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Last updated:
February 15, 2018
Years published: 2018
NORD gratefully acknowledges Dr. Samir Gupta, Medical Director of the Canadian Hepatopulmonary Syndrome Program, for the preparation of this report.
Summary
The hepatopulmonary syndrome (HPS) is a rare lung complication of liver disease.
When the liver is not functioning properly, blood vessels in the lungs may dilate. If this is severe enough, the lungs can lose their ability to effectively transfer oxygen to the body. This is called hepatopulmonary syndrome (HPS) and it occurs in approximately 5-32% of patients with scarring of the liver (cirrhosis)1.
The most prominent symptom of HPS is usually a severe shortness of breath and low blood oxygen levels. Patients may also notice that their fingertips turn blue or that their fingers take on a club-like appearance2. Supplemental oxygen is often required to manage the symptoms of HPS, but this may not be necessary in milder cases.
Currently, the only known cure for HPS is a liver transplant. After replacing the diseased liver in HPS patients, the lungs return to normal within approximately one year3.
Introduction
The first recorded description of a low level of oxygen in the blood (hypoxemia) with liver dysfunction was by Flückiger in 1884. It was not until nearly a century later, in 1977, that Kennedy and Knudson described a patient with these classic findings, and coined the term “hepatopulmonary syndrome” 5.
Today, HPS is a well-recognized and relatively common complication of liver disease of varying causes (though overall it remains a rare disease, as only patients with liver disease can get it). HPS is defined by a triad of features: (1) liver disease (liver dysfunction or abnormally high blood pressure in the large vein that brings blood from the intestine to the liver and its branches (called portal hypertension), (2) widening of blood vessels entering the lungs (called intrapulmonary vascular dilatations or IPVDs; and (3) abnormal oxygenation. Although there is some variability in the reported literature, and some debate as to the correct oxygenation threshold to identify “clinically relevant” HPS, a consensus group has defined this by an alveolar-arterial gradient (AaDO2) ≥ 15 mm Hg (> 20 mm Hg in patients > 64 years of age).6
It is important to note that portopulmonary hypertension is often confused with hepatopulmonary syndrome, but these are entirely different diseases (see “Related Disorders” below).
The vast majority of HPS patients (82%) initially present with features of their liver disease, while a minority (18%) present with lung (pulmonary) complaints first. Overall, the most common complaint is an insidiously progressive shortness of breath (dyspnea) at rest or upon exertion, reported in 95% of patients and usually developing after years of liver disease2. However, given the high prevalence and often multifactorial nature of dyspnea in cirrhotic patients, this complaint is easily overlooked, and HPS patients reportedly have respiratory symptoms for a mean of 4.8 years before diagnosis 7. In a majority of patients, dyspnea and hypoxemia progress over time 8. Furthermore, this progressive decline often occurs despite stable liver function 9.
A more specific complaint is that of platypnea – breathlessness experienced in the upright position which is improved when lying down (supine position)7. This in turn correlates to the objective finding of orthodeoxia, a drop of 4mmHg in PaO2 or 5% in saturation when moving from the supine to the standing position, occurring in as many as 88% of HPS patients7.
Other clinical manifestations of HPS include:
• Spider angiomata (small, dilated blood vessels clustered very close to the surface of the skin. (likelihood of HPS 21%)
• Clubbing of fingers or toes (likelihood of HPS 78%)
• Cyanosis (abnormal bluish discoloration of skin or mucous membranes due to tissues near the skin surface having low oxygen saturation) (likelihood of HPS 100%)2
It is important to note that chest x-ray and thoracic CT scanning are often unremarkable in HPS; a lack of radiographic abnormalities is not sufficient evidence to rule out HPS.
It should also be noted that HPS is not limited to patients with severe liver dysfunction; in fact, many patients with moderate to severe HPS have comparatively well preserved hepatic function1.
