Good afternoon, and welcome back to the second half of our joint SIG program, which is a collaboration between the Portal Hypertension and Pediatric SIGs, entitled Controversies in the Diagnosis and Management of Non-Serotic Portal Hypertension in Children and Adults. In this second session, our moderators are going to be Dr. Nanda Kerkar and Dr. Scott Biggins. I'm Elizabeth Verna, and here's the rest of the schedule for our session. I'm going to be speaking today about non-serotic portal hypertension, monitoring of disease progression and medical management in adults, and here are my disclosures. Non-serotic portal hypertension, as you heard in the first session today, is really a broad group of disorders characterized by elevated portal pressures in the absence of cirrhosis, and it represents a final common pathway of several different forms of diseases, some of which are extremely rare, and these diseases do not all necessarily have the same clinical manifestations and natural history. Non-serotic portal hypertension really remains a major diagnostic challenge, as oftentimes the liver tests are normal, there's variable histology, and there really is a lack of a gold standard diagnosis. In addition, it's important to remember that non-serotic portal hypertension happens in the background of many different types of disease states, and in fact, the disease that has put the patient at risk for non-serotic portal hypertension does have a big impact on the natural history of the disease as well as the outcome of the patient. The diagnosis of idiopathic non-serotic portal hypertension, which as you heard earlier today has many other phrases that have been associated with it, currently requires clinical signs of portal hypertension, including splenomegaly, esophageal varices, ascites, increased HVPG or portovenous claterals on imaging, the exclusion of cirrhosis on liver biopsy, which remains a mainstay of the diagnosis of this disorder, exclusion of other chronic liver disease, including viral hepatitis, non-alcoholic fatty liver disease, and others, exclusion of other specific causes of non-serotic portal hypertension, including congenital hepatic fibrosis, sarcoidosis, and schistosomiasis, and finally, the demonstration of the lack of clot in the portal and hepatic veins. There remains debate about this terminology, and there's new terminology that's been proposed that is an attempt to make this diagnosis a little bit more inclusive of earlier phases of the disease, or perhaps the same histology is observed, but there aren't yet clinical manifestations of portal hypertension. This has been proposed to be termed portal sinusoidal vascular disease, and this is something that continues to be debated. Non-serotic portal hypertension really does have clinical characteristics that are different from patients with cirrhosis and portal hypertension. Generally speaking, it occurs in both children and adults, whereas cirrhosis and portal hypertension is more common in adults. Non-serotic portal hypertension more commonly presents with severe splenomegaly and pancytopenia, while it normally has relatively normal or mildly elevated liver enzymes and pretty preserved synthetic function, which is in stark contrast to cirrhosis with portal hypertension. In addition, as we'll see later in the talk, it oftentimes has either a normal or only slightly elevated HVPG, which does not correlate well with directly measured portal pressures. In addition, it very commonly presents with esophageal varices and esophageal variceal hemorrhage, while ascites and encephalopathy are relatively rare, again, in contrast to patients with cirrhosis and portal hypertension. The natural history of non-serotic portal hypertension is quite variable, and only recently do we have cohorts with relatively larger number of patients followed for a long period of time. But generally speaking, the most common complications, again, are esophageal varices and splenomegaly. The distribution of this varies a little bit geographically based on the underlying diseases in local populations, and again, impaired synthetic function and encephalopathy are quite rare. Overall, the survival is quite good, and it's relatively rare to have a liver-related death related to non-serotic portal hypertension, but in fact, it's oftentimes the associated condition that is the major determinant of overall survival. Among patients with clinical portal hypertension, the 10-year survival is about 50% to 80%, which is generally speaking higher than that of cirrhosis and portal hypertension. However, now that we're observing patients for longer periods of time, it's clear that there is some progression to synthetic dysfunction that we are seeing in patients that have this condition over prolonged periods. So, as I said, varices is really the most common clinical manifestation of this disease. This is a cohort where they had 69 patients with idiopathic portal hypertension and followed them for a median of almost seven years, and among the 50 patients that had not previously had bleeding before enrolling into this study, a pretty large percentage of them had varices on their initial endoscopy, so well over half, and overall, there was a high rate of progression of varices and also esophageal variceal bleeding. In contrast, only about a quarter of patients had ascites any time during the clinical follow-up, and less than 10% had encephalopathy. This is a similar study with 89 patients