Thank you for coming here. My name is Hector Cajigas. I am part of this session today, and again, I do appreciate very much that you guys are spending your Wednesday here in a chest. So I have to read that you have to keep your phone handy because it's an audience response system, so use the app to answer audience response questions by finding the session in your schedule and clicking on the polling link at the bottom of the session details. There will also be a QR code you can scan each time a question is asked. So we're going to go through the four presentations, and if there are any questions, we can do those at the end of the sessions, and I believe that we are on time to start now. So my topic is to speak about updates on portopulmonary hypertension, and what I'm going to try to do because, you know, this is a rare disease and a complicated one, so we really don't have a lot of updates, so I'm going to try to use the last five years of information that we have had, so I'm going to try to give you some data in regards of that. So what are the objectives that we want to cover? I would like to review concept and definition of portopulmonary hypertension. I know many of you already know this. Learn a quick update on pathobiology of this disease and update, review whatever is available newer on diagnosis and diagnostic challenges in portopulmonary hypertension, and also briefly speak about the changes in lung liver transplant eligibility and MELD exception scores that have been implemented in the last years for patients with portopulmonary hypertension. That's the QR code. I'll leave that for a few seconds. So let's talk about portopulmonary hypertension now as a disease. It belongs to the WHO Group 1 of pulmonary arterial hypertension, and it is defined that you have to have a patient with portal hypertension and a right heart catheterization value of a mean pulmonary arterial pressure more or equal than 20 millimeters of mercury, a pulmonary capillary weight pressure less than 15 millimeters of mercury, and a PBR more or equal than two wood units. This was changed, and this is how it is now as well defined as any other PAH subcategory. The prevalence of this disease is variable. It depends on hemodynamic definitions and the population studies. So portopulmonary hypertension is very interesting because this is one of the diseases where most of the data derives from retrospective data. So we have managed, we have changed how we do things on portopulmonary hypertension with retrospective disease. So if somebody doesn't believe in retrospective studies, this is an example of how we have changed this condition by this type of studies. It's not influenced by the severity of liver disease. So let's start with the first question. What is the incorrect statement? BMPR2 mutation occurs sporadically in POPH. BMP9, a ligand of BMPR2 receptor, is increased in portopulmonary hypertension patients. There is an association between estrogen pathway and portopulmonary hypertension. Or the small pulmonary arterioles of patients with POPH demonstrate similar histopathology changes to those patients with PAH. So let's see what your votes tells us. All right. So we're hearing that number two, BMP9, a ligand of BMPR2 receptor, is increased in portopulmonary hypertension as the true incorrect statement. And that is true. Actually, BMP9 is decreased in patients with portopulmonary hypertension. And the others, as mentioned, are incorrect. And the small pulmonary arterioles of patients with POPH, they do actually have similar changes to patients with PAH. That's why they are group 1 disease. So quickly reviewing that, BMP9 and 10 in pulmonary vascular complications of liver disease was studied. And it did show that in patients who have portopulmonary hypertension compared to controls, there is a significant decline on the level of BMP9, which is actually a ligand of BMPR2. So actually, there have been the idea that BMPR9 or BMPR9 restitution could actually help this patient as well. So there is a 43% lower BMPR9 in patients with portopulmonary hypertension in this particular study. Also, by my friend, Dr. Anna Manning, she described that pulmonary vascular complications group in the liver disease study group on 37 patients found that patients with portopulmonary hypertension had higher levels of estrogen signaling. Estrogen signaling has been associated to inflammation, and it's more common to have higher estrogen levels in those patients who have pulmonary arterial hypertension as well. And so she found an association of a SNP in the aromatase genes with risk of portopulmonary hypertension with a significant risk. So estrogen binds to the promoter region of BMPR2 and regulates its expression. So we know now estrogen is associated to the development or to the pathobiology of portopulmonary hypertension. Dr. Jose at the University of Cincinnati then continued to do single nucleotide RNA-seq in liver tissue samples, the nine patients after liver transplant and four of them with portopulmonary hypertension. It's a very elegant study. He did a fantastic job here. And basically what he described, again, is similar to what was seen to some degree before, noticing that there was an increment in estrogen signaling in those patients. There was vascular endothelial growth factor, GD515, and inflammatory mediators, particularly in macrophages in those patients who had portopulmonary hypertension. Also