The cause of HPS remains unclear and it is unknown why some patients with liver disease develop IPVDs while others do not. Hypoxemia in HPS is primarily due to limitations to the movement of oxygen from the lungs into the bloodstream (diffusion limitation), and mismatching between air moving through the lungs and blood moving through the lungs (ventilation-perfusion mismatch), caused by the presence of IPVDs1.
Accordingly, efforts to decipher the cause of HPS have focused on the cause of the IPVDs that underlie the hypoxemia of HPS. Autopsies in HPS patients have confirmed that small blood vessels (capillaries) in the lungs are severely enlarged (dilated).10. These enlargements may result from increased production or impaired liver clearance of chemicals that cause blood vessels to relax (vasodilators), or from decreased production or lack of sensitivity to a chemical normally coming from a healthy liver that causes blood vessels to contract (vasoconstrictor). Though the nature of this underlying “liver factor” remains unclear, it is clear that at the level of the pulmonary blood vessels, nitric oxide (NO) has emerged as an important cause of this dilatation of blood vessels (vasodilation). The NO may be released through several pathways, including by inflammation caused by bacteria and bacterial material escaping from the gut into the blood circulation in patients with cirrhosis (gut bacterial translocation), which causes recruitment of cells called macrophages to the pulmonary blood vessels, where they produce and release NO14. In addition, rats with HPS demonstrate liver overproduction of a chemical called endothelin-1, with causes local NO production and release in the lungs 15,16.
As our understanding of the cause of HPS evolves, it is more and more evident that these NO-mediated changes in pulmonary blood vessel size likely result in a more chronic change in the structure of the blood vessels themselves, which is called vascular remodeling. In turn, this may result from an imbalance of liver-released factors stimulating and preventing pulmonary blood vessel cell (endothelial cell) growth, that have yet to be identified17.
Among cirrhotic subjects awaiting orthotopic liver transplantation (replacing the recipient liver with the donor liver), approximately 70% complain of dyspnea, 34-47% have intrapulmonary vascular dilatations (IPVDs), and 5-32% have HPS 6,18-23.
HPS occurs in children and adults, in both males and females, and in people of all ethnic backgrounds. Though HPS has been reported in people with non-cirrhotic portal hypertension with normal synthetic liver function (e.g. nodular regenerative hyperplasia), the most common cause remains cirrhosis, though no specific etiology nor severity of cirrhosis has been found to be correlated with the incidence or severity of HPS.
Because dyspnea is common in liver disease, HPS is often missed or diagnosed late. In the absence of an alternative explanation, a saturation of < 96% is suggestive of HPS.24 Worsening dyspnea in the upright compared to supine position (platypnea) and orthodeoxia (PaO2 drop by more than 5% or 4 mmHg in the upright position) occur in only 25% of patients6 but are highly specific for HPS (thought to be from gravitational re-distribution of blood flow to basilar parts of the lungs, where vascular dilatations are more severe), as are clubbing or cyanosis (in any patient with liver disease).21 Accordingly, clinicians should think of HPS in patients with liver disease and an unexplained oxygen saturation of < 96%, or any of: platypnea, orthodeoxia, clubbing, or cyanosis. After pulmonary evaluation, any patient with a PaO2 < 80 mmHg or alveolar-arterial oxygen gradient (AaDO2) ≥ 15 mmHg that cannot be fully explained by other diagnoses should be referred for a diagnostic workup for possible HPS25.
The diagnostic approach to HPS involves objective testing for each of the three components of its definition (see above). To begin with, evidence for (1) liver disease is sought through abdominal imaging for liver abnormalities including cirrhosis, as well as ancillary signs of portal hypertension, such as enlarged veins (varices) and/or enlarged spleen (splenomegaly). Furthermore, blood tests that show biochemical evidence of synthetic liver dysfunction, including albumin, bilirubin and international normalized ratio (INR) provide evidence for cirrhosis. Next, evidence for (2) IPVDs is sought through contrast echocardiography (or macroaggregated albumin shunt testing), and the presence of (3) an elevated alveolar-arterial oxygen gradient is determined by analysis of arterial blood gasses (ABG). Due to the important effect of orthodeoxia, in cases of suspected HPS, it is recommended that ABGs be performed only after 15 to 20 minutes at rest in the standing position.
