All right, good afternoon, good evening, good morning, wherever you are in the world. My name is Patrick Northup. I am a professor of medicine surgery at NYU Langone Transplant Institute in New York City. And it is my distinct pleasure to introduce you to this webinar. And we have two world-renowned speakers today that are going to help give us insight into this enigmatic problem that we struggle with when we diagnose patients with it or diagnose this disease process in the setting of portal hypertension. So I have a few details to sort out and a few housekeeping issues. So welcome to the webinar. We'll cover the diagnosis and new treatments for this disease described with the newly coined term portosinusoidal vascular disorders. The topics that we will cover today are listed on the website and you can filter through those as you like. Financial disclosures for this program have been reviewed and any relevant conflicts of interest have been mitigated. This is a event that is CME credited. So in order to receive your CME credits, we ask that you complete the evaluation which will include some self-assessment questions. The ASLD will email everyone who's registered for this webinar the link to the evaluation and completion of that will allow you to get your CME credits today. So that is how you go through your credits. We have an hour for this. We'll have two speakers and then at the end of the session, we'll take questions, we'll have a open discussion, whatever is appropriate for it. You can enter your questions into the chat or into the Q&A tab that's built into Zoom as well. So with no further ado, I will introduce our first speaker and I'm gonna pull up his bio because it's long and my German is not so good. But Andrea DeGattarde is a professor and co-head of the Gastroenterology and Hepatology Division at Luzerner Kantonspital in Luzern, Switzerland. He trained in Switzerland and Germany and Barcelona. Whoops, my screen is going wild here. Yes, in Barcelona and has contributed to vascular liver disease and portal hypertension in various forums, including serving as the chair for the Esel Valdig Consortium, the president of the Swiss Association for the Study of the Liver. And he's also co-founder of the Swiss Liver Patient Association and organizes the annual hepatology preceptorship for that organization. So Andrea, thank you for attending and please take it away. Thank you very much, Patrick. Thank you very much to ASLD for this very kind invitation. I'm honored to be here and to be able to share with you some information about PSVD. I'm going to share my screen and I'm just asking you to confirm that you are seeing it. We see it. Okay, great. So my task today is to give an introduction to this entity called portal sinusoidal vascular disorder. To do that, I will start with this kind of circle, giving an overview about the gates patients enter these PSVD diagnosis. They can do that via findings on abdominal imaging with some suggesting features that we are going to see. They can do that because they have some associated conditions. For example, immunology disorders, genetic syndromes or thrombophilic syndromes. They can get attention, medical attention because of some abnormal liver laboratory results. We are going to see them in detail. Or the most frequently, at least up to now, they come to medical attention because they have a problem of portal hypertension. For example, they have a very severe bleeding. And finally, they can access this circle because liver biopsy shows, first of all, no cirrhosis and some suggestive features that call our attention in terms of possible PSVD. The importance of liver biopsy was nicely already described by George, but in 1853, he wrote, it is impossible to explain or to understand the morbid appearances of the liver without referring to its intimate structures. And this is fundamental, but in order to understand PSVD, we have to start from the clinic. And I would like to give you two examples. The first one, first case is a man, 59-year-old, presenting with diffuse abdominal pain. He's slightly overweight. Otherwise, his clinical examination is more or less normal. And you see that the lab data are completely normal except for a slight increase in gamma GT. On the other hand, we have the second case, which is a woman, 23-year-old, presenting with emathemesis and melina. Clinically, she was normal except for splenomegaly and lab data showed, once again, a slight increase in gamma GT and thrombocytopenia. Imaging was revealing in case number one. So the man, portal vein and mesenteric vein thrombosis, and as you can see here and here, liver stiffness measured by fibroscan was normal for the liver and normal for the spleen. We consider values normal below 36 kilopascal. In contrast to the young lady, who had a clear splenomegaly also on these images, and she had an increased portal vein wall thickness here on ultrasound. Her liver stiffness was normal, but spleen stiffness was clearly increased, suggesting the presence of a portal hypertension. And portal hypertension was confirmed by endoscopy. You see on the right side, her endoscopy with a bit of GL viruses, while the 59-year-old man had no signs of portal hypertension. Both received liver biopsy and both had no signs of cirrhosis, either with or without portal hypertension. What was particular in these patients were some particular and unusual signs of dilated sinusoid here, or herniated portal vein. I'm going back to this point. And also here, we see a bit of dilatation of