found that, similar as before, BMP9 was decreased as well, and the mediators going into nitric oxide were decreased as well, as well decrementing BMPR2. So again, this is a recent study, and actually he did a good job demonstrating those abnormalities. So let's go to the next question. What would be the correct statement in these questions now? The new ESC-ERS 2022 guidelines in PAH do not include patients with portopulmonary hypertension. Number two, in patients with portopulmonary hypertension and PBR between two and three, no treatment should be offered. Number three, portopulmonary hypertension patients are included in most of PAH medication trials. And the PORTICO trial, a randomized controlled trial of macitendin versus placebo in portopulmonary hypertension, demonstrated a reduction in PBR of 35%. Let's see what the audience had decided. Is that correct statement? Very nice. So yes, obviously the guidelines do include portopulmonary hypertension. So patients with portopulmonary hypertension and PBR between two and three should be offered treatment. We'll speak about that in a second. They are not included in the majority of the PAH trials. That's one of the problems that we have. The PORTICO trial is the landmark trial, the only one that is randomized controlled difficulties recruitment, but actually they were able to get to demonstrate that decreases PBR. So what about the diagnosis? Does it have any impact now that we do decrease the mean PAH pressure to 20 and the PBR to two to make this diagnosis? Does it impact portopulmonary hypertension? The problem with many of these patients is that they have significant issues with how volume high output state. So this is a Japanese retrospective study where they actually did find in 186 patients, and this is done this year, who were diagnosed with portal hypertension and cirrhosis. The diagnosis increased from 1.1 to 2.2 basically here when the mean PAH pressure was reduced. So I know the numbers are small, but this is actually the prevalence. But if you can think about it, this is 100% change in diagnosis. So I think there is going to be some impact when we actually push the diagnosis, but we need to be very careful making sure that those patients actually do have the right PBR to make the diagnosis. Now a French group sent a letter to the European Respiratory Journal in 2022 saying, what happens to PBR between two and three? Does it matter now? Because before we used to say three. So what about these cases? How do they do? And they did actually a retrospective study of the French registry, and they found that 22 of them had that PBR between two and three, and they met criteria for pulmonary artery pressure elevation. And actually, when they followed this patient, 81% in follow-up developed a PBR of more than three. So what is the message? That those ones who had between two and three, they did not get much better. They did get worse. So that's, again, to speak about the update on, should we treat these cases? The answer, very likely yes, because these patients evolve into worse disease if we don't follow them or even if we follow them carefully. Also interesting, in this Spanish PAH registry of 130 patients, they wanted to see what the response of PDE5 inhibitors treatment had after one year of follow-up, and this was all PAH comers. And 33% were classified as responders, after you look at them. Responders meaning that they went into low-risk criteria based on the ESC guidelines, so these patients actually did improve and maintain low-risk category in 33%. But portal pulmonary hypertension was among the independent predictor of favorable response to PDE5, either as a mono or combination therapy. That's an important piece of information. Again, this is retrospective, and you can, again, talk about what is the value of that. I think the value is significant, in my opinion, but again, this is from 2023. Ambrescentin, we know about a Dr. Preston trial of prospective multi-center open-label trial, 24 weeks, and they found PBR decreased a mean of 7.1 versus 5, I mean, plus minus 5 versus 3.8 in controlled patients. So this was actually published in 2020, and it showed that there was a significant improvement, so we know Ambrescentin could work for this purpose as well. What about Portico? We talked about this. This is the only prospective randomized trial, 85 patients, 36 centers, and it found a 35% decrement in PBR. It did exclude patients with very severe liver disease, MELD-19, but there was no change in functional capacity of 6-minute walk distance, and the patient tolerated it well. So that's what we have about Portico, which, again, was in 2019, and we use this medication very much. And then a 2020 meta-analysis of 26 studies that included 1,000 patients with portopulmonary hypertension published in 2020 showed that a substantial proportion of patients treated with pH became eligible for transplant, 44%. Survival with treatment was actually better at the end when it was analyzed, when it was added with liver transplantation, and the risk of death in treatment only was higher than liver transplant. So 50% of patients' pH meds can be discontinued post-liver transplant. So it tells us that these patients actually do respond to therapy. Okay, question three. In patients with portopulmonary hypertension, which hemodynamic profile grants MELD exception score when candidates for liver transplant? Number one, mean PA