with idiopathic non-cirrhotic portal hypertension, and they had two control groups, including 64 patients with non-cirrhotic portal vein thrombosis and 77 patients with cirrhosis, and followed these patients prospectively, and again demonstrated that the initial prevalence of varices, variceal bleeding, and ascites was similar between all of the groups, but in follow-up, there was a very significant increased risk of esophageal variceal progression, esophageal variceal bleeding, and also portal vein thrombosis in patients with non-cirrhotic portal hypertension compared to those with cirrhosis. Overall, there was no difference in survival. This is not the only study that has shown this. This is another prospective study out of Japan with 22 patients with idiopathic portal hypertension compared to 70 patients with cirrhosis. These patients had Doppler ultrasounds at least annually for a period of over 10 years and had 41% of patients with idiopathic portal hypertension develop portal vein thrombosis versus 10% with cirrhosis, so pretty stark difference in portal vein thrombosis rates. There is also an increasing number of case reports and case series of patients with non-cirrhotic portal hypertension that require transplant, and this is an interesting series, retrospective series where they found 16 patients who had undergone liver transplantation but did not have cirrhosis on explant, so this was not necessarily patients that had been diagnosed with non-cirrhotic portal hypertension as their indication. They excluded other causes or other liver diseases that would require transplant in the absence of cirrhosis, including acute liver failure, cancer, and other traditional indications, and among the patients left with non-cirrhotic portal hypertension on explant, they found that seven out of these 16 cases had been diagnosed with cryptogenic cirrhosis and two with NAFLD and various other diseases. Nine of the patients had clear risk factors for non-cirrhotic portal hypertension. All of them had clinically apparent portal hypertension at the time of transplant, and very interestingly, two patients had recurrent NRH in the post-transplant period. There are other more rare complications of non-cirrhotic portal hypertension, including case reports and case series of hepatopulmonary syndrome. This is one of the larger series looking at this, where they had 31 patients with non-cirrhotic portal hypertension of varying causes, including portal vein thrombosis and congenital hepatic fibrosis, compared to 46 patients with cirrhosis, and found that when they did contrast echoes and then lung perfusion scans on all of these patients, that approximately 10% of the non-cirrhotic portal hypertension and also approximately 10% of the patients with cirrhosis had evidence of hepatopulmonary syndrome. This is a reminder that just like in patients with cirrhosis, this may be a syndrome that we are under-diagnosing in patients with non-cirrhotic portal hypertension, and it's something we really need to look out for. There really are lots of challenges in terms of the staging and prognosis of non-cirrhotic portal hypertension. We don't have a diagnostic gold standard. There's no accepted staging system that can accurately determine the disease severity or predict clinical outcomes. There's no prognostic markers like we have in cirrhosis, because MELD and child's class and other things that rely on markers of synthetic function really do not correlate well with severity of disease in non-cirrhotic portal hypertension. Non-invasive markers of fibrosis don't correlate with disease severity, and even HVPG is often either not elevated or mildly elevated and does not reflect the degree of portal hypertension seen when the portal pressure is measured directly. Here is one of the first examples where HVPG was actually systematically compared between patients with idiopathic portal hypertension, patients with non-cirrhotic portal vein thrombosis, and patients with cirrhosis. Even though these patients had very similar clinical manifestations of their portal hypertension with similar rates of varices and ascites, you can see here that their mean HVP measurements were quite different. For the patients with idiopathic portal hypertension, the mean HVPG was seven, with only five patients with a level over 10, and actually six patients with an HVPG less than five, despite having clinical manifestations of portal hypertension. This sits in stark comparison to patients with cirrhosis and portal hypertension where their mean HVPG was 17. While there's lots of reasons for this discrepancy, another interesting thing that was demonstrated in this study and other similar studies is that about half of patients with non-cirrhotic portal hypertension have these hepatic vein-to-vein communications that can be seen at the time of HVPG measurement and venography. These can make it either impossible to actually measure the HVPG or certainly could impact the accuracy of HVPG. Other important findings in this study is that HVPG was not associated with ascites, variceal bleeding, or any lab abnormalities in the patients with idiopathic portal hypertension, and it did not correlate well with the small number of patients that had their portal pressures measured directly. In the same cohort, they also looked at ultrasound elastography as a measure of liver stiffness, and they found similar findings. Again, in the patients with idiopathic portal hypertension, the mean