Hepatopulmonary syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

In 1884, Flückiger was the first to report the association between liver dysfunction and the development of hypoxemia. The term “hepatopulmonary syndrome” was first suggested by Kennedy and Knudson almost 100 years later,in 1977 during describing a patient with the classic findings of hepatopulmonary syndrome. HPS can be classified in term of severity based on arterial blood gas analysis.The exact pathogenesis of hepatopulmonary syndrome is not fully understood. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental hepatopulmonary syndrome, and thus might underlie hepatopulmonary syndrome in humans. It is thought that hepatopulmonary syndrome is the result of microscopic intrapulmonary arteriovenous dilatations due to either increased liver production or decreased the liver clearance of vasodilators, possibly involving nitric oxide. The progression to hepatopulmonary syndrome is believed that involves the nitric oxide metabolism. The dilation of these blood vessels causes overperfusion relative to ventilation, leading to ventilation-perfusion mismatch and hypoxemia. Patients with hepatopulmonary syndrome have platypnea-orthodeoxia syndrome (POS); that is, because intrapulmonary vascular dilations (IPVDs) predominate in the bases of the lungs, standing worsens hypoxemia (orthodeoxia)/dyspnea (platypnea) and the supine position improves oxygenation as blood is redistributed from the bases to the apices. Additionally, late in cirrhosis, it is common to develop high output failure, which would lead to less time in capillaries per red blood cell, exacerbating the hypoxemia.
Mild hypoxemia occurs in 30 percent of patients with chronic liver disease. It may be due to common cardiopulmonary diseases such as congestive heart failure, chronic obstructive pulmonary disease (COPD) or pneumonia. Pulmonary vascular bed malfunction also might be responsible for certain conditions such as Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH). Hepatopulmonary syndrome (HPS) must be differentiated from portopulmonary hypertension (PPH) and hereditary hemorrhagic telangiectasia (HHT). Neither specific etiology nor severity of cirrhosis have been found to be correlated with the incidence or severity of hepatopulmonary syndrome. Hepatopulmonary syndrome occurs in both males and females, in children and adults, and in people of all ethnic backgrounds. Even patients with non-cirrhotic portal hypertension with normal synthetic liver function (e.g. nodular regenerative hyperplasia) may develop HPS, nonetheless, cirrhosis remains the most common cause of HPS. There are no established risk factors for hepatopulmonary syndrome. Literally, It can happen in almost every patient with liver disease regardless of their disease stage, severity, chronicity, age, sex, or race. Nevertheless, polymorphism in nitric oxide and angiogenesis genes has been observed in patients who develop hepatopulmonary syndrome. There is insufficient evidence to recommend routine screening for hepatopulmonary syndrome. Nevertheless, it should be considered as a differential diagnosis in every patient with known liver disease or sign and symptoms of liver disease that present with hypoxemia, and dyspnea. Nevertheless, serial pulse oximetry as a simple, low cost and widely available technique, is recommended in cirrhotic patients. It could detect and also determine the severity of hypoxemia in patients with hepatopulmonary syndrome. Hence, pulse oximetry screening might improve management of HPS in cirrhotic patients. If left untreated, prognosis is generally poor, and the 2.5 year mortalityl rate of patients with hepatopulmonary syndrome is approximately 40% to 60%. With liver transplantation, the 5 year survival rate is 74%, which is comparable to patients who undergo liver transplants who do not suffer from hepatopulmonary syndrome. There is no single diagnostic study of choice for the diagnosis of hepatopulmonary syndrome, but hepatopulmonary syndrome can be diagnosed based on history of liver disease, atrial blood gas analysis (widened alveolar-arterial oxygen gradient measurement); and evidences of intra-pulmonary vascular dilation or arterio-venous communications that result in a right-to-left intrapulmonary shunt.

Physical examination of patients with hepatopulmonary syndrome is usually remarkable for liver disease findings such as jaundice, palmar erythema, spider angiomata, gynaecomastia ,abdominal distension, caput medusae, splenomegaly either with or without sign and symptoms of hypoxemia such as cyanosis and clubbing.The presence of platypnea on physical examination is highly suggestive of hepatopulmonary syndrome. Atrial blood gas analysis (ABG) is used both for diagnosis and evaluating the severity (grade) of hepatopulmonary syndrome.

Both contrast-enhanced transthoracic and transesophageal echocardiography may be helpful in the diagnosis of hepatopulmonary syndrome. In fact, contrast-enhanced transthoracic echocardiography with agitated saline is the most practical method to detect pulmonary vascular dilation. It can not only diagnose the presence of shunt but also can distinguish between intracardiac and intrapulmonary shunt. Findings on an echocardiography suggestive of hepatopulmonary syndrome include the presence of agitated saline bubbles after injection in a peripheral vein in the patient’s arm. The timing of the appearance of the left-sided bubbles after injection can determine the source of the shunt. while bubbles appear in the left chambers three cardiac cycles after the appearance of the bubbles in the right heart chambers in intracardiac shunting, in intrapulmonary shunting, four to six cardiac cycles are passed before appearance of the bubbles in the right heart chambers. Transesophageal echocardiography (TTE) is also helpful in the diagnosis of hepatopulmonary syndrome. TTE can detect intrapulmonary vascular dilations with greater specificity compared to transthoracic echocardiography since the examiner can directly observe microbubbles in the pulmonary veins as they enter the left atrium. Additionally, cardiac function and pulmonary artery pressures can also be evaluated. Technetium 99m-labeled macroaggregated albumin scanning also may be helpful in the diagnosis of hepatopulmonary syndrome. labeled albumin macroaggregates (>20 microns in diameter) are injecting intravenously. Macroaggregates exceed the normal pulmonary capillary diameter and should be trapped normally. Scans that identify uptake of the radionucleotide by the brain suggest that the macroaggregates passed through either an intrapulmonary or intracardiac shunt. A calculated shunt fraction of above 6% is abnormal. Nevertheless, it can not distinguish between intracardiac and intrapulmonary shunting and has a lower sensitivity compared to contrast-enhanced echocardiography. Pulmonary function tests may be helpful in the diagnosis of hepatopulmonary syndrome. Findings suggestive of hepatopulmonary syndrome include A decrease in the single-breath diffusing capacity for carbon monoxide (DLCO) suggesting a diffusion impairment as a frequent finding in hepatopulmonary syndrome (occurring in up to 80% of patients). Six minute walk test with and without an oxygen titration can also use as an objective assessment of exercise capacity. There is no medical treatment for hepatopulmonary syndrome. The mainstay of treatment for hepatopulmonary syndrome is surgery. Orthotopic liver transplantation is the only available treatment for patients with hepatopulmonary syndrome. Supportive therapy for hepatopulmonary syndrome includes oxygen therapy. Effective measures for the secondary prevention of hepatopulmonary syndrome include considering the diagnosis in every patient with liver disease which present with hypoxemia and shortness of breath, looking for diffusion defects in arterial blood gas analysis, and considering specific examinations such as agitated saline contrast echocardiography in selected patients.