pressure 55, PBR 5, 40, PBR 2.5, 35, PBR 5, mean pulmonary pressure 55, or PBR of 2.5. Okay? So we have mixed messages here, which is actually good, because we can talk a little bit more about it. So the majority said a mean pulmonary pressure of 35 with a PBR of 5. So this is quite PBR elevation here. The correct answer is a mean pulmonary pressure of 40 with a PBR of 2.5, and I will tell you why. So my colleague, Hilary Dubrock, actually did look at these patients, of those ones who have a mean PA pressure between 35 and 50, because before 50, 100% death. That's what we know. If they have, they were looking for 35 or less. Now what happens to those in between? So they said 50% mortality if you are 35 between 50. So we wanted to look at those, and she did, and she looked at 16 patients with those numbers, and actually they all were on therapy. Therapy decreased pressures, PBR as well, and they were able to get transplanted. These are patients, actually, who got to be transplanted, and the survival was similar to those ones, actually, who were, with the ones who achieved less than 35. So since then, the male exception criteria that before, from 2006 to 2021, said this is the diagnosis, more than 35, and PBR, more than 3. Actually, initial diagnosis was made. That's what the Liver Transplant Society said, but then after treatment, it was expected to have this. Now, the revised male criteria, since February 2021, shows that we can have a melt of less than 35, a mean pulmonary pressure less than 35, PBR definitely less than 5 with units, but then we will have a mean pulmonary pressure of 35, 45, but then a lower PBR when you still have a good RV. So this is the change. So we have to keep repeating right haircut every three months to make sure that we meet this criteria. So in conclusion, developments in biology associated to portal pulmonary hypertension include the role of BMP9 and estrogen. New cutoffs of the diagnosis may impact new diagnosis of portal pulmonary hypertension. The importance of milder cases with PBR between 2 and 3, they should be recognized that they mostly evolve into more severe disease. PAH medications have an impact on hemodynamics and outcomes. PAH therapies can facilitate liver transplantation when needed, and the male exception criteria have been modified to include mean PA pressure 35 to 45 if PBR and the RV are acceptable. Those are kind of the updates we have. Thank you very much. Great. Thank you so much, everybody, for attending our talk today, our session on pulmonary complications of liver disease. And for the next 15 minutes, I'll be talking about hepato-pulmonary syndrome. And I really liked this picture. It was taken from a case report that was published in the New England Journal of Medicine. It just really displays and illustrates the degree of clubbing that can occur in patients with this condition. My name is Sarah Medrick. I'm an assistant professor in pulmonary critical care disease at the University of New Mexico, and I'm also affiliated with the New Mexico VA health care system. I have no disclosures to report. And in this session, I would like to share information on the pathophysiology diagnosis and treatment of hepato-pulmonary syndrome. So what is hepato-pulmonary syndrome? And it's characterized by a triad of the following three things, first being have some degree of liver disease, so having portal hypertension, chronic liver disease, or congenital portosystemic shunts. And it's interesting, hepato-pulmonary syndrome can actually occur irregardless of the severity of liver disease. So patients with relatively mild liver disease can develop it, whereas on the other hand, patients with severe liver disease may not develop this complication. And this complication can actually be seen in up to 20% of patients with cirrhosis. And it's important to recognize the condition because the presence of hepato-pulmonary syndrome is associated with increased mortality, actually in some reports up to a doubling of mortality. This condition is characterized by having abnormal oxygenation, in addition to having the underlying liver disease. And the abnormal oxygenation is graded based on the alveolar arterial gradient, the AA gradient, and that does vary slightly based on age. And then the third criteria for having this syndrome is really the hallmark of the condition. And it is having the presence of inter-pulmonary vascular dilations. So what is an inter-pulmonary vascular dilation? So you'll see in this diagram the normal alveolar capillary interface. In the alveolus, there's gas, of course, with oxygen, and that interfaces with the capillary. The deoxygenated blood enters the capillary, and then gas exchange occurs along this blood vessel, which is normally 8 to 15 microns in diameter. And you can see pictorially that this is effective. The red blood cells are able to oxygenate, pick up the oxygen, and then carry that oxygen back to the heart in the systemic circulation. In patients that have hepato-pulmonary disease and inter-pulmonary vascular dilations, these blood vessels have an increased diameter. They have a diameter of greater than 15 microns, and I'll have you remember that number because it will come up again in later slides. And as you can see here pictorially, gas exchange is less effective in patients with this inter-pulmonary vascular dilation. There is some degree of only partial oxygenation that occurs after the gas exchange