Hospital Medicine

Hepatopulmonary syndrome

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I. What every physician needs to know.

Mild hypoxemia occurs in approximately one third of all patients with chronic liver disease and is usually multifactorial. It may result from common cardiopulmonary diseases such as pneumonia, congestive heart failure, chronic obstructive pulmonary disease. Cirrhosis may also be complicated by pulmonary vascular complications.

This interaction between the lung and the liver has been studied since 1884, when Flückiger first noted a woman with cirrhosis, cyanosis, and digital clubbing. Several authors have since confirmed this finding. The term "hepatopulmonary syndrome" was first suggested by Timothy Kennedy and Ronald Knudson in 1977 when they described the association of severe hypoxemia with intrapulmonary vascular dilations in the setting of hepatic dysfunction.

Today, the hepatopulmonary syndrome is characterized by a defect in arterial oxygenation in the setting of liver disease, induced by pulmonary vascular dilatations or arterio-venous communications leading to physiologic or anatomic shunting, respectively. It is most commonly associated with portal hypertension (i.e. gastrointestinal bleeding, esophageal varices, ascites, splenomegaly). Chronic liver disease of virtually any etiology can be associated with this syndrome, and it has even been reported in some patients with acute liver diseases.

The most important pathogenic feature in the hepatopulmonary syndrome is a dilation of the pre-capillary and post-capillary pulmonary vasculature, which results in impaired oxygenation of the venous blood as it traverses through the lungs. Specifically, because the capillary has an expanded diameter, oxygen molecules from adjacent alveoli cannot diffuse to the center of the dilated vessel to oxygenate hemoglobin in red blood cells at the center stream of venous blood.

The cause of this vascular pathophysiology is speculative as the exact pathogenesis of the hepatopulmonary syndrome is not completely understood. An imbalance between potential pulmonary vasodilators and vasoconstrictors is likely. It is unclear whether a particular vasodilatory substance is not cleared by the diseased liver or whether there is an abnormal sensitivity by the pulmonary vascular bed to a substance in patients with cirrhosis.

The most extensively investigated vasodilator is nitric oxide. Increased levels of exhaled metabolites of nitric oxide are found in patients with the hepatopulmonary syndrome; levels return to normal after liver transplantation, with normalization of oxygen saturation. Additionally, increased levels of endothelin-1, observed in cirrhosis, have been correlated with intrapulmonary molecular and gas exchange abnormalities, suggesting a possible contribution to the pathogenesis of this disease.

Recognizing the characteristics of this disease, allowing prompt investigation into the diagnosis, is important as the severity of this syndrome influences survival and is useful in determining the timing of liver transplantation, the only successful treatment to date.

II. Diagnostic Confirmation: Are you sure your patient has hepatopulmonary syndrome?

The diagnosis of hepatopulmonary syndrome requires the triad of liver disease; a widened, age-corrected, alveolar-arterial oxygen gradient on room air (with or without hypoxemia); and evidence of intrapulmonary vascular dilations or arterio-venous communications that result in a right-to-left intrapulmonary shunt.

Liver disease of nearly any underlying cause can be implicated and is already known in most patients who undergo a diagnostic evaluation. As such, the diagnostic confirmation usually focuses on the detection of the other two abnormalities, and screening for the hepatopulmonary syndrome with the use of arterial blood gases is recommended in patients with chronic liver disease who report dyspnea.

A. History Part I: Pattern Recognition:

The clinical symptoms of the hepatopulmonary syndrome are characteristic but are not unique. The patient with this syndrome most often presents with hepatic manifestations rather than pulmonary complaints.

Nearly 80% of patients present with symptoms of chronic liver disease (i.e. weakness, fatigue, anorexia, a history of gastrointestinal bleeding due to esophageal or gastric varices, inability to concentrate, menstrual irregularities, decreased libido, skin fragility, easy bruising, pruritis). The remainder are either found asymptomatic or present with dyspnea as their initial symptom. Therefore, the diagnosis should be suspected in a cirrhotic patient with a pulse oximetry level below, or equal to, 96%, although mild hypoxia is quite common in this patient population and usually multifactorial.