In 1884, Flückiger was the first to report the association between liver dysfunction and the development of hypoxemia. (Flückiger M. Vorkommen von trommelschlagel-formigen fingerendphalangen ohne chronische veranderungeng an den lungen oder am herzen. Wien Med Wochenschr. 1884;34:1457.) The term “hepatopulmonary syndrome” was first suggested by Kennedy and Knudson almost 100 years later,in 1977 during describing a patient with the classic findings of hepatopulmonary syndrome.

There is no established system for the classification of hepatopulmonary syndrome. Nevertheless, HPS can be classified in term of severity based on atrial blood gas analysis.

The exact pathogenesis of hepatopulmonary syndrome is not fully understood. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental hepatopulmonary syndrome, and thus might underlie hepatopulmonary syndrome in humans. It is thought that hepatopulmonary syndrome is the result of microscopic intrapulmonary arteriovenous dilatations due to either increased liver production or decreased the liver clearance of vasodilators, possibly involving nitric oxide. The progression to hepatopulmonary syndrome is believed that involves the nitric oxide metabolism. The dilation of these blood vessels causes overperfusion relative to ventilation, leading to ventilation-perfusion mismatch and hypoxemia. There is an increased gradient between the partial pressure of oxygen in the alveoli of the lung and adjacent arteries (alveolar-arterial [A-a] gradient) while breathing room air. Patients with hepatopulmonary syndrome have platypnea-orthodeoxia syndrome (POS); that is, because intrapulmonary vascular dilations (IPVDs) predominate in the bases of the lungs, standing worsens hypoxemia (orthodeoxia)/dyspnea (platypnea) and the supine position improves oxygenation as blood is redistributed from the bases to the apices. Additionally, late in cirrhosis, it is common to develop high output failure, which would lead to less time in capillaries per red blood cell, exacerbating the hypoxemia. As discussed below a variety of angiogenesis-related genes polymorphism has been linked to hepatopulmonary syndrome. Increased levels of endothelin-1 in cirrhotic patients have been correlated with intrapulmonary molecular and gas exchange abnormalities, hypothesizing a probable contribution to the pathogenesis of hepatopulmonary syndrome.

The most common cause of hepatopulmonary syndrome is chronic liver disease with any etiology. Less common causes of hepatopulmonary syndrome include acute liver disease.

Mild hypoxemia occurs in 30 percent of patients with chronic liver disease. It may be due to common cardiopulmonary diseases such as congestive heart failure, chronic obstructive pulmonary disease (COPD) or pneumonia. Pulmonary vascular bed malfunction also might be responsible for certain conditions such as Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH). Hepatopulmonary syndrome (HPS) must be differentiated from portopulmonary hypertension (PPH) and hereditary hemorrhagic telangiectasia (HHT).

Neither specific etiology nor severity of cirrhosis have been found to be correlated with the incidence or severity of hepatopulmonary syndrome. Hepatopulmonary syndrome occurs in both males and females, in children and adults, and in people of all ethnic backgrounds. Even patients with non-cirrhotic portal hypertension with normal synthetic liver function (e.g. nodular regenerative hyperplasia) may develop HPS, nonetheless, cirrhosis remains the most common cause of HPS.

The most common cause of cirrhosis in the United States is chronic and heavy alcohol use, while the most common cause of cirrhosis worldwide and in Asian countries is the hepatitis virus. The gender that is most commonly affected by cirrhosis varies, depending upon the etiology. The incidence of cirrhosis increases with age; the median age of diagnosis of cirrhosis due to alcoholic liver disease is 52 years. The median age of diagnosis of cryptogenic/NAFLD/NASH cirrhosis is 60 years.

There are no established risk factors for hepatopulmonary syndrome. Literally, It can happen in almost every patient with liver disease regardless of their disease stage, severity, chronicity, age, sex, or race. Nevertheless, polymorphism in nitric oxide and angiogenesis genes has been observed in patients who develop hepatopulmonary syndrome.

There is insufficient evidence to recommend routine screening for hepatopulmonary syndrome. Nevertheless, it should be considered as a differential diagnosis in every patient with known liver disease or sign and symptoms of liver disease that present with hypoxemia, and dyspnea. Nevertheless, serial pulse oximetry as a simple, low cost and widely available technique, is recommended in cirrhotic patients. It could detect and also determine the severity of hypoxemia in patients with hepatopulmonary syndrome. Hence, pulse oximetry screening might improve management of HPS in cirrhotic patients.

If left untreated, prognosis is generally poor, and the 2.5 year mortalityl rate of patients with hepatopulmonary syndrome is approximately 40% to 60%. With liver transplantation, the 5 year survival rate is 74%, which is comparable to patients who undergo liver transplants who do not suffer from hepatopulmonary syndrome.

There is no single diagnostic study of choice for the diagnosis of hepatopulmonary syndrome, but hepatopulmonary syndrome can be diagnosed based on history of liver disease, atrial blood gas analysis (widened alveolar-arterial oxygen gradient measurement); and evidences of intra-pulmonary vascular dilation or arterio-venous communications that result in a right-to-left intrapulmonary shunt.

The hallmark of hepatopulmonary syndrome is platypnea and orthodeoxia. A positive history of liver disease and dyspnea is suggestive of hepatopulmonary syndrome. Other sign and symptoms of hepatopulmonary syndrome may include spider angiomata, clubbing of fingers or toes, and cyanosis.