happens at the alveolar capillary border. So inter-pulmonary vascular dilations lead to hypoxemia by multiple mechanisms, and I'll go through these next. And the first mechanism is our favorite as pulmonologists, VQ mismatch. Due to this increased diameter of the blood vessel, you have increased flow to that part of the lung, and due to that increased perfusion, you don't have an increase in ventilation. So although you have the increased perfusion due to the inter-pulmonary vascular dilation, you still have the same air that's available for gas exchange. And so due to the increased perfusion relative to the ventilation, you have VQ mismatch. And this is a really important mechanism in these patients that contributes significantly to hypoxemia. We also have diffusion limitation, and this occurs due to the increased alveolar capillary distance. So you can kind of see in the picture how those red blood cells remain deoxygenated because they don't appropriately interface with the alveolar capillary border. You also have a reduced capillary transit time, again, due to the increased diameter of the blood vessel. Blood is flowing faster, and there's less time that's available for gas exchange. And so this also contributes to the diffusion limitation that we see in this condition. And then abnormal angiogenesis also contributes to the development of hypoxemia. And this is the mechanism that lots of times we think about with the condition, and that shunt is contributing to the hypoxemia that develops. And this is true, that patients with the condition have abnormal angiogenesis, which leads to the creation of abnormal arterial venous bypass, and leads to deoxygenation through this mechanism. The pathophysiology of hepatopulmonary syndrome is thought to be due to enhanced vasodilation in angiogenesis. And I took this diagram from this paper, and it's a little bit busy, but I think my take-home points from this are that you have increased vasodilation through mechanisms which could include bacterial translocation, leading to increased endotoxin exposure in the systemic circulation, and also just due to other pathophysiologies, such as increased cardiac output state, leading to abnormal vascular mediators, and thus vasodilation. Moving on a little bit to the clinical features of hepatopulmonary syndrome, we have symptoms that could include, like we saw in our introduction slide, of clubbing. We can have cyanosis, and we can have hypoxemia. The most common symptom that patients typically complain about, though, is just shortness of breath, dyspnea with exertion. One of the hallmark features that sometimes you see in this situation in patients with hepatopulmonary syndrome is that they have platypnea. And this is the opposite of orthopnea. So platypnea is shortness of breath when patients are in the seated position, and that shortness of breath improves when they lay down. And it's thought that this occurs because the intrapulmonary vascular dilations are more prevalent in the bases of the lungs, and so when a patient sits up, there's more blood flow to the bases of the lungs, and then that increases the hypoxemia. So that's the symptom that patients have. They have platypnea, and that correlates to the sign, which is orthodeoxia, which is a decrease in the PaO2 of more than 5% or more than 4 millimeters of mercury when a patient moves from a separate supine to an upright position. The diagnosis of hepatopulmonary syndrome does require the evidence that the patient has these intrapulmonary vascular dilations, and the best first way to try to find this is by using contrast and echocardiography. And you'll see in this diagram, kind of walking through the different panels, the first panel shows the normal heart after you initially identify the heart, and you then inject bubbles into the venous circulation, and the bubbles travel to the right side of the heart. And then you watch the heart, and you watch the cardiac contractions occur. And if you see bubbles that transfer over to the left side of the heart in less than three cardiac cycles, that's considered to be an intracardiac shunt. However, if you see bubbles that are seen after three to four cycles, that's considered an intrapulmonary shunt, and it would be evidence that a patient has intrapulmonary vascular dilations that would support a diagnosis of hepatopulmonary syndrome. The same phenomenon can be illustrated using nuclear medicine studies, and also technetium-labeled macro-aggregating albumin scintigraphy can be used to diagnose hepatopulmonary syndrome. And these albumin particles are approximately 20 microns in diameter. And so, in normal patients that have those pulmonary couplers that are 8 to 15 microns, these pieces of albumin get trapped in the pulmonary circulation. However, if you have the vascular dilations, as seen with hepatopulmonary syndrome, they're able to traverse the lungs and go to other parts of the body, such as the brain. And so, you'll see the normal on the left there, and there's no uptake in the brain, whereas in a patient with hepatopulmonary syndrome, you do see uptake in the brain, because those particles are able to make it through the lungs. And this study is nice, because you can actually calculate a shunt fraction and quantify the severity of the disease in that way. Patients that are undergoing liver transplant evaluation should be evaluated for this condition. And the best first step