Concerning the pulmonary symptoms, dyspnea on exertion, at rest, or both is the predominant presenting symptom, usually after years of liver disease. However, dyspnea is a non-specific finding. More specific to hepatopulmonary syndrome is platypnea, which is defined as dyspnea induced by the upright position and relieved by recumbency and is "classically" found concomitantly with orthodeoxia in patients with the hepatopulmonary syndrome.

It is hypothesized that these findings are caused by the preferential perfusion of the intrapulmonary vascular dilations in the lung bases when the patient is upright. Quality of life may be significantly impaired as patients may become bed or home-bound due to severe dyspnea.

B. History Part 2: Prevalence:

Prospective, multicenter prevalence studies have not been performed; however, data from liver-transplantation centers indicate that the prevalence of all stages of the hepatopulmonary syndrome ranges from 5-32%. This syndrome develops independent of the underlying cause of liver disease; and, unfortunately, there is no severity of liver disease or laboratory abnormality that predicts the development of this disease.

C. History Part 3: Competing diagnoses that can mimic hepatopulmonary syndrome.

Dyspnea is usually the predominant presenting pulmonary symptom in hepatopulmonary syndrome. However, dyspnea is a nonspecific finding that is common in patients with advanced liver diseases because of a range of hepatic complications such as anemia, ascites, effusions, muscle wasting, malnutrition and deconditioning. Furthermore, there are specific diseases affecting the liver that have etiology-specific diseases associated in the lungs (i.e., panacinar emphysema in α-1antitrypsin deficiency, fibrosing alveolitis and pulmonary granulomas in primary biliary cirrhosis).

Pulmonary vascular disorders can occur in liver disease with portal hypertension and comprise two distinct clinical entities that are frequently confused: hepatopulmonary syndrome and portopulmonary hypertension. These two syndromes seem pathogenetically linked to the presence of portal hypertension, but their pathophysiological mechanisms differ: in hepatopulmonary syndrome dilation of the pulmonary vascular bed and angiogenesis occur whereas in portopulmonary hypertension there is vasoconstriction and remodeling in resistance vessels. The reason for this paradox is unknown.

As is the case for hepatopulmonary syndrome, portopulmonary hypertension is not associated with a particular cause or degree of portal hypertension. Its development has major clinical and prognostic implications (it is associated with mortality in excess of the model for end-stage liver disease [MELD] score) and requires specific treatment considerations from the hepatopulmonary syndrome.

Establishing elevated pulmonary arterial pressure and increased pulmonary vascular resistance helps distinguish portopulmonary hypertension from hepatopulmonary syndrome.

D. Physical Examination Findings.

Similar to the presenting symptoms of the hepatopulmonary syndrome, the signs of this disease can be grouped together based upon the consequences of hepatic or pulmonary dysfunction, though there are no hallmarks found on physical examination.

These patients may have signs of chronic liver disease: ascites, anasarca, nail changes, splenomegaly, a large or small liver, caput medusae, gynecomastia, palmar erythema, testicular atrophy, jaundice. Two hemodynamic complications of liver dysfunction are worth noting; spider nevi (also known as spider angiomata or nevi araneus) and hyperdynamic circulation:

  • Spider nevi are a common clinical feature of patients with the hepatopulmonary syndrome. These lesions are characterized by a central red arteriole surrounded by a radial pattern of thin-walled capillaries. It has been noted that patients with cutaneous spider nevi had more systemic and pulmonary vasodilation, more profound gas exchange abnormalities, and less hypoxic pulmonary vasoconstriction, suggesting that these lesions may be a cutaneous marker of intrapulmonary vascular dilations.

  • Patients with the hepatopulmonary syndrome have systemic hemodynamics resembling those patients who have cirrhosis without this disease: cardiac output often exceeds 7L/min, systemic and pulmonary vascular resistance decreases, and the difference between the arterial and the mixed-venous oxygen content narrows. The magnitude of the systemic hemodynamic change is related to both the development of portal hypertension and the degree of impairment of liver function. These dynamic changes may compound the oxygen defects of the hepatopulmonary syndrome.

Common pulmonary signs include cyanosis, digital clubbing, hypertrophic osteoarthropathy, and orthodeoxia.

  • Orthodeoxia is defined by a decrease in the partial pressure of oxygen by 5% or more or by 4mmHg or more when the patient moves from a supine to an upright position. It has been hypothesized that it is caused by preferential perfusion of intrapulmonary vascular dilations in the lung bases so that the physiologic shunt is increased when the patient is upright. Although this finding is not pathognomonic of the hepatopulmonary syndrome, it strongly suggests the diagnosis in the setting of liver dysfunction.