sinusoids. So taken together, these cases, as far as clinical presentation is concerned, presented with one end portal vein thrombosis and on the other end portal hypertension. The lab findings had in common a slight increased gamma GT. Thrombophilia in the patient with portal vein thrombosis was negative, for thrombophilia surge. And the liver panel was negative in the young lady. Imaging was showing thrombosis and a certain atrophy of the peripheral segments of the liver. And in the young woman, increased portal vein wall and splenomegaly. And liver biopsy was showing in both cases, no cirrhosis, some dilated sinusoids and portal herniations. And the situation was, or is quite clear for the young lady who has non-cirrhotic portal hypertension. And this is a syndrome, if you want, with features that are the presence of a sinusoidal or presinusoidal cause of portal hypertension, in which HPPG measurement is normal or has increased and that preserved liver function. And in these patients, portal hypertension is associated with classical complication of portal hypertension, as we see in cirrhotic patients, that is with esophageal or gastric viruses. And they can develop hepatic encephalopathy, bleeding, hypersplenism, or ascites. The difference is that in a non-cirrhotic portal hypertension, the outcome is more favorable than in patients with portal hypertension due to cirrhosis. By definition, and maybe we can discuss about it later on, non-cirrhotic portal hypertension, of course, excludes the presence of cirrhosis, but also the presence of portal vein thrombosis or other causes of liver diseases. And I was mentioning before that this condition can be associated with other big groups of diseases, for example, infections. And this may explain why we see very big differences in the prevalence of the disease, according to where you are in the Western world, in Asia, or in other parts of the world. HIV has been associated with this condition, especially with the use of d-diagnosing. Pro-thrombotic states, in particular, factor V Leiden or other mutations. And immunologic disorders, either as an increase in the direction of autoimmunity, celiac disease, scleroderma, et cetera, or in the direction of immune deficiency. Finally, some medications and toxin has been associated with these syndromes and some rare genetic factors. So based on these different associations with very different disease areas, one of the possible explanation, and of course it is impossible to explain everything in one slide, but it's just to give you a broad idea that there are two central processes, on one hand, inflammation, and on the other hand, immunity. Mediators of inflammation are TNF-alpha, IL-6, IL-1-beta, et cetera. The cells involved in these processes are mainly endothelial cells, neutrophils, and macrophages. And the processes of these are cell adhesion, permeability, apoptosis, and the migration of leukocytes into inflamed tissue. On the other end, important dysregulations of adapted immune cells are known, as well as the presence of autoantibodies. The activation of endothelial cells and of the complement systems belong to the possible mechanisms, as well as an enhanced immune cell chemotaxis and adhesion. And if we translate this observation in the liver, possibly, but this remains an hypothesis, the hepatic endothelial cell activation together with leukocyte recruitment may lead to the formation of local microprombosis, leading to hemodynamic disturbances at the level of the hepatic microvasculature. And this is associated or could be associated with area of hypo and area of hyper circulation, originating then into atrophy, hypertrophy complex, as we can observe, for example, in nodular regenerative hypercreation. So if we stay with the example of the young woman, she has non-steroid portal hypertension, but according to the definition that was valid until some years ago, when we were thinking about PSVD, there are some points that weren't further consideration because more and more the medical community was aware that liver lesions may be presence without portal hypertension. So the question is what happens before the patients with non-steroid portal hypertension develops portal hypertension? It's not a condition that's developed so suddenly. The second point was that other forms of chronic liver disease may be presence if they are clinically not relevant, for example, chronic viral hepatitis or steatotic liver disease. And finally, thrombosis was an exclusion factor, but in reality thrombosis can be a complication of PSVD. So it appeared to be not correct to consider this criteria because they were too stringent to a reality that we were more and more observing. And this led to this scheme where we see the upper part, that in the presence of portal hypertension, the concept of non-steroid idiopathic portal hypertension was completely fine, except maybe for the possible coexistence of other liver diseases and the presence of portal vein thrombosis. However, there was and there still is kind of diagnostic gap. So what happens with patients who do not have portal hypertension? Are they in a pre-portal hypertension stage? What are they developing? And this led us to simply describe a kind of expanded concept in which on one hand patients presented on liver biopsy a series of already known changes, for example, obliterative portal venopathy, NRH, non-steroid portal fibrosis, hepato-portal sclerosis or incomplete septal cirrhosis, and this is in yellow here, together with the presence of portal