is just doing pulse oximetry to see whether or not there's any hypoxemia that's present. It should be followed up by an arterial blood gas in order to see what the AA gradient is. And if there is an elevation in the AA gradient, then you should pursue a method that could demonstrate the present of intrapulmonary vascular dilations, and the best first study usually is a contrast-enhanced echocardiogram. The severity of the hepatopulmonary syndrome can be graded according to the degree of derangement in the PaO2. And a treatment of hepatopulmonary syndrome is primarily supportive. Supplemental oxygen is typically recommended to be used at rest and with exercise and during sleep. Unfortunately, there are no medical therapies that are definitively established or FDA-approved for the treatment of hepatopulmonary syndrome. Coil decompression with tips is of uncertain benefit in patients with hepatopulmonary syndrome. In rare cases, coil embolization may improve oxygenation in select patients with hepato-ulmonary syndrome. And this is more likely to be beneficial in a patient that has a CT scan of the thorax that shows an AV malformation that's visible. So only for relatively large malformations is this offered. In younger patients, correction of congenital portosystemic shunts may be beneficial. And then pulse oximetry is advised for oxygenation monitoring. Just to dig a little bit into the treatment that has been evaluated for the treatment of hepato-ulmonary syndrome, many things have been tried in a variety of studies. Unfortunately, none have had clear benefit. The most recent candidate that had been evaluated is sorafenib, which is tyrosine kinase inhibitor that decreases VEGF expression. And unfortunately, it did not show a clear benefit. Other medications that have been tried for the treatment of this condition are listed. And unfortunately, currently, there are not very many ongoing trials looking at other further candidates for the treatment of hepato-ulmonary syndrome. When I looked at clinicaltrials.gov, those were the only two studies I found. However, the good news is that liver transplantation does improve oxygenation. And it is important to identify these patients with hepato-ulmonary syndrome while being evaluated for liver transplant, because patients that have hepato-ulmonary syndrome do receive mild exception points, and this can improve their liver transplant candidacy. Liver transplantation improves survival, in addition to improving oxygenation. And survival did not differ based on pre-transplant PaO2, based on this study here. So I'd like to pose, just kind of wrapping up my portion of this session, I just wanted to propose that hepato-pulmonary syndrome and portal pulmonary hypertension are two distinct adverse pulmonary vascular consequences of liver disease. And I thought this was really well illustrated by this case report from 2019 that was published in the European Respiratory Journal. And just to kind of talk you through what was clinically happening with this patient, it was a patient with portal hypertension that was initially diagnosed with portal pulmonary hypertension. And you can see the baseline hemodynamics there in the first column. The patient was initiated on therapy with Tadalafil and Masutentin, and had improvements initially in six-minute walk distance. You'll see at the follow-up that walk distance improved from 412 to 473 meters. But unfortunately, this came at the cost of worsened oxygenation. So a follow-up right heart catheterization was done, which did show improvement in hemodynamic parameters, but again, the worsened hypoxemia. So this patient actually was stopped on the Masutentin and had the Tadalafil continued with some improvement in oxygenation. So I just propose that, as with anything in life, balance is important. And in this case, we would like to have balance between the vasodilation that sometimes can be seen in hepato-pulmonary syndrome and vasoconstriction that is more of a hallmark of portal pulmonary hypertension. Thank you. Thank you. Thank you so much for the invitation. And over the next 10, 15 minutes, I'm going to talk about a comprehensive hemodynamic evaluation of these patients. These are my conflict of interest. The learning objectives I hope that I can work on, and the understanding of the components of the comprehensive evaluation in patients with liver disease, trying to differentiate portal pulmonary from other conditions that also cause high pulmonary pressure in patients with liver disease, and then describe tools that we could use during the hemodynamic evaluation of these patients that could differentiate different causes of hypoxemia. As Hector already talked about the definition, the guidelines have decreased now the PVR from 3 to 2. It's essential to rule out, even if you have pre-capillary pH, other conditions that can cause a pre-capillary component or pulmonary arterial hypertension. For example, we had a patient that develops scleroderma and also cirrhosis, and the reason for the pulmonary hypertension was likely the autoimmune disease. There are two important measurements that are essential during the rheumatic catheterization to assess these patients, the wedge pressure and the cardiac output, and you will see here in a minute why. It's important to know what's portal pulmonary, but also important to know what's not portal pulmonary. These patients have volume overload due to this