Hepatopulmonary Syndrome

Etiology

Hepatopulmonary syndrome is most commonly associated with portal hypertension due to chronic liver disease or cirrhosis. However, portal hypertension without underlying liver disease can also cause hepatopulmonary syndrome. Acute liver disease, like acute hepatitis resulting in acute liver failure, is a rare cause of hepatopulmonary syndrome. The presence and severity of HPS do not correlate with the severity of liver disease.

Epidemiology

Hepatopulmonary syndrome occurs more frequently in White individuals compared to Hispanic or Black individuals and appears less commonly among patients who smoke.[4] Reports from liver transplantation centers have documented an incidence of hepatopulmonary syndrome in patients with cirrhosis ranging from 5% to 32%.[5] The condition tends to develop in those with cirrhotic portal hypertension and severe hepatic dysfunction, while cases in children remain rare.[6]

Pathophysiology

The primary cause of hepatopulmonary syndrome is believed to be pulmonary vascular dilatation resulting from an imbalance between vasodilators and vasoconstrictors. The exact mechanism of vasodilation is not precise, and multiple studies are ongoing to elucidate the actual mechanism. Pulmonary endothelial nitric oxide synthetase (eNOS) stimulation occurs in the lungs as a result of increased hepatic production of endothelin 1 (ET1) and pulmonary endothelin B (ETB) due to stress. eNOS stimulation causes increased nitric oxide production, which is a potent vasodilator. 

Translocation of intestinal bacteria and endotoxemia in liver disease patients leads to massive accumulation of macrophages and monocytes in the lungs. These macrophages release tumor necrosis factor-alpha (TNF-alpha) in pulmonary vessels, leading to inducible nitric oxide synthetase (iNOS) activation. iNOS stimulation also causes increased production of nitric oxide. Bacterial accumulation and increased nitric oxide cause increased levels of heme oxygenase. Heme oxygenase catalyzes the degradation of heme, resulting in increased carbon monoxide production. The increased production of these potent vasodilators plays a crucial role in pulmonary vasodilatation. Additionally, macrophages, monocytes, and TNF-alpha activate vascular endothelial growth factor (VEGF), resulting in increased angiogenesis in the pulmonary vasculature.[3][7] 

Vasodilation and angiogenesis lead to arteriovenous (AV) shunt formation within the pulmonary vasculature, leading to a mismatch of ventilation-perfusion. The pulmonary capillaries are dilated to 15 to 500 µm in hepatopulmonary syndrome compared to a normal diameter between 8 and 15 µm.[8][9] Dilatation of the pulmonary vasculature leads to reduced transit time for blood cells and a large amount of blood passing through the pulmonary vasculature without undergoing gas exchange. Some blood may pass through AV shunts without encountering alveoli, so gas exchange does not occur in these blood cells. Increased pulmonary capillary wall thickness has also been observed, which causes impaired diffusion of gases.

This pulmonary vasodilation, AV shunts, and impaired diffusion lead to ventilation-perfusion mismatch, creating increased alveolar-arterial gradient and hypoxemia.[10][11] Pulmonary vasodilation is most distinct in the lung bases, which explains the symptoms of platypnea (increased dyspnea in the upright position) and orthodeoxia (decrease in arterial oxygenation in the upright position) associated with hepatopulmonary syndrome. Both conditions improve when the patient returns to the recumbent position. 

Two patterns of hepatopulmonary syndrome have been identified based on the location of dilated pulmonary vessels:

• Type I: Dilatation of vessels at the precapillary levels near gas exchange units of the lungs; supplemental O₂ increases PaO₂ in this type of hepatopulmonary syndrome
• Type II: Larger dilatation of vessels causing arteriovenous shunts away from gas exchange units of lungs; supplemental O₂ is not helpful [12]

History and Physical

The patient usually presents with dyspnea in the setting of liver disease. The onset is insidious, and the dyspnea worsens with exertion. In the early stages, most patients are asymptomatic. The patient may have associated signs and symptoms of chronic liver disease.