hypertension. But certain proportion of patients did not have this classical histological changes or and did not have portal hypertension. And for these reasons, we reasoned that something was happening and this process in the liver was happening in the area, in the portal sinusoidal area. And this was the reason why we came up with this purely descriptive concept of portal sinusoidal vascular disease. At the beginning, we are today speaking about disorder, but of course this is a definition in evolution and certainly it's going to change with time in the future. And here we have the definition of PSVD with a criteria. The most important is the exclusion of liver cirrhosis together with one specific sign of portal hypertension and the specific signs are here, viruses, portal hypertensive bleeding or collaterals. And this is a classical view. However, the concept of PSVD also included the possibility of having one single specific histological lesions. And the histological lesions are here, the obliterative portal venopathy, the nodular regenerative hyperplasia or the incomplete septal fibrosis. And these conditions are not necessarily associated with the presence of portal hypertension. And we expanded more by including the possibility of non-specific signs either of portal hypertension or of histology suggesting PSVD. And for portal hypertension, we considered ascites, thrombocytopenia and splenomegaly. And as far as histology is concerned, portal tract abnormalities, architectural disturbances as for example, the irregular distribution of the portal tracts and central veins, a non-zonal sinusoidal dilatation or a mild pericynoidal fibrosis. And these are the examples of these main lesions that are not new. The community of non-cirrhotic portal hypertension has since years recognized these lesions. You see on the left side, the obliterative venopathy with this sclerotic portal tract. You see in the center, a typical picture of a nodular regenerative hyperplasia. And you see on the right side, what we mean with incomplete septal fibrosis. Incomplete septal fibrosis is a controversial term and maybe we can discuss also at the end of the presentation. And then we have some non-specific histological lesions and we don't know exactly what the meaning of this is. For example, here you have the so-called herniated portal vein nicely seen here on the right side. Or we can also have here some anomalies of the periportal vessels with an increase in number of the vessels, where normally there are one or two portal veins. So we have seen that histology is essential, associated diseases are important, but also other results are associated with it or may be associated with the presence of PSVD. Here is the example of liver elastography. These are results from French group where you see on the left side that results of liver elastography in PSVD patients were significantly lower than the results in patients with cirrhosis, either alcohol-associated HCD or steatotic liver disease associated. The authors observed that in this cohort of patients, patients with a liver stiffness measurement of less than 10 kilopascal should be considered for liver biopsy, while patients with more than 20 kilopascal in the liver had a very low probability of PSVD and here biopsy was not recommended. And there is a gray area between 10 and 20 kilopascal where biopsy should be considered. And going on with images, more and more, there are radiological signs that are recognized to be associated with PSVD. For example, an increased ecogenicity around the larger interpathic portal vein branches as here, a process of atrophy or hypotrophy of the peripheral right liver segment seen here, or a significantly lower nodularity in patients with PSVD. And going on with results of blood examinations, we're also suggesting that there might be markers of PSVD. This is a recent work of a multi-centric Italian study where patients who received liver biopsy due to elevated gamma GT were re-analyzed for their diagnosis. And you see here that two-thirds of them presented features of PSVD and key predictors of PSVD were male sex, liver stiffness of less than 10 and gamma GT elevated, but less than 200 units per liter. And there is a quantity of research going on in this area looking for explanations for what we observe in this portosinozoidal area, but that we at least for now do not understand. Here are some examples of genome sequencing, evidencing that they are aware in a family from Lebanon, that there were mutations in molecules involved in mTOR signaling. There have been studies about transcriptome data in patients. Note that the number of patients remain relatively low because it remains at least what we think a rare disease. Stressing the fact that there were profiles of deranged hemostasis or coagulation, vascular homeostasis, lipid metabolism, or oxidative phosphorylation. And moreover, recent data also showed that there is an association between patients with short telomeres and the presence of PSVD, as well as the presence of autoimmune markers, in particular, presence of autoantibodies against anti-endothelial cell antibodies in patients with PSVD. So if we move to the management, this is relatively easy in patients with portal hypertension, because therapeutic options are more or less the same as in patients with cirrhosis, although there is no validation of this, but tips can be used to treat varicial bleeding and complications. And liver transplantation may be also used in this context. And data were recently