Hepatopulmonary syndrome was first proposed in 1977 based on autopsy and clinical findings. Autopsies showed dilated pulmonary vasculature in patients with liver cirrhosis and were thought to cause some of the pulmonary manifestations seen in patients with chronic liver disease.
The definition of hepatopulmonary syndrome (HPS) is a reduced arterial oxygen saturation due to dilated pulmonary vasculature in the presence of advanced liver disease or portal hypertension.
Diagnostic criteria for HPS
The severity of HPS is based on PaO2 levels:
HPS is most commonly associated with portal hypertension due to chronic liver disease or cirrhosis. However, portal hypertension without underlying liver disease can also cause HPS. Acute liver disease like acute hepatitis resulting in acute liver failure is a rare cause of HPS. The presence and severity of HPS do not correlate with the severity of the liver disease.
Pulmonary vascular dilatation resulting from an imbalance between vasodilators and vasoconstrictors is thought to be the main reason for HPS. The exact mechanism of vasodilation is not precise, and multiple studies are ongoing to elucidate the exact mechanism. Pulmonary endothelial nitric oxide synthetase (eNOS) stimulation happens in the lungs due to increased hepatic production of endothelin 1 (ET1) and pulmonary endothelin B (ETB) due to stress. eNOS stimulation causes increased nitric oxide (NO) 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 nitric oxide (NO) production. Bacterial accumulation and increased NO cause increased levels of heme oxygenase. Heme oxygenase causes the degradation of heme and leads to increased carbon monoxide (CO) production. Being potent vasodilators, this increased production of NO and CO plays a crucial role in pulmonary vasodilatation. Also, macrophages and monocytes and TNF alpha activate vascular endothelial growth factor (VEGF), leading to increased angiogenesis in the pulmonary vasculature.
Vasodilation and angiogenesis lead to arteriovenous (AV) shunt formation within pulmonary vasculature, leading to ventilation-perfusion mismatch. The pulmonary capillaries are dilated to 15-500mm in HPS as compared to a normal diameter between 8-15mm. Dilatation of pulmonary vasculature leads to reduced transit time for blood cells and a large amount of blood passing through pulmonary vasculature without undergoing gas exchange. Some blood may pass through AV shunts without encountering alveoli, and as such, gas exchange does not happen 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. Pulmonary vasodilation is most distinct in the lung bases elucidating the symptoms like platypnoea and orthodeoxia associated with HPS.
Two types of HPS have been based on the location of dilated pulmonary vessels.
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:
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).
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.
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.
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. 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. 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.
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.
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