tool to rule out right-to-left cardiac shunt and to identify presence of microbubble opacification in the left atrium after three to eight heartbeats suggesting vasodilation of the pulmonary vascular bed.
Chest x-ray may show nonspecific bibasilar interstitial pattern. Chest CT may show dilated peripheral pulmonary arteries.
Scintigraphic perfusion scanning: Technetium-99m-labeled albumin found in the brain or spleen indicates dilated pulmonary vasculature or cardiac right-to-left shunt.
Pulmonary angiography is rarely used unless there is a potential to embolize arteriovenous malformations (AVM).

Figure E3 Contrast-Enhanced Echocardiograms in a Patient with Hepatopulmonary Syndrome

Left, Normal Four-Chamber View. Center, Injected Microbubbles Appear in the RV (Arrow). Right, Within Five beats, Microbubbles Appear in the LV (Arrow). The Demonstration of Microbubbles in the Left Cardiac Chambers is Highly Suggestive of the Presence of Intrapulmonary Vascular Dilations, or, Alternatively, of Anatomic Arteriovenous Malformations. LA, Left Atrium; LV, Left Ventricle; RA, Right Atrium; RV, Right Ventricle.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Treatment ⬆ ⬇

Some studies have shown benefit of transjugular intrahepatic portosystemic shunting (TIPS), although it is not currently an established treatment.
Coil embolization in the setting of pulmonary AVMs is another possible treatment.

Nonpharmacologic Therapy

Oxygen to correct hypoxemia; PaO₂ will partially correct with administration of supplemental oxygen.

Acute General Rx

There is no established pharmacotherapy for HPS.

Chronic Rx

HPS is an indication for liver transplantation. Liver transplantation is the only successful treatment; the majority of patients show improvement in oxygenation at 1 yr after transplant.⁵ Fig. E4 illustrates an approach to screening for hepatopulmonary syndrome in potential candidates for liver transplantation.
Some studies have shown benefit of transjugular intrahepatic portosystemic shunting (TIPS), although it is not currently an established treatment.⁶
Coil embolization in the setting of pulmonary AVMs is another possible treatment.⁷

Figure E4 Approach to Screening for Hepatopulmonary Syndrome (HPS) in Potential Candidates for Liver Transplantation

ABG, Arterial Blood Gas; Tte, Transthoracic Echocardiography.

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

Disposition

The diagnosis of HPS confers a poor prognosis. Patients with HPS have high mortality and shorter median survival than other patients with liver disease, even after adjusting for the severity of liver disease. According to one natural history study, compared to patients with similar severities of liver disease and comorbidities whose 5-yr survival was estimated at 63%, patients with HPS had a 5-yr survival rate of only 23%.⁸

Complementary & Alternative Medicine

One study suggested that garlic supplements might reduce the A-a gradient in patients with HPS.⁹

Referral

To pulmonologist to help in establishing diagnosis
To a liver transplant center for potential liver transplant candidacy

Pearls & Considerations ⬆ ⬇

Comments

Consider the diagnosis of HPS in patients with cirrhosis who present with dyspnea without signs of pulmonary edema from fluid overload.

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

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