published, I think, Professor Kamati is going to mention a little bit longer than I, this study. I just underline here that the outcome in these patients is relatively favorable and the presence of severe associated conditions or the presence of ascites at the time of diagnosis were associated with a poor prognosis. Things get complicated when it goes on about the management of patients with PSVD in the absence of portal hypertension, because we don't know what this condition, we don't know what's going on, and we don't know the natural history of these patients. So treatment option can or could aim to prevent the development of portal hypertension. This might be anticoagulation, if we think that microthrombosis play a role. This could be antibiotics or antivirals, if we think that infections are include, are playing a significant role, or other drugs for very rare diseases and shortening of telomeres. So if I come back to the circles that I was presenting in the beginning, abdominal imaging presents some intrapartic portal tract abnormalities, such as an abnormal liver morphology or periportal intensity. Associated conditions are evidenced by autoimmunity, immune deficiency, thrombotic states, infections, mutations, drug exposure, or short telomeres. Abnormal liver laboratory panel tests may be suggesting or associated with PSVD, in particular gamma GT. The presence of clinically significant portal hypertension is well known, and this doesn't need any additional comments. And liver biopsy may include features of obliterative portal venopathy, NREH, or incomplete septal fibrosis. So when should we think about portosinozoidal vascular disorder? While mainly in patients with unexplained liver blood test abnormalities, in particular about isolated gamma GT, although of course this data needs confirmation. Imaging abnormalities concerning the portal vein wall, the presence of thrombosis, or abnormal liver morphology, the presence of prothrombotic conditions, immune disorders, recurrent infections, or a selective drug treatment or genetic conditions, or a typical or no signs of cirrhosis. And if our patient has signs of portal hypertension, liver elastography can help, because if elastography is high, the probability of cirrhosis is very high, and we don't proceed to liver biopsy. However, if liver stiffness is low, then suspicion in this particular context of PSVD is concrete, and we would suggest to go for liver biopsy. And liver biopsy is essential to confirm or not the criteria of PSVD. So my conclusions are that the PSVD circles include imaging, associated conditions, laboratory findings, and symptoms. But most importantly, the diagnosis of PSVD needs liver biopsy to exclude cirrhosis, to look for histological lesions, and to look for signs of portal hypertension. Quite frustrating is the fact that there is currently no causal treatment for PSVD, because we can observe something happening, but we don't understand what are the mechanisms behind. And the natural history and outcome needs for sure further investigation. And this investigation is being realized by the presence of several consortia, and you are all invited to join this consortia if you are interested. And having said that, I'm giving over back to Patrick, and I thank you very much for your attention. All right, thank you, Andre. That was a wonderful overview of this disease process. Now, I did want to mention, I forgot to mention at the outset that this webinar is a product of the Portal Hypertension SIG, Special Interest Group at the AASLD. And anyone who's interested in portal hypertension, whether it's vascular liver disease, or esophageal varices, ascites, the broad spectrum of portal hypertension that we see, you can go to the AASLD's website and sign up for the Portal Hypertension SIG. You can come to our meetings at the liver meeting. You can attend webinars, even single topic conferences. So, get involved if you're interested in portal hypertension. We welcome the diversity of thought in that group. So, thank you again. So, we heard the introduction to this topic, and so elegantly stated, about the last 30 minutes or so. Our next speaker is Dr. Patrick Kamath. He really needs no introduction. In fact, I asked him to send me his short bio, and he just sent me his title. But everyone knows Dr. Kamath. He is professor of medicine at Mayo Rochester Clinic, and has really been involved in many of the landmark issues in hepatology that's developed over the last 25 years, say, maybe more, including development of the MELD score. Patrick has been heavily involved in the Asia-Pacific Liver Society's consensus statement, I guess is the best term, on portosinusoidal vascular disorder, or non-cirrhotic portal hypertension. And he's going to give us some information on some controversies and perhaps some treatments in line for this disorder. So, Patrick, take it away. Thank you so much, Patrick, for that introduction. And Andre, I enjoyed your talk, and really it's a privilege for me to share this podium with you. So, my talk is going to be a little more focused on clinical aspects and really how I deal with these patients and how they present to me. So, I'd like to thank Dominic Valle and Akash Shukla, because I've used one of their slides in this presentation. And in this talk, I'll go over the terminology, how does idiopathic portal hypertension slash PSVD, I'm using these terms synonymously, present, the management, which will be of portal hypertension and the underlying disease, the prognosis, liver