secondary hyperallocerinism that they developed. Also, CKD is very commonly associated. The heart pumps like crazy. The cardiac outputs are super elevated, and then they also have increase in the pressures due to that. When you see a patient with high rheumatoid gastrointestinal pressure and echo, it could be a variety of conditions. We recently published a paper where we describe all possible associations, and as you can see there, it could be a volume overload where you have increase in the wedge, it could be hyperdynamic state where you have increase in cardiac output, it could be portal pulmonary when you have increase in PBR, but it can also have combination of things. So you could have volume overload combined with hyperdynamic state or volume overload with portal pulmonary or all of them at the same time. So it's essential to identify which pattern you have and then treat all the specific conditions. In the right heart catheterization, what you could do is to measure the portal pressure and what we call hepatic venous pressure gradient, and I'll show you how you do that. But as you can see here, this will be the normal drop from the portal vein towards the right atrium. It's a linear and it's a small drop in pressure as it goes, the blood from portal to systemic the right atrial pressure. But in patients with portal hypertension, there's a big drop in the sinus of the liver, and if this change, gradient, is more than five, then you have portal hypertension. And if the gradient is more than 12, that's important because those patients are at risk of significant GI bleed. So this is how you do it in practice. You get the pulmonary arterial catheter to go to the free hepatic vein, and then you measure the free hepatic vein, and free hepatic vein has also an A and a V wave. And then you inflate a balloon there, and as you're inflating the balloon there, then you get the hepatic wedge pressure, and usually you lose the A and the V wave, and depending on the case, it may increase. In this case, for example, increased by 10. So you see the free hepatic vein was 12, and the hepatic wedge pressure was 22. So here's 20, and this is 22. So this patient had portal hypertension. This is essential because you need this component to diagnose portal pulmonary hypertension. It may be a patient that has pre-capillary pH due to another reason, and also cirrhosis. So you don't know. Is that coming, the pulmonary hypertension from the cirrhosis, or some other associated condition? This is a patient, and we measured the portal pressure. And as you can see, this is the free hepatic vein, and this would be the occluded portal vein pressure. And the difference is certainly less than five, so this is a normal hepatic venous pressure gradient. This is an example how you do it. The catheter, we usually use a wire that will take the swan to the inferior vena cava. Then you remove the wire, you turn the pulmonary artery catheter that has a little bit of a C shape, and it easily canalizes the suprahepatic vein, and then when you balloon, you inject dye. And when you inject dye, it's the same thing as when you're doing a wedge pressure in the lung. The contrast doesn't move, because obviously the blood is going in the direction towards the catheter, towards the RA. So once you occlude these, you inject dye, you know that you're in perfect position, there is no leakage, you're measuring the appropriate portal pressure. For the evaluation of patients that are undergoing liver transplantation, we do echocardiography, as was described by Hector, and then we assess the right ventricle, and if the pressures are low, then the patient is ready to go for liver transplantation. But if the pressures are high, and this cutoff will depend on the institution, and my institution is 45, it could be 50, or it could be 40, depending how conservative you want to be. And certainly the IRB has to be normal, but if it is not, then you proceed with RA catheterization. And we do the RA catheterization with nitric oxide challenge and fluid challenge, and you can say, you know, hey, why are you doing that? The nitric oxide is just to see how much the pulmonary circulation responds, particularly how much the PVA dropped, in the event that things get worse during surgery, that you need to act either by nitric oxide or inhale epiprostanol to lower the PVR, as you have the reperfusion when you put the new liver. And then a fluid challenge is because of the massive fluid shifts that occurred during surgery to see how this will impact the right ventricle as you are operating on the patient. So just to give more information to the anesthesiologists that are going to be doing the intervention. And then we're moving on a little bit of what you could do to assess the hypoxemia during this hemodynamic evaluation. As you're seeing patients with liver disease and they have hypoxemia, then yeah, hepato-pulmonary syndrome is high in your list of differentials. But could this patient have a PFO? Could this patient have COPD, ILD? So you could potentially do, during the RA catheterization, an ABG on Romare. You could also inject agitated saline and then do an echo and see whether the patient had bubbles on the left chambers of the heart. And we'll see how that can help you in a minute. And then you can also do a shunt study, see what is the percentage of shunt that this patient has. And this is important because the shunt study, the 