liver stiffness was only 8 kilopascals, and about half patients had measurements less than 7.8. Again, this is strikingly different than patients with cirrhosis and portal hypertension where their mean liver stiffness was 17. Other studies have found similar findings. In a series of 30 patients that had NRH that systematically performed FibroScan and FibroTest and compared these both to clinical manifestations and also liver biopsy findings, they found that there was no significant correlation between these two tests among all these patients with NRH. In addition, neither of these tests correlated well with fibrosis levels on liver biopsy, which you can see in this figure, or the clinical presence of esophageal varices, ascites, or splenomegaly. Do we have any determinants really to understand disease progression noninvasively? Probably one thing that can be monitored is splenomegaly, and again, this has to be interpreted in the context of other causes of splenomegaly, including in hematologic disorders. This is one example where 75 patients with noncirrhotic portal hypertension, as well as 21 controls with viral hepatitis, had liver and spleen volumes measured on CT or MRI that were normalized to height and BMI, and you can see here that among the patients with noncirrhotic portal hypertension that the spleen volume correlated pretty well with whether the patient had an HBPG either above 5 or above 10, where in patients with chronic viral hepatitis, there was really no correlation here. In addition, maybe a step that's a little bit easier, even than monitoring serial imaging with volumetrics, is perhaps looking at platelets as a marker of splenic sequestration and portal hypertension, and these are two examples of studies that show that platelet level correlates well with splenomegaly and with disease progression, so this is in 73 patients with congenital hepatic fibrosis, where you can see here that platelet count really correlated very nicely with spleen volume, even sort of at lower levels, and was the strongest correlation of all the blood tests, while albumin really didn't correlate at all with spleen volume, and prothrombin time and glomerular filtration rate didn't correlate as well as platelets. In another study with almost 200 patients with chronic granulomatous disease with noncirrhotic portal hypertension, interestingly, the slope of decline in platelets over time had a big impact on overall patient survival, so this was the patients that died in their follow-up, and this is the patients that survived, where you can see the slopes are markedly different, and when you plot a survival curve, patients with a slope greater than 9,000 units declined per year were significantly different in their overall survival, so platelets may be another marker that can be followed noninvasively, and the slope of platelet decline is even important when the platelets are still in the normal range. So what about esophageal variceal screening? So certainly, as we've seen, there's high rates of variceal formation and bleeding compared to patients with cirrhosis. Unfortunately, there really are no specific guidelines for screening that are specific to patients with noncirrhotic portal hypertension and really take into account their increased rate of varicease formation and bleeding, and generally, it's recommended that we follow the guidelines similar to patients with cirrhosis. I think, though, that you have to have the following caveat, that you really can't rely upon liver stiffness and HVPG and the other measures that we're now sort of thinking about using to exclude clinically significant portal hypertension to guide whether you're going to do serial EGDs for screening and surveillance in this population because, as we've seen, those markers really don't correlate with portal pressures. So all patients should have a screening EGD at the time of their diagnosis. So to summarize, how are we going to monitor patients with noncirrhotic portal hypertension? There's clearly a paucity of data for evidence-based recommendations. However, I would say we have to consider disease-specific risks. We know that traditional measures, including markers of synthetic function, HVPG, and noninvasive fibrosis markers don't reflect portal pressures or disease severity. However, a decline in platelet levels, even when they're in the normal range, may reflect progression of portal hypertension or perhaps increasing splenomegaly seen on serial imaging. Guidance on portal hypertension and esophageal variceal screening and prophylaxis in the setting of cirrhosis should generally be followed. And screening for portal vein thrombosis has also been recommended, including from the most recent Bovino guidance, perhaps using Doppler ultrasound approximately every six months. So what about medical management of noncirrhotic portal hypertension? So unfortunately, disease progression really cannot be prevented with medical management with the therapies that we currently have. And so really, the goals of medical management are to optimize treatment for the underlying disease, whatever that may be, and then also treat and prevent complications of portal hypertension. There has been some debate about the role of anticoagulation in this group, because as we've seen, esophageal variceal bleeding is their most common complication, but they are also at very high risk of portal vein thrombosis. And at this time, there really are no data to support