transplantation, what are the results, and finally, some take-home messages. So, in terms of terminology, I think what is largely the same disease has been described over the years, initially in 1959. I like Jim Boyer's terminology, which he used in 1967, idiopathic portal hypertension, and that is the term that I still use, which is the term a clinician would use. And so, there are histological terms, and most recently, Dr. Gotthardy's group on PSVD. So, the terminology over the years has been based either on histology called nodular regentive hyperplasia, non-serotic portal fibrosis, obliterative portal venopathy, PSVD, or the clinical presentation, which is idiopathic portal hypertension. And so, over the years, it's been either histology or the clinical presentation that drives terminology. PSVD is a histological term, I prefer the clinical terminology, and that's why I typically use the term idiopathic portal hypertension, and with PSVD being the histological counterpart. Now, there have been a little differences initially in what was described by the Asia Pacific Society on non-serotic portal fibrosis slash idiopathic portal hypertension and PSVD, but if you look very carefully, the changes are not really that much different, okay? So, portal hypertension was important, whereas for PSVD, you can have the diagnosis even without portal hypertension. Previously, blood diseases were not mentioned, and if you had portal vein thrombosis, that would exclude the diagnosis of IPH. Little difference in histology, really, which I think is very minor, and then if you had an additional diagnosis, you could still make a diagnosis of PSVD, but if you had an additional diagnosis, for instance, like PBC, which is what we see most often in our practice, giving rise to this picture, we would exclude that because our thinking has been that it's the other disease which is going to drive the natural history. So, if you have PBC, classic features of PBC, but also seeing changes of focal nodular hyperplasia or nodular regentive hyperplasia in this, it is really still the PBC which is going to drive the long-term picture. So, these have been changes over the years which have been really minor, and I think they've been trivial, and if you look at the most recent iteration from APARCEL, which was published late last year, I would think they are almost identical conditions. So, in terms of terminology, I prefer IPH, since the conditions described are nearly identical. I'm a clinician. I like the clinical diagnosis of IPH. Also, I'm an old-timer, so this was a term coined in 1967. I like to follow that. Like I said, Jim Boyer coined the term. I follow that, and this is the term which APARCEL used, and I think they represent 60% of the world population, so I follow what they say, but PSVD is a term preferred in Europe, but I think the important message here is we still need a better term. PSVD or IPH, the prognosis depends on what the underlying condition is. I think there are stages of this condition, so I think there have to be several subtypes and stages, and I think that is going to be the work in progress, and in terms, this is what I tell my fellows. They say, what do I call it? I say, call it whatever you want. Call it whatever you're comfortable with. To me, it's more important how you manage these patients, and I think essentially the management is identical, irrespective of what you call it. So, what are the presentations in our practice? Ours is a referral practice, so we have a little bias in there, so in my clinic, these patients that I see, either those with portal hypertension with well-preserved liver function. They may come with unexplained splenomegaly and cytopenias. They may come because a liver biopsy carried out for some other reason and elevated liver tests. There were other systemic illness, either hematological, inflammatory, or drug-related showed nodular regentral hyperplasia, one of those other changes, and now we are seeing more and more. We have short telomere syndrome. We have a short telomere clinic, and we see more of these patients. So, we are seeing the association with pulmonary complications, so with common variable immunodeficiency and HIV, they tend to have a lot of hepatopulmonary syndrome, which is hypoxemia. They also have pulmonary hypertension, or they can have pulmonary fibrosis, which we see with the short telomere syndrome. So, they have different presentations. When we think of this, we used to biopsy before. We do more MR elastography here. We are still not completely comfortable with splenic stiffness here, and so this is what we find, but essentially, it is exactly what Andre showed you. He showed you on a FibroScan. For us, an MR elastography, the liver stiffness is less than what we would take to diagnose cirrhosis, which is typically more than 5, and a splenic stiffness over liver stiffness measurement. So, if we take a ratio of greater than 1.23, almost always, this is going to be what we call idiopathic portal hypertension, NCPF or PSVD, whatever you call it, and so nowadays, we are not carrying out a liver biopsy routinely for diagnosis because we remain unconvinced that it is going to change the management. What is the management? Very briefly, these patients present with portal hypertension, and they have an underlying disease. So, the management is of the portal hypertension complications. It is usually bleeding at an earlier stage, and ascites and hepatic encephalopathy are only at a later stage. More aggressive, we have done shunts for