Hepatopulmonary syndrome overview

# Overview
In 1884, Fluckiger 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 patients 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.

# Historical Perspective
In 1884, Fluckiger was the first to report the association between liver dysfunction and the development of hypoxemia. (Fluckiger 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.

# Classification
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.

# Pathophysiology
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  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.

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

# Differentiating Hepatopulmonary Syndrome from Other Diseases
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).

# Epidemiology and Demographics
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.

# Risk Factors
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.

# Screening
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.

# Natural History, Complications, and Prognosis
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.

# Diagnosis

## Diagnostic Study of Choice
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.

## History and Symptoms
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
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.

## Laboratory Findings
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.

## Electrocardiogram
There are no ECG findings associated with hepatopulmonary syndrome.

## X-ray
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.

## Echocardiography and Ultrasound
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 patients 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.

## CT scan
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.

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

## Other Imaging Findings
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.

## Other Diagnostic Studies
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.

# Treatment

## Medical Therapy
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.

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

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

## Primary Prevention
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.

## Secondary Prevention
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.