Clinical Testing and Work-Up
All of the tests used to evaluate possible HPS are non-invasive. Initial workup should include some or all of the following tests:
Pulmonary Function Tests
Pulmonary function tests in HPS patients usually reveal normal flows and lung volumes, though patients may have reduced lung volumes from accumulation of fluid in the abdomen (tense ascites) or excess fluid around the lungs (pleural effusions)26. Reduced movement of oxygen from the lungs into the bloodstream (diffusion impairment) is a frequent finding in HPS, occurring in up to 83% of patients in one series 7, however this finding is frequent in people with cirrhosis who do not have HPS as well, occurring in 50-70% of cirrhotic patients 20,27. Still, HPS subjects have been noted to have more profound reductions in diffusion capacity, with a mean DLCO of 55% predicted versus a mean of 72% predicted in people with cirrhosis who do not have HPS 20.
Six Minute Walk Test, and if required, an Oxygen Titration
A six-minute walk test allows for objective assessment of exercise capacity and any low blood oxygen level (desaturation) with exercise. If patients do desaturate to below 88% with exertion, an oxygen titration study should then be performed to identify and match oxygen requirements.
Liver Function Tests
Includes imaging with abdominal ultrasound and/or CT scan and some blood tests to determine the severity of a patient’s liver disease.
Arterial Blood Gas
For this test, a small amount of blood is drawn from an artery in the wrist. The oxygen and carbon dioxide levels in the blood are then analyzed to help determine if a patient’s lungs are functioning properly.
Echocardiogram
An echocardiogram, also known as a cardiac ultrasound, is a technique that uses sound waves to take images of the heart. In HPS patients, a small amount of salt water (agitated saline solution) is injected into a vein in the arm during the echocardiogram. This test helps determine whether or not the blood vessels in the lungs are dilated–a hallmark symptom of HPS.
2-D transthoracic agitated saline contrast echocardiography (CE) has become the test of choice for identifying IPVDs. Saline microbubbles ranging from 15-180 um in size are created by mixing 10 ml of normal saline with 10 ml air, and are injected intravenously during normal transthoracic echocardiography. Within seconds, these bubbles appear in the right-sided heart chambers, and in the absence of IPVDs, become trapped in the pulmonary capillary bed, and are eventually absorbed. However, in HPS, IPVDs allow bubbles to pass through the pulmonary vascular bed, resulting in detectable bubbles in the left-sided heart chambers. Since an intracardiac shunt could have the same effect, the timing of left-sided bubble appearance is closely monitored, and the shunt is likely to be intracardiac if bubbles appear within 1-3 beats, and intrapulmonary if they appear after 3 beats (usually within 4-6 heartbeats)23.
Macroaggregated Albumin Lung Perfusion Scan
Sometimes a technetium-99 labeled macroaggregated albumin total body scan (MAA scan) will be ordered to determine the extent to which HPS is contributing to a patient’s oxygenation abnormalities. For this test, a small amount of safe, radioactive particles called Tc99m-MAA are injected into the patient’s arm and then a specialized camera is used to detect where in the body these particles end up. This is a more specific technique to test for the presence and severity of dilated blood vessels in the lungs.
Especially in patients with evidence of coexisting cardiorespiratory disease, an MAA scan may be used to help establish the contribution of HPS to gas exchange abnormalities. In this technique, radioisotope labeled aggregates of albumin ranging between 20-60 um in diameter are injected into the venous circulation. In healthy people, these albumin aggregates are trapped in the pulmonary blood vessels, and nuclear scintigraphy reveals majority pulmonary uptake of the radioisotope. However, in the presence of IPVDs or an intracardiac shunt, these aggregates escape the filtering pulmonary capillaries and enter the body (systemic) circulation, becoming trapped primarily in brain, kidney and liver capillary beds. The amount of this anatomically shunted radioisotope can then be measured, enabling a calculation of the shunted fraction of the total blood pulmonary blood flow26,28,29.