bleeding. We have not required a shunt thus far for ascites, so TIPS is reasonable, but we also used to do surgical shunts still very recently, and we are still training a surgeon now to do shunts. So, when do we do shunts? So, I remember we had a patient who is head of a university. He requires brain functioning. I wanted to avoid the TIPS in that patient, so we did a distance splenorenal shunt. They tolerate these shunts very well because the liver function is normal in these patients, and there are patients, especially the younger patients, who have got this huge spleen with very low counts. If they have a bleed, we do not do it purely for hyposplenism, but if they have a bleed, then we might do a splenectomy and a proximal splenorenal shunt. These patients have associated diseases. Now, those have to be treated, and again, no matter what we call it, the management is important. So, specific treatment in short telomere syndrome, we treat them with danosol for the hematological conditions we are following how the liver is doing. There's the paper from the NIH where they treated patients with danosol, but some of them had fibrous scans of the liver before and after treatment and that showed improvement. So danosol probably helps, but we don't use it primarily for the liver disease. Prognosis again depends. So 10-year survival is highly variable. It depends on what you look at. So if they present as idiopathic portal hypertension with a significant associated disease not diagnosed, I've said not diagnosed because some of these patients probably have a condition which is not diagnosed, 80% 10-year survival. So very good. Now this is our own experience. So we looked at patients who had nodular regenerative hyperplasia. So that is one of the specific histological terms for PSVD. If they had an associated systemic disease, then the 10-year survival was 40% and this was typically hematological disease. So the prognosis varies quite a bit. It just depends on what the associated disease is. So to summarize, prognosis depends on complications of portal hypertension, but it also depends on the underlying systemic disease. Liver transplantation, very briefly. This is the European data and this is a slide given to me by Dominic Waller. So liver transplant free survival, similar to generally reported about 75% and with transplant graft survival is pretty good with five-year survival, again about 75%. So they do well. And as I told you that those who have got an underlying systemic disease or had a ascites, those tend to do not as well as the others. Now these are our data. The five-year survival similar to transplant for complications of cirrhosis, and I think this is about 29 patients. The question is, can you get this post-transplant de novo? And yes, you can get it de novo post-transplant. So we find that it comes at two different times. We call it early recurrence, usually within the first four years and invariably related to vascular complications of transplantation, you fix the vascular problem. This tends to get better. So commonly, for instance, hepatic artery thrombosis can be associated with this. We also get late occurrence. So after four years, so these typically don't have at least a gross vascular problem. And I agree with Andrea that these are probably microthrombi, but in our experience thus far, these have been asymptomatic. The big question is, does this recur after transplant? So if you transplant for IPH or PSVD, does this recur post-transplant? And certainly in our experience, when we did the protocol liver biopsies, we did not see the occurrence of IPH if they were transplanted for IPA. So generally, these patients will do well post-transplant. So my take-home messages, so the current terminologies, I think they're suboptimal since they're descriptive and not mechanism-based. We also need a subclassification and association with disease. The presentation is quite variable. So it could be an incidental finding, do liver tests, and then you get a liver biopsy. They may present with really a torrential portal hypertension bleeding, or they might have portal hypertension and pulmonary complications with HIV, CVID, short telomere syndrome. And the three mutations that we see with these are the TURK mutation, TURK, and dendritin mutations. And I think we need a subclassification of diseases rather than lumping of disease into one category, because I think the prognosis is quite different based on what the underlying condition is. And ultimately, again, the take-home message is it really doesn't matter to me what we call it. The management is largely of the portal hypertension and the underlying disease. So thank you. And I think Andrea DeCotardi and I are both ready to take some questions. Yes, we'll allow people to type the questions into the boxes on the Zoom interface. I have a few that came in early. We'll take them in the order that they were asked. The first, perhaps towards Andrea, is, is there a role of EUS in the early diagnosis of PSVD? I guess that applies to the portal vein changes that are seen and that sort of thing. Probably EUS is more sensitive than conventional ultrasound. I don't know, there are no data in this. There is more and more the concept of endoscopic pathology. So via EUS, you can biopsy, you can measure pressure, you can do everything. I think in specialized centers, yes. Otherwise, for the moment, we already have problems in characterizing what we are seeing with conventional methods. So it's possible, but we don't know, actually, what