100% shunt study that we do in the lab, in the PFT lab, is not reliable in this condition because it's not effective in patients with very hard cardiac output, like in this one. Because when you do it in the PFT lab, you're assuming a difference between the arterial and the venous oxygen content of five, which might not be true in patients with liver disease. So during the catheterization, we get ABG, BVG, and then we can calculate precisely the shunt and 100% shunt study. Currently here, people have seen bubbles on the left-sided chambers of the heart as you do this agitated saline, and we're doing more and more in the ICU. So people are very comfortable with that. So the issue is that, hey, when do these bubbles appear? Do these bubbles appear after the fourth beat to call it hepatopulmonary syndrome, or could they appear on the first three beats where you will have a PFO? Some patients have cardiac outputs that are 15 liters per minute, and that massive cardiac output, as soon as you inject bubbles, if you have hepatopulmonary syndrome, rapidly goes up to the left atrium. So we have done this study where we showed that you could see bubbles, even in the first beat or second and third beats, in patients that did not have PFO. And they're all related to hepatopulmonary syndrome. So even when you have it so early, it could potentially be from hepatopulmonary syndrome. How do you differentiate that? One way to do that is during the Raja catheterization, you could inject bubbles, agitated saline from the superior vena cava through the collateral of the introducer, or you could also inject it from the distal port of the swan. As you inject it from the distal port of the swan, you already bypassed the heart. So if you were to see bubbles on the left atrium, those bubbles are coming from the intrapulmonary shunts, and not from the heart. If you want to take it to the highest level of assessment to see whether you have PFO or not, we published this paper where one of our cardiologists, an intracardiac echo. So with an intracardiac echo, you have the echo here positioned on the RA. And now you can perfectly see when you're injecting bubbles from the superior vena cava that there is no bubbles crossing the septum. But you can also see the left atrium, and you start seeing that when you inject bubbles in the distal part of the swan, bubbles coming back to the heart through the pulmonic veins. So that will tell you for sure whether you have PFO versus hepatopulmonary syndrome. So in summary, portopulmonary hypertension is uncommon, associated with high mortality. You screened by echo, and you confirmed by RAHC authorization, and you wanted to exclude or at least understand other conditions that cause an elevated pulmonary pressures, particularly overload and hyperdynamic state. Transplant management is essential, not only to improve quality of life, but to increase the candidacy for liver transplant, and a multidisciplinary team is essential since you need a lot of components, either from a liver team, from surgeons, from anesthesiologists, all to end up taking the patient to a good outcome. And with that, I conclude. Thank you. Good morning, everyone. I'm the last and final speaker for today. I will be basically discussing other pulmonary complications of liver disease. I'm Nishal Brambat. I'm actually one of the faculties here at Queens Medical Center as part of the university group, and I have nothing to disclose. Learning objectives today, briefly identify the other lesser known pulmonary complications of, I apologize, that's liver disease, not pulmonary disease, and then sort of running through the diagnostic criteria and treatment management. We will be running through hepatic hydrothorax, spontaneous bacterial empyema. CF-related liver disease is a huge topic, so it's going to be a very superficial review, and then alpha-1 and trichopsin as well. So starting out with hepatic hydrothorax, this is a condition that affects anywhere from 5% to 15% of individuals with liver disease. It is associated with a higher mortality and is characterized by an accumulation of a pleural effusion of more than 500 mLs in patients who have no other etiology for the effusion. In general, the effusion is right-sided, and this is seen in about 85% of the patients. Left-sided effusion can occur in about 15% of patients. As I mentioned earlier, it is associated with a higher mortality, but patients may also present with encephalopathy and acute kidney injury. The exact pathogenesis of this process is unknown, however, there is some thought process in the literature that says that the negative intrathoracic pressure that's generated during inspiration will promote the passage of fluid from the peritoneal cavity into the pleural space through the defects in the diaphragm. This fluid is generally known to be a transudate, and the management of the fluid is going to be with sodium restriction, diuretic therapy, and an emergent evaluation for transplant as well. Thoracentesis should be considered for symptomatic relief for the patients. I'm not going to go through the details of this, but this is basically the lab pleural fluid findings that you should be looking at for the diagnosis of the hepatohydrothorax. So moving on to the spontaneous bacterial empyema, this also occurs in about 2% of patients with cirrhosis, but generally occurs in about 15% of patients who have a hepatic hydrothorax. The risk