E. What diagnostic tests should be performed?

Liver disease is already known in most patients who undergo a diagnostic evaluation for suspected hepatopulmonary syndrome. As such the diagnostic tests should focus on the detection of impaired oxygenation and evidence of intrapulmonary vascular dilations or arterio-venous communications, as outlined in the laboratory studies and imaging studies sections.

Other than the above mentioned studies, there is further testing that often occurs, since the cause of the patient's symptoms may be uncertain or additional diagnoses are being considered. Among the most common include chest radiography, high resolution computed tomography, and pulmonary function tests.

The chest radiograph is frequently nonspecific and subtle. Some studies reveal a mild interstitial pattern in the bilateral, lower lung fields, which may reflect the pulmonary vascular dilatations. These markings are sometimes misinterpreted as interstitial lung disease.

High resolution computed tomography of the chest may reveal dilated peripheral pulmonary vessels and increased pulmonary artery to bronchus ratios, characteristic findings of intrapulmonary vascular dilatations. Additionally, direct arterio-venous communications may be less commonly seen.

During pulmonary function testing in patients with the hepatopulmonary syndrome, a decrease in the single-breath diffusing capacity for carbon monoxide (DLCO) is usually the only consistently abnormal result. However, this low diffusing capacity is not specific to the disease.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Other than the usual laboratory studies that can be measured to assess the synthetic function of the liver, an arterial blood gas is a most helpful laboratory study to help diagnose the hepatopulmonary syndrome. The definition of arterial hypoxemia associated with the hepatopulmonary syndrome is based on measurements from the arterial blood gas that are performed with the patient in a standardized position, preferably sitting and at rest.

The most sensitive measure of impaired oxygenation is an elevated alveolar-arterial oxygen gradient (defined as >/= 15 mmHg) when breathing room air. This gradient is important because it can increase abnormally before the partial pressure of oxygen itself becomes abnormally low (defined as < 80 mmHg) as the gradient measure compensates for the reduced levels of arterial carbon dioxide and hyperventilation, along with respiratory alkalosis, that are common in cirrhosis.

Once the diagnosis of hepatopulmonary syndrome has been made, the arterial blood gas additionally provides information to assess the degree of severity:

  • Mild: Alveolar-arterial oxygen gradient above, or equal to, 15mmHg, partial pressure of oxygen above, or equal to, 80mmHg.

  • Moderate: Alveolar-arterial oxygen gradient above, or equal to,15mmHg, partial pressure of oxygen above, or equal to, 60 up to 80mmHg.

  • Severe: Alveolar-arterial oxygen gradient above, or equal to, 15mmHg, partial pressure of oxygen above, or equal to, 50 up to 60mmHg.

  • Very severe: Alveolar-arterial oxygen gradient above, or equal to,15mmHg, partial pressure of oxygen below 50 mmHg (< 300mmHg while the patient is breathing 100% oxygen).

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The presence of intrapulmonary vascular dilations can be confirmed using one of three imaging modalities: contrast-enhanced echocardiography, technetium 99m-labeled macroaggregated albumin scanning, and pulmonary angiography.

  • Contrast-enhanced transthoracic echocardiography with agitated saline is the most practical method to detect pulmonary vascular dilation. The shaken saline produces microbubbles greater than 20 microns in diameter, which is larger than the normal range of pulmonary capillary diameter - less than 8 to 15 microns. The agitated saline is administered in a peripheral vein in the patient's arm. Under normal circumstances, these microbubbles are filtered by the pulmonary capillary bed and do not appear in the left side of the heart. However, in the presence of an intrapulmonary or intracardiac right-to-left shunt, the microbubbles will opacify the left heart chambers.

The distinction between intracardiac and intrapulmonary shunt depends on the timing of the appearance of the left-sided bubbles after injection. In intracardiac shunting, the microbubbles generally appear in the left heart chambers within three cardiac cycles after the appearance of the bubbles in the right heart chambers. In intrapulmonary shunting, the appearance of the microbubbles in the left heart chambers occur within four to six cardiac cycles after the appearance of the bubbles in the right heart chambers.