Physical examination of patients with hepatopulmonary syndrome is usually remarkable for liver disease findings such as jaundice, palmar erythema, spider angiomata, gynaecomastia ,abdominal distension, caput medusae, splenomegaly either with or without sign and symptoms of hypoxemia such as cyanosis and clubbing.The presence of platypnea on physical examination is highly suggestive of hepatopulmonary syndrome.

Atrial blood gas analysis (ABG) is used both for diagnosis and evaluating the severity (grade) of hepatopulmonary syndrome. A variety of laburatory tests might be used for the management and followup of patients with cirrhosis among them are, serum bilirubin levels, aminotransferase levels, alkaline phosphatase, gamma-glutamyl transpeptidase , prothrombin time/INR, complete blood count (CBC), electrolytes, blood urea nitrogen (BUN) and creatinine.  

There are no ECG findings associated with hepatopulmonary syndrome.

An x-ray may be helpful in the diagnosis of hepatopulmonary syndrome. Although, chest x ray studies are frequently nonspecific and subtle. Findings on an x-ray suggestive of hepatopulmonary syndrome include mild interstitial pattern in the bilateral, lower lung fields due to the pulmonary vascular dilatation that might misinterpreted as interstitial lung disease. We should keep in mind that chest x-ray is often unremarkable in patients with hepatopulmonary syndrome, and hence a a normal radiograph does not rule out hepatopulmonary syndrome.

Both contrast-enhanced transthoracic and transesophageal echocardiography may be helpful in the diagnosis of hepatopulmonary syndrome. In fact, contrast-enhanced transthoracic echocardiography with agitated saline is the most practical method to detect pulmonary vascular dilation. It can not only diagnose the presence of shunt but also can distinguish between intracardiac and intrapulmonary shunt. Findings on an echocardiography suggestive of hepatopulmonary syndrome include the presence of agitated saline bubbles after injection in a peripheral vein in the patient’s arm. The timing of the appearance of the left-sided bubbles after injection can determine the source of the shunt. while bubbles appear in the left chambers three cardiac cycles after the appearance of the bubbles in the right heart chambers in intracardiac shunting, in intrapulmonary shunting, four to six cardiac cycles are passed before appearance of the bubbles in the right heart chambers. Transesophageal echocardiography (TTE) is also helpful in the diagnosis of hepatopulmonary syndrome. TTE can detect intrapulmonary vascular dilations with greater specificity compared to transthoracic echocardiography since the examiner can directly observe microbubbles in the pulmonary veins as they enter the left atrium. Additionally, cardiac function and pulmonary artery pressures can also be evaluated.

Chest CT scan and particularly high resolution ct scan (HRCT) may be helpful in the diagnosis of hepatopulmonary syndrome. Although CT Scan studies are frequently nonspecific and subtle. Findings on CT scan suggestive of hepatopulmonary syndrome include characteristic findings of intrapulmonary vascular dilatation, increased pulmonary artery to bronchus ratios, dilated peripheral pulmonary vessels and barely direct arterio-venous communications. Nevertheless, we should keep in mind that Ct scan is often unremarkable in patients with hepatopulmonary syndrome, and hence a normal radiograph (either chest x-ray (CXR) or CT Scan) does not rule out hepatopulmonary syndrome.

There are no MRI findings associated with hepatopulmonary syndrome. However, a MRI may be helpful in the diagnosis of complications of cirrhosis.

Angiography may be helpful in the diagnosis of hepatopulmonary syndrome. Non-invasive studies are preferred in diagnosis and management of patients with hepatopulmonary syndrome. Pulmonary angiography is indicated in known cases of HPS if sever hypoxia (partial pressure of oxygen is < 60 mmHg) is present, if the patient is a poor responsive to 100% oxygen, and if there is a strong suspicion of direct arterio-venous communications that would be amenable to embolization, based on chest CT scan findings. Rather than direct visualization of the pulmonary dilations (IPVSs), it can also demonstrate type of micro dilation in pulmonary vasculture.

Technetium 99m-labeled macroaggregated albumin scanning also may be helpful in the diagnosis of hepatopulmonary syndrome. labeled albumin macroaggregates (>20 microns in diameter) are injecting intravenously. Macroaggregates exceed the normal pulmonary capillary diameter and should be trapped normally. Scans that identify uptake of the radionucleotide by the brain suggest that the macroaggregates passed through either an intrapulmonary or intracardiac shunt. A calculated shunt fraction of above 6% is abnormal. Nevertheless, it can not distinguish between intracardiac and intrapulmonary shunting and has a lower sensitivity compared to contrast-enhanced echocardiography.

Pulmonary function tests may be helpful in the diagnosis of hepatopulmonary syndrome. Findings suggestive of hepatopulmonary syndrome include A decrease in the single-breath diffusing capacity for carbon monoxide (DLCO) suggesting a diffusion impairment as a frequent finding in hepatopulmonary syndrome (occurring in up to 80% of patients). Six minute walk test with and without an oxygen titration can also use as an objective assessment of exercise capacity.

There is no medical treatment for hepatopulmonary syndrome. The mainstay of treatment for hepatopulmonary syndrome is surgery. Orthotopic liver transplantation is the only available treatment for patients with hepatopulmonary syndrome. Supportive therapy for hepatopulmonary syndrome includes oxygen therapy.

There are no recommended therapeutic interventions for the management of hepatopulmonary syndrome.

Surgery is the mainstay of treatment for hepatopulmonary syndrome. Orthotopic liver transplantation is the only available treatment for patients with hepatopulmonary syndrome.

There are no established measures for the primary prevention of hepatopulmonary syndrome. Development of hepatopulmonary syndrome neither related to the severity nor to the etiology of liver disease. Although most of the cases develop in chronic liver disease particularly cirrhosis, it could develop in acute liver disease as well.

Effective measures for the secondary prevention of hepatopulmonary syndrome include considering the diagnosis in every patient with liver disease which present with hypoxemia and shortness of breath, looking for diffusion defects in arterial blood gas analysis, and considering specific examinations such as agitated saline contrast echocardiography in selected patients.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

• In 1884, Flückiger was the first to report the association between liver dysfunction and the development of hypoxemia. (Flückiger M. Vorkommen von trommelschlagel-formigen fingerendphalangen ohne chronische veranderungeng an den lungen oder am herzen. Wien Med Wochenschr. 1884;34:1457.) The term “hepatopulmonary syndrome” was first suggested by Kennedy and Knudson almost 100 years later,in 1977 during describing a patient with the classic findings of hepatopulmonary syndrome.