interpretation we should give to the findings we see. Yeah, I think this is still to be determined for sure. Another viewer asked, the previously well-known pathologies of extra hepatic portal vein obstruction and non-cirrhotic portal fibrosis or idiopathic pulmonary hypertension, they are clinically as well as pathologically very different. Is there any benefit, or what is the benefit of using the new terminology to club these together in the same category? Is there diagnostic or even therapeutic benefit? That is some of the point of the last two talks, I guess, but maybe a response to that by Patrick to start with. Follow up on the first question. I was at a meeting in India two weeks ago, and they presented some EUS data on diagnosis. Personally, I think it's too complicated. I agree with Andrea. We've got simple ways of diagnosing it, trying not to complicate things. And it's still investigational, so I would not recommend that in here. So like I said, to answer the second question, is there any point in clubbing it? It's a histological diagnosis. So if you take NCPF, that's a histological diagnosis. If you take PSVD, it's a histological diagnosis. So it's a question of what's going to drive the picture. I think PSVD is a good way to start. And if this is the endpoint of multiple diseases, then we call this a sort of basket disease. And if we find a common abnormality, then we can probably treat a lot of disease. So the terminology is reasonable. It's a starting point. And I can see that the Valdi group is also looking at how patients reach this. And I think once we understand this better, and you can disagree with me, Andrea, but I think once you understand this better, I think we'll change a little bit of the terminology to say what this disease ultimately is. So I think it's a good starting point for investigation. So PSVD to me is looking to the future, following these patients who have just the biopsy findings, but no clinical presentation. Follow them with time, see what happens to them, see how things behave. When we say non-serotic portal fibrosis, portal enthrombosis, that is the clinical presentation, which may be a later stage of the same thing. So that is what we're going to deal with as clinicians. So that PSVD to me is a starting point for investigators. The other diagnosis is where we, as clinicians, where we are seeing them. But maybe you can add something on, Andrea. Difficult to add something I completely agree with. It's, I think that we are advancing on a trial and error basis. You know, we are in a situation where we are observing something that happens in the liver, but we are not understanding, especially in patients without portal hypertension, what is going on. We don't know if what we are observing, if we take as PSVD or another nomenclature, this is secondary to me. But it is important that we find a common basis, a common language in order to collect data and in order to make studies that allow us to at least understand a little bit what's happening. And once we understand, we will be able to design clinical trials and to see whether or not it is necessary. And as you mentioned, already the fact of being able to distinguish which patients are going to remain in stable conditions from the group that is going to evolve into non-cirrhotic hypertension would be of great importance. But we are not so far. So, I think today it is very important that independently from the name we give to this condition is that we collect forces and we study this condition because we are not understanding anything for the moment. Well, well put. There's a question about sinusoidal dilation on biopsy and how specific that is, or if it is, you know, is it diagnostic of PSVD? Either of you want to take that one? So, about 20 years ago, we used to see this sinusoidal dilatation. The report would come as rule out hepatic penis outflow obstruction, and we do this huge work up and find nothing. And so, we collected a group of these patients and we found that they tend to have systemic disease, and I think one of the pathogenesis is inflammatory. And I think there was a hypothesis paper which Dominic Waller had in hepatology for why this possibly occurs. So, I think you can see it as part of systemic disease. We have also followed these patients long term. I think we've got a paper somewhere that really not much happens to them in terms of the liver. It is the underlying condition on which the prognosis depends. So, yes, we see it. Right now, if I see it, I look at the patient well, and I don't do this huge workup that we did before. We even went to the extent of doing venograms. I don't do it now. I stopped maybe 15 years ago. Both of you mentioned treating this portal hypertension part of this syndrome, as you would in someone with cirrhosis. Are there data on beta blockers specifically in this disorder that comes from another viewer? Yeah, if I can take that. Yes. Yes, they are, but they're not very good data. So, there aren't children. Beta blockers have been used in pre-breeding. If you look at the standard, which is a randomized control trial, then the answer is no. We've got observational data. But to me, I really wonder whether we need such a study. You know, there is increased flow. In fact, there's probably more flow in these patients than in cirrhosis. And you use beta blockers. They work. You probably require a huge study to show that. And you're not going to have a control arm with no treatment. So, it's always going to be against ligation or beta blockers. So, it's