widespread use of prophylactic anticoagulation in these patients, unless there's another reason to be on anticoagulation, including the diagnosis of a prothrombotic disorder. And even for treatment of portal vein thrombosis as in cirrhosis, there's no data that anticoagulation alters the natural history of disease when you take everybody together. But perhaps if you're doing surveillance for portal vein thrombosis and you detect the thrombosis early, it could prevent progression or even improve recanalization rates. And generally speaking, including, as you see here from the last bovino consensus conference, they recommend screening for the development of portal vein thrombosis and also the initiation of anticoagulation in patients who develop portal vein thrombosis, perhaps after screening endoscopy to risk stratify for variceal bleeding. In addition, what about esophageal variceal prophylaxis? So similarly, there's only very small numbers of patients with idiopathic non-sorotic portal hypertension that have been included in trials of primary or secondary esophageal varices prophylaxis approaches. Interestingly, there's one randomized trial that included non-sorotic portal hypertension patients, although overall there were less than 20 patients that didn't have portal vein thrombosis, where they enrolled and randomized them to serial ligation versus beta blockers with a target heart rate and found that there was no difference in rates of bleeding or death or complications. However, there really is, again, insufficient evidence on which therapy is preferred for non-sorotic portal hypertension prophylaxis, and the management really should be in accordance with the guidelines for cirrhosis and esophageal varices. So what about other treatments? You're going to hear in the next few talks about considerations for interventional radiology and surgical approaches, and I would say you have to think about referring to IR or to surgery when they develop complications that would also prompt referrals in the setting of cirrhosis. And this could include refractory complications of portal hypertension, including bleeding or refractory ascites, progressive liver failure with synthetic dysfunction that may lead you to transplant, or perhaps even very extensive and progressive thrombosis. So what are the key takeaways from non-sorotic portal hypertension management in adults? Clearly non-sorotic portal hypertension is the manifestation of a heterogeneous group of diseases. You have to have a high index of suspicion for this disease because we don't have great diagnostic markers, particularly in patients that have manifestations of portal hypertension, but the absence of elevated HVPG, if it's measured, or liver stiffness on non-invasive fibrosis markers. Non-invasive monitoring of the disease progression is really challenging because many of our normal markers non-invasively really don't correlate with portal pressures in this particular group of patients, but platelet counts and also possibly spleen size are the best markers we have now. There are no medical therapies that prevent disease progression, but esophageal variceal treatment and prophylaxis should follow cirrhosis guidelines, and continuing to think about just treating the underlying diseases should be a major focus of the management of these patients. Thank you for your attention, and I hope you enjoy the rest of the session. In this session of Controversies in the Diagnosis and Management of Non-Sorotic Portal Hypertension, I will be focusing on children, clinical features, nomenclature, monitoring, and management. I'm Nanda Kerkar, Director of Pediatric Liver Disease and Liver Transplantation from the University of Rochester, New York. This is my disclosure slide. Portal hypertension is the elevation of portal blood pressure above 5 millimeters of mercury. When the portal pressure gradient is above 10 millimeters of mercury, complications of portal hypertension are seen. Portal hypertension is usually associated with cirrhosis, but as the name implies, in non-sorotic portal hypertension, there's no cirrhosis on histology. In the cartoon on the right, a balloon catheter is seen being introduced through the jugular vein into the vena cava, the heart, and coming out through the hepatic veins. The pressure measurement which is made with the balloon occluded is called the wedged hepatic venous pressure, and with the balloon uninflated is called the free hepatic venous pressure. The hepatic venous pressure gradient is the difference between the wedge pressure and the free hepatic venous pressure. It is customary to do a transjugular liver biopsy at the time of portal pressure measurements. The most common cause of non-sorotic portal hypertension in children is extra hepatic portal vein obstruction or portal vein thrombosis. Often on history, one is told that there's umbilical vein catheterization done in the neck or on investigation sometimes a procoagulant state can be found, but often there is no etiology that can be identified. The thrombosis can sometimes be in the splenic vein and this is called a left-sided portal hypertension. The measurements of wedged hepatic venous pressure, free hepatic venous pressure, and the gradient are all normal in this form of non-sorotic portal hypertension. Cavernous transformation is when the obstructed portal vein is replaced by a spongy trabeculated venous lake with extension into the gastroduodenal ligament. Portal biliopathy is