• In 1884, Flückiger was the first to report the association between liver dysfunction and the development of hypoxemia. (Flückiger M. Vorkommen von trommelschlagel-formigen fingerendphalangen ohne chronische veranderungeng an den lungen oder am herzen. Wien Med Wochenschr. 1884;34:1457.)
• The term “hepatopulmonary syndrome” was first suggested by Kennedy and Knudson almost 100 years later,in 1977 during describing a patient with the classic findings of hepatopulmonary syndrome.^[1]

• Currently the only definitive treatment is liver transplantation. Alternative treatments such as supplemental oxygen or somatostatin to inhibit vasodilation remains anecdotal.
• Here are the landmarks of liver transplantation pathway.

• In the 1960s, Thomas Starzl used dogs as the first animals for research on liver transplantation in Boston and Chicago.
• In 1963, the first liver transplant in humans was attempted by a surgical team led by Dr. Thomas Starzl of Denver, Colorado, United States.
• Dr. Starzl performed many additional transplants until he was successful in 1967 with the first one-year survival post-transplantation.
• In 1970, the regimen for immunosuppressive therapy following transplant was introduced, but azathioprine and steroids did not improve survival rates of patients.
• In the 1980s, with the introduction of cyclosporine by Sir Roy Calne, there was an improvement in rejection rates.
• In 1983, liver transplantation was no longer an experimental modality, but a clinically accepted form of therapy for both adult and pediatric patients with appropriate indications.
• In 1986, the introduction of monoclonal antibodies such as muromonab-CD3 [OKT3] further contributed to improvement of quality of immunosuppressive therapy used in patients, with significant decline in rejection rates.
• In 1988, University of Wisconsin (UW) solution was developed, which ensured a smooth surgery and longer preservation period.
• In 1992, the concept of xenotransplantation and cloning techniques were introduced by Starzl.
• In 1999, approximately 5000 procedures were carried out, in contrast to 100 which had been performed a decade earlier.
• Recently, the introduction of newer immunosuppressive agents such as IL-2 receptor blockers and tacrolimus, have drastically increased patient survival ratesto 1 and 5-year rates of approximately 85 and 70 percent respectively.
• In December 2016, 147,128 liver transplants were performed in the US as compared to 7217 in 1998 based on data from the United Organ Sharing (UNOS) network.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

There is no established system for the classification of hepatopulmonary syndrome. Nevertheless, HPS can be classified in term of severity based on arterial blood gas analysis.

There is no established system for the classification of hepatopulmonary syndrome (HPS).^[1]

HPS can be classified in term of severity based on atrial blood gas analysis, as follows:

• Mild: Alveolar-arterial oxygen gradient above, or equal to<math>\geq</math> 15mmHg, partial pressure of oxygen <math>\geq</math> 80mmHg.
• Moderate: Alveolar-arterial oxygen gradient <math>\geq</math>15mmHg, partial pressure of oxygen <math>\geq</math> 60 up to 80mmHg.
• Severe: Alveolar-arterial oxygen gradient <math>\geq</math> 15mmHg, partial pressure of oxygen <math>\geq</math> 50 up to 60mmHg.
• Very severe: Alveolar-arterial oxygen gradient <math>\geq</math>15mmHg, partial pressure of oxygen below 50 mmHg (< 300mmHg while the patient is breathing 100% oxygen).^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

The exact pathogenesis of hepatopulmonary syndrome is not fully understood. Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental hepatopulmonary syndrome, and thus might underlie hepatopulmonary syndrome in humans. It is thought that hepatopulmonary syndrome is the result of microscopic intrapulmonary arteriovenous dilatations due to either increased liver production or decreased the liver clearance of vasodilators, possibly involving nitric oxide. The progression to hepatopulmonary syndrome is believed that involves the nitric oxide metabolism. The dilation of these blood vessels causes overperfusion relative to ventilation, leading to ventilation-perfusion mismatch and hypoxemia. There is an increased gradient between the partial pressure of oxygen in the alveoli of the lung and adjacent arteries (alveolar-arterial [A-a] gradient) while breathing room air. Patients with hepatopulmonary syndrome have platypnea-orthodeoxia syndrome (POS); that is, because intrapulmonary vascular dilations (IPVDs) predominate in the bases of the lungs, standing worsens hypoxemia (orthodeoxia)/dyspnea (platypnea) and the supine position improves oxygenation as blood is redistributed from the bases to the apices. Additionally, late in cirrhosis, it is common to develop high output failure, which would lead to less time in capillaries per red blood cell, exacerbating the hypoxemia. As discussed below a variety of angiogenesis-related genes polymorphism has been linked to hepatopulmonary syndrome. Increased levels of endothelin-1 in cirrhotic patients have been correlated with intrapulmonary molecular and gas exchange abnormalities, hypothesizing a probable contribution to the pathogenesis of hepatopulmonary syndrome.

Nitric oxide

The normal physiology of nitric oxide can be understood as follows:

• The endothelium (inner lining) of blood vessels use nitric oxide to signal the surrounding smooth muscle to relax, thus dilating the artery and increasing blood flow. This underlies the action of nitroglycerin, amyl nitrate, “poppers” (isobutyl nitrite or similar) and other nitrate derivatives in the treatment of heart disease: The compounds are converted to nitric oxide (by a process that is not completely understood), which in turn dilates the coronary artery (blood vessels around the heart), thereby increasing its blood supply. Nitric oxide also acts on cardiac muscle to decrease contractility and heart rate. The vasodilatory actions of nitric oxide play a key role in renal control of extracellular fluid homeostasis. Nitric oxide also plays a role in erection of the penis. Nitric oxide is also a second messenger in the nervous system and has been associated with neuronal activity and various functions like avoidance learning.