just accepted. I agree without great data, but it's accepted practice now. Is there another question? Shouldn't TIPS be essentially a cure for this disorder if there's portal hypertension? Andre? It is. I think we are not so far, just because we have more data about the use of beta blockers. But similarly to the case of cirrhosis, where we are more and more generous in the indication of TIPS, I think that's in non-cirrhotic portal hypertension, the trend will follow. And we will be using more and more TIPS, probably not as frequently as beta blockers. But there is certainly, what I personally see, certainly a possibility of TIPS, especially because the function of the liver is much better than in cirrhosis. So, also the complications of TIPS are less relevant. One of the viewers asked about exception points in the US for PSVD, as these patients have nearly normal liver function. How do we transplant these folks with good MELD scores, Patrick? So, I don't think there are exception points. And the major problem they have is bleeding. And so, you don't need a transplant for that. So, TIPS would be fine. So, the ones who need transplants are those who are going to get encephalopathy, refractory ascites, and worsening liver disease. And that's late in there. And as I don't have the actual data, but I think they don't need MELD exception points. The disease itself gives them the points. Towards the late stage, they behave more like sort of child B, child C cirrhosis. That makes sense. I don't know if we have time to open this can of worms, so to speak, Pandora's box. We used to do a lot of HVPG measurements in this disease process. And the results are confusing, in my opinion. When should we consider doing HVPG measurements? And is there a value to that? Or does it change your management from a viewer as well? Good. Maybe we'll give two different perspectives. Andrew, you can go first to the European and I'll tell you what I sort of personally do or do not do. Well, I would not be clear cut to do or not do. But I think for the current management, we don't need HVPG. Maybe in the future. But the point is that the pre-sinozoidal part or component of this disease or disorder is not taken into account with transjugular measurement of the gradient. There might be a possibility by the direct measurements US guided. Maybe yes. But probably we will make it with much easier methodologies. Yeah, I'm exactly the same. I think HVPG is a bit confusing. There's a pre-sinozoidal component in there. So it doesn't reliably reflect. And I was telling you about that EUS presentation that I heard about two weeks ago. And you can see the direct portal pressure on EUS is really much higher. There's a direct portal pressure is probably better here. But again, it's too complicated. It doesn't change what I'm going to do for these patients. Yeah, agreed. I think it's confusing at best. Do you recommend genetic testing in young patients after an extended etiological study with no apparent underlying disease process found? General genetic testing? I assume for short telomere syndrome. Is that the implication? I don't know. Maybe Patrick, you have... Yeah, we do. We have an interest in this hematologist. So we have a short telomere syndrome clinic. I think we probably have about 130 families now with short telomere syndrome. It's around. It's just that we've not suspected it. So whom do we suspect short telomere syndrome in? Exactly as you said, Patrick, young patients with portal abtention, family history of portal abtention, which is not cirrhosis related. The so-called idiopathic, you know, the cirrhosis when we see a young patient. And we look for certain physical signs in these patients. I always ask them, is there premature graying in your family? That's typically a mark of short telomere syndrome. Unexplained cytopenias. You can see changes in the neck and you can see changes in the nails. So looking at the patient, we can also decide that. But I think it is around. You look at the telomere length, you know, telomere shortened with age. To make a diagnosis, the telomere length has to be in less than the one percentile. Below 10, you suspect that. And we do more extensive investigation in those. This is an unfortunate condition. It's autosomal dominant. So the child is born with the length of the telomere that the parent passed on. So if the parent passed on the telomere at a five percentile, that child starts off with five percentile. So at the age of 20 is going to have less than one percentile and then present with the disease. So I think it's important to look for these conditions. It's fascinating. I think there's more to come over the next several years on that disease process. We work with our lung transplant folks quite a bit on them as well. So we have a relatively hard stop at one o'clock p.m. Eastern, and we just told that bell. So I'd like to thank both of our speakers for these great talks. Feel free to email them directly or to me. And I can forward to them if there are specific questions, because I know there are a lot of questions that we didn't get to. But thank you again for attending this. Remember to claim your CME and have a good rest of the day. Thank you very much. Thanks so much. Thank you, Patrick. Thanks, Andrea. Thank you to you. Take care. Bye bye.

portosinusoidal vascular disorders

PSVD

portal hypertension

liver biopsy

obliterative portal venopathy

nodular regenerative hyperplasia

idiopathic portal hypertension

gamma GT levels

TIPS

liver transplantation