Hepatopulmonary syndrome may also occur in conjunction with other cardiopulmonary diseases, thereby exacerbating ventilation-perfusion abnormalities. The physical exam may show the following:

• Cyanosis
• Digital clubbing [13][14][15] 
• Diffuse telangiectasia: In several studies, spider naevi are more likely associated with HPS.[7][16] 
• Platypnea: Worsening of dyspnea when moving from a supine to an upright position [17]
• Orthodeoxia: Decrease in PaO2 of >5% or >4 mm Hg when moving from supine to upright; orthodeoxia is very specific for hepatopulmonary syndrome in the presence of liver disease (the sensitivity of orthodeoxia is low but increases with the severity of hepatopulmonary syndrome)

Evaluation

Several methods may be utilized to evaluate patients for hepatopulmonary syndrome.

Pulse Oximeter 

The initial screening for hepatopulmonary syndrome involves using a pulse oximeter to evaluate the saturation of peripheral oxygen (SpO₂). An oxygen saturation of <96% signifies PaO₂ <70 mm Hg and is considered a positive screen. If the screen is positive, the patient should undergo arterial blood gas (ABG) analysis, which helps to determine PaO2 and A-aO2.

Contrast-enhanced Echocardiography

Contrast-enhanced echocardiography with agitated saline is the test of choice for diagnosing pulmonary vascular dilatation due to its low risk and high sensitivity. Normal saline is agitated to generate microbubbles >10 µm in diameter. Normal saline is injected into a peripheral vein in the arm, and simultaneous transthoracic echocardiography (TTE) is performed. Usually, microbubbles are trapped in the pulmonary circulation and absorbed by alveoli. However, in the presence of pulmonary dilatation and AV shunts, microbubbles evade pulmonary capture and reach the left atria of the heart, which can be seen via TTE in the left atrial chamber. The appearance of microbubbles in the left atria between the fourth and sixth cardiac cycle indicates pulmonary vasodilatation. If the microbubbles appear on the heart's left side before the third cardiac cycle, that indicates intracardiac shunting.

Transesophageal Echocardiogram

A transesophageal echocardiogram study is superior to transthoracic echocardiography in diagnosing pulmonary dilation and intracardiac shunting. However, this test is invasive, and esophageal varices are a concern in many patients with cirrhosis and portal hypertension.

Radioactive Lung Perfusion Scanning

Radioactive lung perfusion scanning is another method used to assess pulmonary vessel dilatation, although this modality is less sensitive than contrast-enhanced echocardiography. Radioactive lung perfusion scanning does not distinguish between intrapulmonary and intracardiac shunting. However, this test may help decide if hepatopulmonary syndrome is contributing to hypoxemia in patients with concomitant lung disease. Radiolabeled albumin aggregates measuring approximately 20 µm in diameter are infused into the peripheral vein. Typically, particles of this size are trapped in the pulmonary microvasculature, and scintigraphy reveals nearly complete uptake in the lungs. When significant intrapulmonary shunting is present, a fraction of the albumin passes through the pulmonary vasculature and into the systemic circulation. Scintigraphy can reveal uptake in organs other than the lungs, which allows for the calculation of the shunt fraction. Brain shunt fraction >6% is considered significant.

Pulmonary Angiography

Pulmonary angiography can diagnose and distinguish between type I and type II hepatopulmonary syndrome. However, this test is more expensive and invasive, and therefore not a preferred method of diagnosis. Pulmonary angiography is also less sensitive than contrast-enhanced echocardiography with agitated saline.

Additional Tests

Additional tests include chest x-rays, computed tomography (CT), and pulmonary function tests. 

• Chest X-ray: May be normal or show increased bibasilar nodular opacities coinciding with increased pulmonary dilatation (can exclude coexistent pulmonary pathology)
• CT of the chest: May show enlarged dilated vessels; usually done to exclude pulmonary pathology
• Pulmonary function tests: May show decreased diffusion capacity for carbon monoxide (DLCO) [18]

Treatment / Management

Oxygen Therapy 

Oxygen therapy is recommended for patients with severe hypoxemia and is usually given until a more definitive treatment, like liver transplantation, can be performed. Increasing oxygenation and reducing hypoxemia lead to better exercise tolerance and improved quality of life.[19]