It should also be noted that transesophageal echocardiography can also be used to detect intrapulmonary vascular dilations with greater specificity due to the direct visualization of microbubbles in the pulmonary veins as they enter the left atrium, though this technique is more invasive. This transthoracic, qualitative approach is more sensitive than the injection of technetium 99m-labeled macroaggregated albumin and less invasive than pulmonary angiography. The additional benefit is that cardiac function and pulmonary artery pressures can also be evaluated.

  • Technetium 99m-labeled macroaggregated albumin scanning is an alternative method to identifying possible intrapulmonary vascular dilations. This technique involves injecting labeled albumin macroaggregates (>20 microns in diameter) intravenously. Similar to the concept used in contrast-enhanced echocardiography, these macroaggregates exceed the normal pulmonary capillary diameter and should be trapped. Scans that identify uptake of the radionucleotide by the brain suggest that the macroaggregates passed through either an intrapulmonary or intracardiac shunt. In normal patients 3% to 6% of albumin macroaggregates pass through the pulmonary vasculature; therefore, a calculated shunt fraction (percent of uptake in brain compared to lungs) of above 6% is abnormal.

The radionucleotide is also taken up by other organs, and the shunt fraction can be calculated in the kidneys as well. Two observances may make the brain more preferable. First, free technetium deposits in the kidney but not in the brain and might falsely elevate the calculation. Second, renal blood flow decreases significantly in cirrhotics and anemic patients with hyperdynamic circulation, whereas cardiac output to the cerebrum maintains fairly constant in anemic subjects with hyperdynamic circulation, although this has not been validated in cirrhotics.

The major limitations of the technetium 99m-labeled macraggregated albumin scanning are its inability to distinguish between intracardiac and intrapulmonary shunting and its lower sensitivity than contrast-enhanced echocardiography.

  • Pulmonary angiography can directly visualize the intrapulmonary vascular dilations in patients with the hepatopulmonary syndrome. There have been two types of pulmonary vascular dilations noted on angiography:

    • ◦ Type 1 (minimal): characterized by a pattern of finely diffuse, spidery infiltrates; it may evolve into type 1 (advanced).

    • ◦ Type 1 (advanced): characterized by a diffuse spongy or blotchy angiographic appearance

    • ◦ Type 2: characterized by discrete, localized arterio-venous communications

Because it is the most invasive method used to evaluate intrapulmonary vascular dilations, it has been less often used than the other methods. It has the benefit of excluding alternative causes of hypoxia and/or identifying the type of dilations noted above.

In patients with the hepatopulmonary syndrome, pulmonary angiography should be performed only when the hypoxia is severe (i.e., the partial pressure of oxygen is < 60 mmHg), poorly responsive to the administration of 100% oxygen, and when there is a strong suspicion (on the basis of a chest computed tomographic scan) of direct arterio-venous communications that would be amenable to embolization.

III. Default Management.

Theoretically, the ideal treatment of the hepatopulmonary syndrome would consist of reversing the intrapulmonary vascular dilations, either by enhancing vasoconstriction or by inhibiting vasodilation, in hopes of correcting the major clinical manifestation of hypoxemia.

A variety of therapeutic agents have been used in the treatment of the hepatopulmonary syndrome. Data from several uncontrolled trials and anecdotal evidence indicate that treatment with almitrine, antibiotics, beta-blockers, cyclooxygenase inhibitors, garlic preparation, systemic glucocorticoids, cyclophosphamide, inhaled nitric oxide, nitric oxide inhibitors, and somatostatin has been associated with, at best, minimal improvement in oxygenation and shunt.

Long-term oxygen therapy remains the most frequently recommended therapy for symptoms in patients with severe hypoxemia (i.e., dyspnea), although the only evidence supporting this treatment has been indirectly extrapolated from patients with other hypoxemia-inducing lung diseases. Additionally, compliance with this treatment and its cost-benefit value remain unsettled.

In patients who do not initially respond to oxygen therapy, type 2 hepatopulmonary syndrome should by considered, which may be amenable to embolization. In patients with progressive, refractory hypoxemia or the presence of an anatomic right-to-left shunt, liver transplantation should be considered.

D. Long-term management.

No medical therapy for the hepatopulmonary syndrome has been consistently effective. Once oxygen therapy becomes ineffective, liver transplantation appears to improve mortality in patients with this disease and offers the most promise for successful treatment.