• Nitric oxide is synthesized by nitric oxide synthase (NOS). There are three isoforms of the NOS enzyme: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) – each with separate functions. The neuronal enzyme (NOS-1) and the endothelial isoform (NOS-3) are calcium-dependent and produce low levels of gas as a cell-signaling molecule. The inducible isoform (NOS-2) is calcium-independent and produces large amounts of gas which can be cytotoxic.

• Nitric Oxide (NO) is of critical importance as a mediator of vasorelaxation in blood vessels. Platelet-derived factors, shear stress, angiotensin II, acetylcholine, and cytokines stimulate the production of NO by endothelial nitric oxide synthase (eNOS). eNOS synthesizes NO from the terminal guanidine-nitrogen of L-arginine and oxygen and yields citrulline as a byproduct. NO production by eNOS is dependent on calcium–calmodulin and other cofactors. NO, a highly reactive free radical then diffuses into the smooth muscle cells of the blood vessel and interacts with soluble guanylate cyclase. Nitric oxide stimulates the soluble guanylate cyclase to generate the second messenger cyclic GMP (3’,5’ guanosine monophosphate)from guanosine triphosphate (GTP). The soluble cGMP activates cyclic nucleotide-dependent protein kinase G (PKG or cGKI). PKG is a kinase that phosphorylates a number of proteins that regulate calcium concentrations, calcium sensitization, hyperpolarize cell through potassium channels, actin filament and myosin dynamic alterations that result in smooth muscle relaxation.(see smooth muscle article). [3].

Angiogenesis

• The underlying mechanisms behind angiogenesis are beginning to be discovered.
• The process may begin with vasodilatation mediated by nitric oxide followed by an increase in permeability mediated by VEGF.
• This increased permeability allows for plasma protein extravasation and scaffold formation.
• Endothelial cell migration is supported by adhesion molecules such as PECAM-1 and cadherins.
• The vascular smooth muscle cells detaching and loosening signaled by Ang2 enables the migration and sprouting of endothelial cells.
• The process of angiogenesis is initiated by VEGF by Ang1 and is required to stabilize the endothelial networks and to increase periendothelial cell interactions.
• Platelet-derived growth factor (PDGF) stimulates inflammatory cells and promotes cell-cell interactions by molecules such as integrin.
• VEGF has morphogenic effects which allow endothelial cells cords to acquire and enlarge their lumen.
• Unfortunately, muscularization of the network is poorly understood. The process appears to be tissue-specific.
• In the coronary arteries, the epicardial layer appears to be the source of smooth muscle cells which migrate under PDGF-BB and VEGF stimulation.
• TGF-beta and downstream transcription factors Smads promote extracellular matrix production and solidify cell-cell interactions.
• FGF can help further this process resulting in arteriogenesis.
• In pathologic conditions such as ischemic myocardium, arteriogenesis can allow for as much as a 20-fold enlargement of collateral network vessels.
• Chemokines and cytokines are upregulated by increased collateral flow which results in monocyte recruitment.
• Monocytes produce proteinases which cause medial destruction and further remodeling.
• Hypoxia-inducible transcription factors (HIF), and their stabilization by peptide regulator 39 help induce and potentiate the neovascularization process.
• Newer imaging techniques utilize knowledge of molecular mechanisms to help enhance image resolution and improve sensitivity and specificity.

Stimulator	Mechanism
FGF	Promotes proliferation & differentiation of endothelial cells, smooth muscle cells, and fibroblasts
VEGF	Affects permeability
VEGFR and NRP-1	Integrate survival signals
Ang1 and Ang2	Stabilize vessels
PDGF (BB-homodimer) and PDGFR	recruit smooth muscle cells
TGF-β, endoglin and TGF-β receptors	↑extracellular matrix production
CCL2	Recruits lymphocytes to sites of inflammation
Histamine
Integrins αVβ3, αVβ5 (?) and α5β1	Bind matrix macromolecules and proteinases
VE-cadherin and CD31	endothelial junctional molecules
ephrin	Determine formation of arteries or veins
plasminogen activators	remodels extracellular matrix, releases and activates growth factors
plasminogen activator inhibitor-1	stabilizes nearby vessels
eNOS and COX-2
AC133	regulates angioblast differentiation
ID1/ID3	Regulates endothelial transdifferentiation
Class 3 semaphorins	Modulates endothelial cell adhesion, migration, proliferation and apoptosis. Alters vascular permeability

Pulmonary microvascular dilation and angiogenesis are two central pathogenic features that drive abnormal pulmonary gas exchange in experimental hepatopulmonary syndrome, and thus might underlie hepatopulmonary syndrome in humans.^{[1] [2] [3]}

^[4]

Vasodilators

• The exact pathogenesis of the hepatopulmonary syndrome is not completely understood.

• It is thought that hepatopulmonary syndrome is the result of microscopic intrapulmonary arteriovenous dilatations due to either increased liver production or decreased liver clearance of vasodilators, possibly involving nitric oxide.^[5]

^{[6] [7] [8] [9]}

• The progression to hepatopulmonary syndrome is believed that involves the nitric oxide metabolism.
• The dilation of these blood vessels causes overperfusion relative to ventilation, leading to ventilation-perfusion mismatch and hypoxemia.
• There is an increased gradient between the partial pressure of oxygen in the alveoli of the lung and adjacent arteries (alveolar-arterial [A-a] gradient) while breathing room air.
• Patients with hepatopulmonary syndrome have platypnea–orthodeoxia syndrome (POS); that is, because intrapulmonary vascular dilations (IPVDs) predominate in the bases of the lungs, standing worsens hypoxemia (orthodeoxia)/dyspnea (platypnea) and the supine position improves oxygenation as blood is redistributed from the bases to the apices.
• Additionally, late in cirrhosis, it is common to develop high output failure, which would lead to less time in capillaries per red blood cell, exacerbating the hypoxemia.