Liver Transplantation

Liver transplantation is the only established treatment shown to provide long-term survival benefits for patients with severe hepatopulmonary syndrome. Those with severe hepatopulmonary syndrome and PaO₂ <60 mm Hg should be referred for liver transplant evaluation. Liver transplant improves hypoxemia in most patients within 6 to 12 months. Studies have shown that PaO₂ and A-aO2 reverse rapidly after transplant. Intrapulmonary shunts also reverse but may take longer than 6 months. DLCO has also been shown to improve in some patients in one study.[20][21]

Patients with severe hepatopulmonary syndrome may qualify for additional “exception” points added to the model for end-stage liver disease (MELD) score, which would improve their priority on the wait list for liver transplantation. Those patients with very severe hypoxemia (PaO2 <50 mm Hg) may be considered too high risk for liver transplant due to the concern for increased posttransplant mortality, but this determination is facility-dependent.

Extracorporeal membrane oxygenation (ECMO) has been explored as a rescue therapy for liver transplant patients with hepatopulmonary syndrome who experience respiratory failure and refractory hypoxemia. Wu et al summarize global experience with ECMO in liver transplant patients with hepatopulmonary syndrome, demonstrating that despite the severe illness at the time of transplant, most patients in the cohort survive hospitalization and successfully wean from supplemental oxygen.[22][23](A1)

Other Treatments

Currently, no approved medical therapy for hepatopulmonary syndrome has been established. Many medical treatments, including garlic, pentoxifylline, mycophenolate mofetil, aspirin, methylene blue, inhaled nitric oxide, nitric oxide inhibitors, and somatostatin, have been tried; however, none have been of conclusive benefit, and none are FDA-approved.

Transjugular intrahepatic portosystemic shunt 

Limited data exist on the use of transjugular intrahepatic portosystemic shunt (TIPS), and clinical outcomes vary. Studies on TIPS in hepatopulmonary syndrome have yielded mixed results. Some studies have reported short-term improvements in pulmonary function following the procedure; however, these effects are transient and often diminish over time.[24] TIPS can aggravate the hyperkinetic circulatory state, increasing intrapulmonary vasodilatation and shunting and worsening hypoxemia. Hepatic decompensation and encephalopathy have a higher risk of occurrence after TIPS.

Pulmonary arterial coil embolization

This procedure is limited in its application, as it can only be used in select cases where there are significant AV communications.

Differential Diagnosis

The differential diagnoses for hepatopulmonary syndrome include the following:

• Portopulmonary hypertension
• Atelectasis
• Recurrent pulmonary emboli
• Atrial septal defect
• Arteriovenous malformations
• Postpneumonectomy 
• Chronic cardiopulmonary disease
• Chronic obstructive pulmonary disease
• Pneumonitis
• Pneumonia
• Hepatic hydrothorax
• Ascites causing reduced pulmonary function

Prognosis

Patients with hepatopulmonary syndrome have 2 times higher mortality compared to those with cirrhosis without hepatopulmonary syndrome. The condition is associated with a poor quality of life and inferior functional status.[4] The average life span (10.5 months) in a patient with hepatopulmonary syndrome is significantly reduced compared with that (40.8 months) of patients with chronic liver disease without hepatopulmonary syndrome. The mortality risk increases with the severity of the disease, with a worse prognosis in patients with very severe disease.[25] Post–liver transplant survival is also slightly reduced in patients with very severe hepatopulmonary syndrome.

Complications

Untreated hepatopulmonary syndrome is a fatal disease that drastically reduces the life span of a patient with liver disease. Most patients will have progressive vasodilation and worsening hypoxemia. Without liver transplantation, death is inevitable, as no other effective medical therapies are currently available.

Post–liver transplantation, more than 80% of patients will have improved oxygenation and decreased AV shunts. However, some patients may develop the following complications:

• Refractory hepatopulmonary syndrome (patients fail to improve oxygenation or develop recurrent hepatopulmonary syndrome after liver transplantation)
• Severe posttransplant hypoxemia causing failure to maintain oxygen saturation above 85%, even on 100% oxygen 
• Posttransplant portopulmonary hypertension (rare complication)