In one observational study, 21% of patients with the hepatopulmonary syndrome who underwent transplantation died compared to 78% of those with the syndrome who did not undergo transplantation. In the largest single-institution series, patients with the hepatopulmonary syndrome had a 5-year survival rate of 76% after liver transplantation, a rate not significantly different from that among patients without the hepatopulmonary syndrome who underwent transplantation.

The early post-operative period tends to be the most significant. Retrospective data show that there is a higher mortality rate after liver transplantation in patients with the hepatopulmonary syndrome than in those without. However, patients who survive this period tend to do quite well. Improvement or normalization of hypoxemia occurs in about 80% of patients after liver transplantation; resolution of intrapulmonary shunting has also been demonstrated. The timeframe for pulmonary vascular changes after successful transplantation is variable and may take months.

Both post-operative mortality and the interval between transplantation and the resolution of arterial hypoxia have been shown to be increased in patients with severe pre-transplant hypoxemia due to this syndrome. The strongest predictor of death in one study was a pre-operative partial pressure of oxygen above, and equal to, 50mmHg and a technetium 99m-labeled macroaggregated albumin scan with a a calculated shunt fraction above, and equal to, 20%.

Because of the poor outcome without liver transplantation, the diagnosis of severe hepatopulmonary syndrome is considered to be an indication for liver transplantation, and these patients are given a higher priority for transplantation (i.e., are eligible for MELD exemption points) than patients with other disorders.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in stardard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

B. Anticipated Length of Stay.

There is no typical length of stay. Should these patients be hospitalized for signs and symptoms of arterial hypoxia, a trial of supplemental oxygen should be attempted. Consider consultation with a transplant hepatologist while hospitalized should the patient not improve with oxygen therapy.

C. When is the Patient Ready for Discharge.

Once the signs and symptoms of symptomatic arterial hypoxia have been stabilized, patients can be safely discharged home.

D. Arranging for Clinic Follow-up

Because patients with cirrhosis and severe hepatopulmonary syndrome have an extremely poor prognosis without transplantation, these patients should have an expedited referral to a hepatologist for an evaluation for liver transplantation.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None

F. Prognosis and Patient Counseling.

The diagnosis of the hepatopulmonary syndrome significantly worsens the prognosis. One observational study demonstrated that patients with the hepatopulmonary syndrome who were not candidates for liver transplantation had a median survival of 24 months and a 5-year survival rate of 23%. The control group of patients without the syndrome, matched for the cause and severity of liver disease, had a median survival of 87 months and a 5-year survival rate of 63%.

The causes of death associated with the hepatopulmonary syndrome are usually multifactorial and often no different from those patients with cirrhosis without the hepatopulmonary syndrome. Severe hypoxemic respiratory failure as the leading cause of death is quite rare in this group of patients.

VI. Patient Safety and Quality Measures

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

There are no guidelines for prophylaxis specific to the hepatopulmonary syndrome. However, the recommendations for primary and secondary prophylaxis in cirrhosis and those specific to the underlying cause should be addressed.

What's the evidence?

Abrams, GA, Jaffe, CC, Hoffer, PB. "Diagnostic Utility of Contrast Echocardiography and Lung Perfusion Scan in Patients With Hepatopulmonary Syndrome". Gastroenterology. vol. 109. 1995. pp. 1283-1288.

Hoeper, MM, Krowka, MJ, Strassburg, CP. "Portopulmonary hypertension and hepatopulmonary syndrome". The Lancet. vol. 363. 2004. pp. 1461-68.

Kochar, R, Nevah Rubin, MI, Fallon, MB. "Pulmonary Complications of Cirrhosis". Current Gastroenterology Reports. vol. 13. 2011. pp. 34-39.

Lange, PA, Stoller, JK. "The Hepatopulmonary Syndrome". Annals of Internal Medicine. vol. 122. 1995. pp. 521-529.

Rodriguez-Roisin, R, Krowka, MJ. "Hepatopulmonary Syndrome-A Liver-Induced Lung Vascular Disorder". The New England Journal of Medicine. vol. 358. 2008. pp. 2378-87.

Sussman, NL, Kochar, R, Fallon, MB. "Pulmonary complication in cirrhosis.". Current Opinion in Organ Transplantation. vol. 16. 2011. pp. 281-288.

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