Angiogenesis

• As discussed below a variety of angiogenesis-related genes polymorphism has been linked to hepatopulmonary syndrome.
• An increased levels of endothelin-1 in cirrhotic patients have been correlated with intrapulmonary molecular and gas exchange abnormalities, hypothesizing a probable contribution to the pathogenesis of hepatopulmonary syndrome.^[10]

• Polymorphisms in genes involved in the regulation of angiogenesis are associated with the risk of hepatopulmonary syndrome.
• According to a study by Roberts et al. After adjustments for race and smoking, 42 single nucleotide polymorphism (SNP)s in 21 genes were significantly associated with hepatopulmonary syndrome. ^[11]
• The following genes had at least 2 SNPs associated with the disease:

• CAV3
• ENG
• NOX4
• ESR2
• VWF
• RUNX1
• COL18A1
• TIE1
  

Conditions associated with hepatopulmonary syndrome include:

• Chronic liver disease of virtually any etiology such as:

• Alcoholic liver disease
• Cirrhosis due to viral disease like HBV, HCV
• None alcoholic fatty liver disease (NASH)
• Toxin and drug-induced liver disease
• Wilson’s disease
• Hemochromatosis
• Autoimmune disorders such as:
  • Autoimmune hepatitis
  • Primary biliary cholangitis
  • Primary sclerosing cholangitis
• Alpha-one antitrypsin deficiency
• Chronic biliary obstruction
• Cryptogenic (idiopathic) cirrhosis
• Hepatocellular carcinoma

• It also, has even been reported in a number of patients with acute liver diseases

• On gross pathology, dilatation of pulmonary precapillary and capillary vessels, as well as an absolute increase in the number of dilated vessels are characteristic findings of hepatopulmonary syndrome.^[12]
• Nevertheless, pathological examination of lungs play no role in the diagnosis and management of hepatopulmonary syndrome.
• On the other hand, diagnosis and management of the chronic liver disease are essentially based on pathological sampling and analysis.

• Hepatopulmonary syndrome results from the formation of microscopic intrapulmonary arteriovenous dilations.
• Nevertheless, pathological examination of lungs play no role in the diagnosis and management of hepatopulmonary syndrome.
• On the other hand, diagnosis and management of the chronic liver disease are essentially based on pathological sampling and analysis.^[2][13]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

The most common cause of hepatopulmonary syndrome is chronic liver disease with any etiology. Less common causes of hepatopulmonary syndrome include acute liver disease.

The most common cause of hepatopulmonary syndrome is chronic liver disease with any etiology. ^[1][2]

Common causes of chronic liver disease as the common cause of hepatopulmonary syndrome may include:

• • Alcoholic liver disease
  • Cirrhosis due to viral disease like HBV, HCV
  • None alcoholic fatty liver disease (NASH)
  • Chronic biliary obstruction
  • Autoimmune disorders such as:
    • Autoimmune hepatitis
    • Primary biliary cholangitis
    • Primary sclerosing cholangitis
  • Cryptogenic (idiopathic) cirrhosis

Less common causes of chronic liver disease as the common cause of hepatopulmonary syndrome may include:

• Alpha-one antitrypsin deficiency
• Wilson’s disease
• Hemochromatosis
• Toxin and drug-induced liver disease
• Less common causes of hepatopulmonary syndrome include acute liver disease.

• Hepatopulmonary syndrome is not caused by a mutation in a gene. nevertheless, the following gene polymorphism might play a role in susceptibility of developing hepatopulmonary syndrome in patients with liver disorders:
  • CAV3
  • ENG
  • NOX4
  • ESR2
  • VWF
  • RUNX1
  • COL18A1
  • TIE1
    

• Abetalipoproteinemia
• Acetaminophen overdose
• Addison-Gull syndrome
• Aflatoxin
• Alagille syndrome
• Alcoholic liver disease
• Alpers disease
• Alpha 1-antitrypsin deficiency
• Alström syndrome
• Amiodarone
• Autoimmune cholangiopathy
• Autoimmune hepatitis
• Bearn-Kunkel syndrome ^[5]
• Berardinelli lipodystrophy syndrome
• Bile duct stricture
• Biliary atresia
• Budd-Chiari Syndrome
• Carbohydrate deficient glycoprotein syndrome type 1a
• Cardiac cirrhosis
• Caroli disease
• Cerebrohepatorenal syndrome
• Ceroid storage disease
• Cholestasis-oedema syndrome, Norwegian type
• Cholesterol ester storage disease
• Congenital hepatic fibrosis
• Constrictive pericarditis
• Cor Pulmonale
• Cruveilhier-Baumgarten syndrome
• Cystic fibrosis
• Erythropoietic protoporphyria
• Ethanol
• Fanconi disease ^[6]
• Fasciola hepatica
• Fructose-1-phosphate aldolase deficiency ^[7]
• Galactosemia
• Glycogen storage disease type IV
• Graft versus host disease
• Granulomatous cirrhosis
• Haemosiderosis
• Hemochromatosis
• Hepatic vein thrombosis
• Hepatitis B
• Hepatitis C
• Hereditary fructose intolerance
• Hypervitaminosis A
• Indian familial childhood cirrhosis
• Isoniazid
• Keratitis-ichthyosis-deafness syndrome, autosomal recessive
• Methotrexate
• Methyldopa
• Non-alcoholic steatohepatitis
• Parenteral nutrition
• Polycystic kidney disease, autosomal recessive
• Porphyria cutanea tarda type 2 (familial)
• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Reynolds syndrome ^[8]
• Right sided cardiac failure
• Sarcoidosis
• Schistosomiasis
• Sickle Cell Disease
• Steatohepatitis
• Thalassemia
• Tricho-hepato-enteric syndrome ^[9]
• Tricuspid insufficiency
• Tyrosinaemia type 1
• Visceral leishmaniasis
• Wilson disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Hepatopulmonary syndrome (HPS) must be differentiated from portopulmonary hypertension (PPH) and hereditary hemorrhagic telangiectasia (HHT).

Mild hypoxemia occurs in 30 percent of patients with chronic liver disease. It may be due to common cardiopulmonary diseases such as congestive heart failure, chronic obstructive pulmonary disease (COPD) or pneumonia. Pulmonary vascular bed malfunction also might be responsible for certain conditions such as Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH).

Hepatopulmonary syndrome (HPS) must be differentiated from portopulmonary hypertension (PPH) and hereditary hemorrhagic telangiectasia (HHT).

Portopulmonary hypertension is often confused with HPS. However, HPS and PPH are not the same disease. Although both are abnormalities of the pulmonary vasculature resulting from liver disease, HPS is characterized by vasodilatation and hypoxemia whereas PPH is characterized by obstruction or narrowing (vasoconstriction) of blood vessels with resulting pulmonary arterial hypertension.

