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

HPS may co-occur with other cardiopulmonary diseases, which can exacerbate the ventilation-perfusion abnormalities.   

The physical exam may show the following:  

1. Cyanosis   
2. Digital clubbing [12][13]  
3. Diffuse telangiectasia. Spider naevi are more likely associated with HPS in several studies.[6][14] 
4. Platypnoea – worsening of dyspnea when moving from supine to upright position.  
5. Orthodeoxia – decrease in PaO2 of more than 5% or more than 4mm Hg when moving from supine to upright position. It is very specific for HPS in the presence of liver disease. The sensitivity of orthodeoxia is low but increases with the severity of HPS.

The initial screening for HPS involves using a pulse oximeter to evaluate PaO2. An O2 saturation <96% signifies PaO2 < 70 mm Hg and is considered a positive screen.   

In the case of a positive screen, the patient should undergo arterial blood gas (ABG) analysis, which helps to determine PaO2 and A-aO2.   

Contrast-enhanced echocardiography with agitated saline is the gold standard for diagnosing pulmonary vascular dilatation. Normal saline is agitated to generate microbubbles > 10 micrometers 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 the alveoli. However, in the presence of pulmonary dilatation and AV shunts, microbubbles evade pulmonary capture and reach the left atria of the heart and can be seen via TTE in the left atrial chamber. The appearance of microbubbles in the left atria between the 4th and 6th cardiac cycle indicates pulmonary vasodilatation. If the microbubbles appear on the heart's left side before the 3rd cardiac cycle, it shows intracardiac shunting.   

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

Radioactive lung perfusion scanning is another test to establish pulmonary vessel dilatation. However, it is not as sensitive as contrast-enhanced echocardiography. This test does not distinguish between intrapulmonary and intracardiac shunting. It may be useful in deciding if HPS is contributing to hypoxemia in patients with concomitant lung disease. Radiolabeled albumin aggregates measuring approximately 20 micrometers in diameter are infused into the peripheral vein. Normally, particles of this size are trapped in the pulmonary microvasculature, and scintigraphy reveals nearly complete uptake in the lungs. When there is the existence of notable intrapulmonary shunting, some fraction of the albumin passes through the pulmonary vasculature and into the systemic circulation. Scintigraphy can be used to reveal uptake in other organs in addition to the lung that allows the calculation of the shunt fraction. Brain shunt fraction >6% is considered significant.  

Pulmonary angiography can be used to diagnose and also distinguish between type I and type II HPS. However, it is a more expensive and invasive test, so it is not a preferred method of diagnosis. It is also less sensitive than contrast-enhanced echocardiography with agitated saline.  

A chest X-ray may be normal or show increased bibasilar nodular opacities coinciding with increased pulmonary dilatation. It helps to exclude coexistent pulmonary pathology.   

Computed tomography (CT) chest may show enlarged dilated vessels but are usually done to exclude pulmonary pathology.   

Pulmonary function tests may show decreased diffusion capacity for carbon monoxide (DLCO).[15]

Oxygen therapy is recommended for patients with severe hypoxemia. It is usually given until a more definitive treatment like liver transplantation can be performed. An increase in oxygenation and reduction in hypoxemia leads to better exercise tolerance and improved quality of life.  

Liver transplantation is the only established treatment shown to provide long term survival benefits for patients with HPS. It improves hypoxemia in 6 to 12 months. Studies have shown that PaO2 and A-aO2 reverse rapidly after transplant, mostly within six months. Intrapulmonary shunts also reverse but may take longer than six months. DLCO has also been shown to improve in some patients in one study.[16] 

Chronic liver disease patients with a model for end-stage liver disease (MELD) score of 15 or greater are referred for liver transplant evaluation. Patients with HPS get exception points added to the MELD score to move them higher on the waiting list for liver transplantation. It is recommended that patients should undergo liver transplantation before the development of severe disease.  

Medical therapies - There is currently no medical therapy approved for HPS. Many medical treatments, including garlic, pentoxifylline, mycophenolate mofetil, aspirin, methylene blue, inhaled nitric oxide, nitric oxide inhibitors, and somatostatin have been tried. Still, none of those have been of conclusive benefit, and the FDA has approved none of them.   

Transjugular intrahepatic portosystemic shunt (TIPS) - There is limited data on TIPS use, and clinical outcomes can vary. TIPS can aggravate the hyperkinetic circulatory state, increasing intrapulmonary vasodilatation, shunting, and worsening hypoxemia. There is also the risk of hepatic decompensation and encephalopathy after TIPS.  

Pulmonary arterial coil embolization – Its use is limited as it can only be used in selected cases where there are large AV communications.

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

Patients with HPS have two times higher mortality as compared to patients with cirrhosis without HPS. It is associated with a poor quality of life and inferior functional status.[4] The average life span in a patient with HPS (10.5 months) is significantly reduced compared to patients with chronic liver disease patients without HPS (40.8 months). Mortality risk increases with the severity of disease with worse prognosis in patients with very severe disease.[17] Post liver transplant survival is also slightly reduced in patients with very severe HPS.

HPS is a fatal disease that drastically reduces the life span in a patient with liver disease. Most patients will have progressive vasodilation and worsening hypoxemia. Death without liver transplantation is inevitable, as no other medical therapies are currently available.   

Post liver transplantation, 80% - 85% of the patients will have improved oxygenation and decreased AV shunts. However, certain patients can develop complications. 

1. Refractory hepatopulmonary syndrome - These patients fail to improve oxygenation or develop recurrent HPS after liver transplantation.  
2. Severe post-transplant hypoxemia is a failure to maintain oxygen saturation above 85%, even on 100% oxygen. 
3. Post-transplant portopulmonary hypertension is a rare complication.

Primary clinicians should screen all patients for alcohol abuse and intravenous drug use. Patients should be educated regarding the harmful effects of intravenous drug use, an overdose of medications like acetaminophen, and excessive alcohol consumption. Resources for rehabilitation for these should be offered. High-risk patients should be screened annually for viral hepatitis.

The management of patients with HPS requires a strong interprofessional team approach involving hepatologists, pulmonologists, transplant surgeons, addiction medicine specialists, primary clinicians, pharmacists, social workers, and nurse educators. Prompt diagnosis and early liver transplant are the only way to alter the course of this fatal disease.