CT Scan of the Chest
This test is done to evaluate for other abnormalities that may be contributing to abnormal oxygenation. Although pulmonary blood vessels are generally dilated, the CT scan itself does not distinguish HPS from liver disease without HPS.30
Follow-up visits will often include pulmonary function tests, a six-minute walk test, an oxygen titration study, and an arterial blood gas to monitor disease progression.
Treatment
Liver transplantation is the only known effective therapy for HPS, with significant improvement in oxygenation observed in the majority of patients within one year of transplantation3. Patients require close assessment and follow-up by lung and liver experts before and after transplant. Long-term oxygen therapy is the mainstay of supportive therapy for HPS, and there may also be a role for pre-and post-operative pulmonary rehabilitation.
It has been clearly shown that HPS patients with a paO2 60 mmHg have significantly better 5-year survival rates with liver transplantation, when compared to supportive therapy 8. As a result, the United Network for Organ Sharing (UNOS) has recommended the allocation of additional points in the MELD (model for end-stage liver disease) organ-allocation prioritization system, for HPS subjects with paO2 < 60 mm Hg, with a goal of transplantation within 3 months of listing 31.
Since hypoxemia is progressive in HPS, and pre-operative prognosis and surgical outcomes are closely linked to the severity of hypoxemia, HPS patients should be listed for transplantation as early as possible. Also, it is of note that within the last decade, increasing interest and expertise has evolved in living-related liver transplantation as well, and it appears as though this procedure has a similar effect on HPS to that of transplantation with a liver from a person who has died.
There are a number of important complications regarding liver transplantation for HPS. Firstly, there have been numerous reports of severe post-transplant hypoxemia32 requiring prolonged mechanical ventilation and innovative techniques to manage hypoxemia33. Also, a number of centers have noted increased post-operative infections and leaks of bile from the connections between bile ducts (anastomotic bile duct leaks), suspected to be the result of delayed wound healing due to hypoxemia. Also, numerous early post-operative blood clots including portal vein and hepatic artery blot clots have been reported, possibly in the context of overproduction of red blood cells (polycythemia) from chronic hypoxemia 34,35. Furthermore, there are reports of post-transplant recurrence of HPS as a result of graft dysfunction from liver inflammation and damage caused by a buildup of fat in the liver (non-alcoholic steatohepatitis or NASH), or recurrent hepatitis C. Also, there has been a report of post-transplant resolution of hypoxemia followed by development progressive pulmonary hypertension. Finally, numerous reports have shown that decreased diffusing capacity of the lungs (DLCO) in HPS does not improve post-transplant, despite an improvement in oxygenation.
Given the chronic organ donor shortage and the high peri-operative mortality associated with liver transplantation in HPS, many medical therapies for HPS have been proposed, but unfortunately, none has been found to be effective. Small uncontrolled studies of agents such as somatostatin, amiltrine, indomethicin, plasma exchange, and aspirin have been negative. In some studies, garlic has shown potential. A pilot crossover randomized controlled trial of norfloxacin was negative36, and prior reports of pentoxifylline have had conflicting outcomes37,38. Studies of NO (nitric oxide) production inhibitors such as inhaled L-NAME (N-nitro-L-arginine methyl ester), or downstream NO inhibitor methylene blue have had conflicting results, and do not represent long-term therapeutic options 39-41. The TIPSS procedure involves angiographic insertion of a low resistance expandable metal stent between the hepatic vein and the intrahepatic portion of the portal vein. It has been proven most useful in life threatening complications such as variceal bleeding, by temporarily reducing the portal pressure. The use of TIPSS has previously been suggested as a possible treatment in HPS, but results have varied across studies and reports42.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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