On the basis pulse oximetry, arterial blood gas (ABG) analysis, contrast enhanced echocardiography, 99mTc scan (lung perfusion scintigraphy with technetium 99mTc labeled macro aggregated albumin), chest CT scan , pulmonary angiography, and pulmonary function test, hepatopulmonary syndrome (HPS) must be differentiated from portopulmonary hypertension (PPH) and hereditary hemorrhagic telangiectasia (HHT).^[1]

Diseases	Clinical manifestations					Para-clinical findings							Gold standard	Additional findings
	Symptoms			Physical examination
						Lab Findings			Imaging			Histo pathology
	Respiratory symptoms	Chronic liver disease symptoms	Platypnea	Orthodeoxia	Chronic liver disease signs	Pulse oximetry	Arterial blood gas (ABG) analysis	Pulmonary function test	Chest CT scan/ Pulmonary angiography	99mTc scan	Contrast enhanced echocardiography
HSP	+	+ (in most of the patients)	+	+	+ (in most of the patients)	SaO2<96%	15 mmHg ≤ AaPO2 PaO2< 80 mm Hg	Diffusion impairment Decreased DLCO Reduced lung volumes	Frequently nonspecific and subtle Dilated peripheral pulmonary vessels Increased pulmonary artery to bronchus ratios Characteristic findings of intrapulmonary vascular dilatations Direct arterio-venous communications may be less commonly seen.	+	+ (could distinguish between intracardiac and intrapulmonary shunt) In intracardiac shunting: three cardiac cycles after the appearance of the bubbles in the right heart chambers. In intrapulmonary shunting: four to six cardiac cycles after the appearance of the bubbles in the right heart chambers.	Plays no direct role in diagnosis	Triad of liver disease ABG (widened alveolar-arterial oxygen gradient Intra-pulmonary vascular dilation or arterio-venous communications that result in a right-to-left intrapulmonary shunt.	N/A
PPH	+ Dyspnea Fatigue Syncope.	+	–	–	+	Hypoxemia	Used for Pulmonary hypertension Class Identification PaO2 is normal or only slightly lower than normal PaCO2 is decreased as a result of alveolar hyperventilation	PFT cannot distinguish PPH from other pulmonary disorders with diffusion impairment Decreased diffusion capacity	Central pulmonary artery dilatation Abrupt narrowing or tapering of peripheral pulmonary vessels Right ventricular hypertrophy Right ventricular and atrial enlargement Dilated bronchial arteries	–	– Right heart dysfunction secondary to pulmonary hypertension Diagnosis and staging is based on the followings: Pulmonary artery pressure >25 mmHg Pulmonary capillary wedge pressure<15 mmHg Pulmonary vascular resistance >240syn·s·cm−5	Plays no direct role in diagnosis	The diagnosis of portopulmonary hypertension is based on hemodynamic criteria: Portal hypertension and/or liver disease (clinical diagnosis—ascites/varices/splenomegaly) Mean pulmonary artery pressure—MPAP > 25 mmHg at rest Pulmonary vascular resistance—PVR > 240 dynes s cm−5 :Pulmonary artery occlusion pressure— PAOP < 15mmHg or transpulmonary gradient—TPG > 12 mmHg where TPG = MPAP − PAOP.	N/A
HHT	+	–	+	+	–	SaO2<96%	Shunt in favor of AVM	Most patients have normal resting pulmonary function values Others might present with restrictive or an obstructive pattern	Arteriovenous malformation (AVM) in lungs, liver, and other organs	+ Due to AVM and hence shunts	+ Due to AVM and hence shunts	TGFβ signalling pathway impairment Arteriovenous malformations (AVMs) in various internal organs	Hereditary hemorrhagic telangiectasia is a clinical diagnosis that is based on the presence of three of four criteria (i.e., epistaxis, telangiectasias, visceral arteriovenous malformations, or family history of the disease)	Spontaneous recurrent epistaxis Multiple teleangiectasias on typical locations (see above) Proven visceral AVM (lung, liver, brain, spine) First-degree family member with HHT

• Platypnea (increased shortness of breath when the body is in a vertical position) and orthodeoxia (3-10 mmHg reduction in РаО2 in capillary blood during transition from horizontal to vertical position)

• 99mTc scan: lung perfusion scintigraphy with technetium 99mTc labeled macro aggregated albumin

• Chronic liver disease symptoms including, Itching, easy bruising, abdominal fullness, decreased libido, abdominal distension, and fatigue.
• Chronic liver disease signs including spider angioma, red palms, edema, gynecomastia
• Respiratory symptoms including shortness of breath, clubbed fingers, and cyanosis.
• Hepatopulmonary syndrome (HPS) must be differentiated from portopulmonary hypertension (PPH) and hereditary hemorrhagic telangiectasia (HHT).
• Severity of HPS is defined based on PaO2, while below 50 is extremely sever, 50-60 is sever, and more than 60 is defined as moderate to mild.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Neither specific etiology nor severity of cirrhosis have been found to be correlated with the incidence or severity of hepatopulmonary syndrome. Hepatopulmonary syndrome occurs in both males and females, in children and adults, and in people of all ethnic backgrounds. Even patients with non-cirrhotic portal hypertension with normal synthetic liver function (e.g. nodular regenerative hyperplasia) may develop HPS, nonetheless, cirrhosis remains the most common cause of HPS.

The most common cause of cirrhosis in the United States is chronic and heavy alcohol use, while the most common cause of cirrhosis worldwide and in Asian countries is the hepatitis virus. The gender that is most commonly affected by cirrhosis varies, depending upon the etiology. The incidence of cirrhosis increases with age; the median age of diagnosis of cirrhosis due to alcoholic liver disease is 52 years. The median age of diagnosis of cryptogenic/NAFLD/NASH cirrhosis is 60 years.