factors are including a high child pew score, a lower serum albumin, a lower pleural fluid protein, and a low pleural fluid C3. Patients who have spontaneous bacterial peritonitis are also at higher risk of developing the bacterial empyema, and that goes hand-in-hand with the pathogenesis that we reviewed earlier. Diagnostic criteria, again, in this case you're looking at a serum and pleural albumin gradient of more than 1.1 grams, PMNs of more than 500, and I think this is most important is going to be the absence of other pneumonia or contiguous infection as noted on imaging. So it should be a diagnosis of exclusion. Management for the SBE is going to be including antibiotics for a duration of 7 to 10 days. Some data to show that albumin administration may offer some mortality benefit if administered on day one and day three. Relief of symptoms and control of infection important, ultimately, however, liver transplantation, just a generic theme, liver transplantation. Moving on to alpha-1 antitrypsin, this is, again, I guess it gets rarer and rarer, but general incidence is going to be 1 in 3,000 to 5,000 individuals of European descent. It is a deficiency in genetics. It is passed on into families and can affect the lungs, liver, and skin. The deficiency in the alpha-1 antitrypsin will result in an increased elastase enzyme, which will then subsequently lead to damage and destruction within the lung parenchyma. Most commonly, patients are going to present with a shortness of breath, excessive cough, phlegm production, wheezing with regards to the liver, fatigue, loss of appetite, weight loss, swelling, jaundice, vomiting. And then dermatologic symptoms will include warm, red, painful lumps under the skin. So diagnosis, I think you have to maintain a higher index of suspicion in your patients who develop or come in who are younger, 30s to 40s, who may have a family history or are being diagnosed with COPD without the necessary risk factors of smoking. Same is true for asthma. A pulmonary function test will reveal obstructive physiology, and the CT scan generally will show panacinar emphysema, although you may see some apical emphysema as well. And then the ultrasound of the liver is also needed as part of the diagnosis. Then modalities, smoking cessation is recommended in individuals who are smoking, reduction of alcohol use as well, lung volume reduction surgery. These are all management therapies, but ultimately enzyme replacement therapy and eventual transplantation if the patient needs that. So moving on to CF-related lung disease, again, as I mentioned earlier, this is an extremely broad topic, and we're not going to be able to cover everything today. But basically, as we all know, these are genetic mutations. Newborns will have screening, or if there's an index of suspicion based on family history or symptoms, that should trigger a sweat chloride test based on where your levels are. If it's either above 60, you have a diagnosis of CF. If it's less than 29, you have effectively ruled it out. Where in that range between 30 to 59 results in further genetic analysis, and you sort of work your way down this pathway to further diagnose cystic fibrosis or rule it out. So how does cystic fibrosis result in lung disease? This was a paper that was good review, but basically you've got an abnormal gene that's resulting in impaired mucociliary clearance. You've got recurrent infections resulting in obstruction, then you've got inflammation, and it's basically a vicious cycle that will eventually lead to structural damage, bronchiectasis, and subsequently respiratory failure. In the world of CF, we all know that endobronchial infections are very common. This is a challenge. We've got a few named organisms that are the frequent offenders as listed over here. And treatment modalities will include antibiotics, inhaled antibiotics, CFTR modulators. As far as the management, of course, pulmonary function testing is going to be needed and secretion management with hypertonic saline and oscillatory systems will help support the patient. The severity with these patients as well, depending on where they fall in the severity of their disease, transplantation is going to be important. There are some guidelines as far as which patient and where in their spectrum of disease should be considered for transplant referral. I'm going to basically, you've got the FEV1 less than 40% with more than two exacerbations requiring antibiotics. You've also got the FEV1 of less than 40% and massive hemoptysis requiring an ICU hospitalization or embolization. FEV1 of less than 40% predicted a pneumothorax. I think what's important to highlight over here is going to be their short stature, even though they haven't met sort of the other criteria up top, means you should probably refer them sooner. And that just has to do with availability of organs, I believe. For females with CF, especially those who are younger, again, these are patients you should be referring sooner rather than later. And that's pretty much all I have for you. But again, I think frequent theme in these patients is going to be management until you get them to transplantation, which then improves their mortality as well. And that's it. We're open for questions. Thank you.

pulmonary complications

liver disease

portopulmonary hypertension

hepato-pulmonary syndrome

pathophysiology

diagnosis

management options

liver transplantation