• There is no report of HPS prevalence worldwide.^[1]

• There is no report of HPS prevalence worldwide.
• Among cirrhotic subjects awaiting orthotopic liver transplantation, approximately 70% complain of dyspnea, 34-47% have intrapulmonary vascular dilatations (IPVDs), and 5-32% have diagnosed HPS.^[2]
• Nevertheless, the prevalence of cirrhosis as the most important risk factor of hepatopulmonary syndrome is higher in:
  • Non-Hispanic blacks
  • Individuals below the poverty line
  • Mexican Americans
  • Areas with high illiteracy rates
• Chronic and heavy alcohol use is responsible for more than half of the cases of cirrhosis in the United States.^[3]

• In [year], the incidence of hepatopulmonary syndrome is approximately [number range] per 100,000 individuals with a case-fatality rate/mortality rate of [number range]%.
• The case-fatality rate/mortality rate of hepatopulmonary syndrome is approximately [number range].

• Patients of all age groups may develop hepatopulmonary syndrome. Age plays no role in the prediction of likelihood of developing HPS in a given patient with cirrhosis.^[4]

^{[5] [1]}

^{[6] [7] [8] [9] [10]}

• Nevertheless, the incidence of cirrhosis increases with age;
• The median age of diagnosis of cirrhosis due to alcoholic liver disease is 52 years.
• The median age of diagnosis of cryptogenic/NAFLD/NASH cirrhosis is 60 years.

• There is no racial predilection to hepatopulmonary syndrome.

• Hepatopulmonary syndrome affects men and women equally.
• Regarding cirrhosis, the gender that is most commonly affected by cirrhosis varies, depending upon the etiology.

• Hepatopulmonary syndrome is a rare disease without any specific geographical distribution.
• Nevertheless, cirrhosis as the main of hepatopulmonary syndrome has different etiologies in different countries.

• Chronic and heavy alcohol use is responsible for more than half of the cases of cirrhosis in the United States.

• Chronic hepatitis B is the most common cause of cirrhosis worldwide, especially South-East Asia, but is less common in the United States.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

There are no established risk factors for hepatopulmonary syndrome. Literally, It can happen in almost every patient with liver disease regardless of their disease stage, severity, chronicity, age, sex, or race. Nevertheless, polymorphism in nitric oxide and angiogenesis genes has been observed in patients who develop hepatopulmonary syndrome.

• There are no established risk factors for hepatopulmonary syndrome.
• Literally, It can happen in almost every patient with liver disease regardless of their disease stage, severity, chronicity, age, sex, or race.^{[1] [2]}

^{[3][4] [5] [6] [7] [8]}

• Nevertheless, polymorphism in nitric oxide and angiogenesis genes has been observed in patients who develop hepatopulmonary syndrome.^[9][10]

^{[11] [12] [13] [14]}

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

There is insufficient evidence to recommend routine screening for hepatopulmonary syndrome. Nevertheless, it should be considered as a differential diagnosis in every patient with known liver disease or sign and symptoms of liver disease that present with hypoxemia, and dyspnea. Nevertheless, serial pulse oximetry as a simple, low cost and widely available technique, is recommended in cirrhotic patients. It could detect and also determine the severity of hypoxemia in patients with hepatopulmonary syndrome. Hence, pulse oximetry screening might improve management of HPS in cirrhotic patients.

• There is insufficient evidence to recommend routine screening for hepatopulmonary syndrome. Nevertheless, it should be considered as a differential diagnosis in every patient with known liver disease or sign and symptoms of liver disease that present with hypoxemia, and dyspnea.^{[1][2][3][4][5]}

• Nevertheless, serial pulse oximetry as a simple, low cost and widely available technique, is recommended in cirrhotic patients. It could detect and also determine the severity of hypoxemia in patients with hepatopulmonary syndrome. Hence, pulse oximetry screening might improve management of HPS in cirrhotic patients.^[6]

^[7]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

If left untreated, prognosis is generally poor, and the 2.5 year mortalityl rate of patients with hepatopulmonary syndrome is approximately 40% to 60%. With liver transplantation, the 5 year survival rate is 74%, which is comparable to patients who undergo liver transplants who do not suffer from hepatopulmonary syndrome.

• Although development of hepatopulmonary syndrome is not directly related to the Age of the patients, the symptoms of hepatopulmonary syndrome usually develop in the 6th decade of life, and start with symptoms such as dyspnea, and particularly platypnea.
• The symptoms of hepatopulmonary syndrome may develop in acute liver disease nevertheless maajority of patients have years of known liver disorder or cirrhosis, particularly candides of liver transplantation are whom with the highest rate of hepatopulmonary syndrome.
• If left untreated, prognosis is generally poor, and the 2.5 year mortalityl rate of patients with hepatopulmonary syndrome is approximately 40% to 60%. With liver transplantation, the 5 year survival rate is 74%, which is comparable to patients who undergo liver transplants who do not suffer from hepatopulmonary syndrome

• Common complications of hepatopulmonary syndrome include:
  • Hypoxemia
  • Impaired cognitive function, increase risk of developing hepatic encephalopathy.
  • Increased asterixis
  • Stroke possibly from paradoxical embolism

• Prognosis is generally poor, and the 2.5 year mortalityl rate of patients with hepatopulmonary syndrome is approximately 40% to 60%.^[1]
• An increased mortality rate has been observed in patients with HPS.
• Hypoxaemia development and progression is not related to the liver function.
• Unfortunately it has been observed that between 40 to 60 percent of patients with HPS will dye in 2.5 years.
• After adjustment for Model of End-stage Liver Disease (MELD) score and liver transplantation setting, mortality risk has been observed to be more than twice that of non-HPS patients (hazard ratio 2.41, 95% CI 1.31–4.42).^[2]
• Nevertheless, almost always mortality is related to portal hypertension and complications of liver disease not HPS and HPS related causes of death.^[3]
• But, the degree of hypoxaemia has been associated with a higher mortality.
• HPS decrease quality of life the patients.
• It is reasonable to anticipate that hypoxaemia impair cognition and contribute as a risk factor for hepatic encephalopathy.
• A higher frequency of asterixis has been observed in HPS versus non-HPS cirrhotics.
• The presence of hepatic encephalopathy is associated with a particularly poor prognosis among patients with hepatopulmonary syndrome.
• Coexistence of hepatic encephalopathy could further worsen the prognosis of patients with HPS.
• With liver transplantation, the 5 year survival rate is 74%, which is comparable to patients who undergo liver transplants who do not suffer from hepatopulmonary syndrome.^[4]