the formation of large collaterals around the bile ducts which actually compress the bile ducts and cause ischemic damage to the bile ducts resulting in cholestasis. Usually this occurs with advanced disease, not so common to see that in children in the United States. Hepatopoietic sclerosis is an entity which is very similar clinically to a portal vein obstruction, so the children will have splenomegaly, hypersplenism, the liver panel is normal, but when Doppler's are done the portal vein is noted to be patent. On angiography you see pruning of the portal veins called a withered tree appearance, and on liver biopsy there's an obliterated venopathy with phlebosclerosis of the small and medium branches and nodular regenerative hyperplasia. This is a liver biopsy from an adolescent with HIV who was on highly active antiretroviral treatment and would come with a big GI bleed. The biopsy shows the asterisk mark where the dilated sinusoids are and then the fibrotic portal tracts. The biopsy also had nodular regenerative hyperplasia which is nodular transformation of the hepatic parenchyma without fibrous tissue between the nodules, and this appears to be kind of related to a heterogeneity in the blood supply, so where there's a lot of blood supply there's hypertrophy and when where there's inadequate blood supply there's atrophy. And this slide shows nodular regenerative hyperplasia, it's a biopsy from the same child. Kirolli disease is the congenital dilatation of the intrahepatic bile ducts. Congenital hepatic fibrosis is the fibrous enlargement of the portal tracts. Congenital hepatic fibrosis is often associated with autosomal recessive polycystic kidney disease, and Kirolli syndrome is the combination of Kirolli disease with congenital hepatic fibrosis. When there's obstruction to the outflow from the liver because of diseases involving the hepatic vein, then there's increase in the wedge pressure, the portal pressure gradient, and the free hepatic venous pressure. The etiologies are listed below. In this part of the talk, the recommendations have been based on what has been published in hepatology, which was a summary of the Boveno 6 Pediatric Satellite Symposium. In terms of clinical features seen in portal vein thrombosis, more than two-thirds of the children present with upper gastrointestinal bleeding. Almost all of them have an enlarged spleen, usually asymptomatic, but if the spleen is really enlarged, then they have abdominal discomfort. Hypersplenism can be seen, and sometimes, rarely, they have acute abdominal pain if they've got splenic infarction. A third may also have an enlarged liver, and about 10% have dilated abdominal veins, a bit like a Kaput Medusae, but not quite. Many have growth failure, impaired quality of life, and sadly, scholastic function is often affected. A third have minimal hepatic encephalopathy, particularly those who have Shands, and orthodexia may occur if hepato-pulmonary syndrome develops. The advice that we give to patients is to avoid contact sports so that their enlarged spleen doesn't get ruptured by direct trauma, and we advise a spleen guard to be put on if they insist on playing games. Pulse oximetry in the upright position will show a dip in the saturations compared to the supine position if one is screening for hepato-pulmonary syndrome. For the laboratory tests, the platelets and white cell counts are usually reduced, but instead of just paying attention to the absolute numbers, looking at the trend is important. Procoagulant screen, if present and diagnosed in the beginning, will allow the patient to be on anticoagulation and perhaps prevent thrombosis of other vessels. Ultrasonography with Doppler's to measure the spleen size, the liver size, development of ascites, flow in the blood vessels, and patency of the Shands, if any, is important. Vibration control, transient elastography, fibroscan is a useful tool at the bedside. Now, it's not validated. There are no validated measurements in non-sorotic portal hypertension. What has been published is that the values are less than what you see in portal hypertension secondary to cirrhosis, but it's more than in the healthy population, and measurements of liver and spleen are performed. Hepato-pulmonary syndrome is the association of liver disease, hypoxemia, and pulmonary vascular dilatation. The patient may be clinically sinused with clubbing, and when pulse oximetry is done in the upright position, the saturations are less than 92%. If an arterial blood gas is done, then the partial pressure of oxygen is less than 70 millimeters of mercury. In terms of diagnosis, bubble echocardiography is the most sensitive test to make a diagnosis of hepato-pulmonary syndrome. In this method, agitated saline is injected intravenously and appears in the left side of the heart because there are these pulmonary arteriovenous shunts. The macroaggregated albumin scan is a method in which quantification of the shunt can be done, and the principle of both the tests is because there's this pulmonary arteriovenous shunting, the space is enlarged, and so the bubbles can pass from the right to the left side, or the macroaggregated albumin as well can pass through the pulmonary shunting and then get into systemic circulation and go into the brain. If a child is diagnosed with hepato-pulmonary syndrome, it's advised that the child be referred to a transplant center, and special points are allocated by UNOS to give extra points for hepato-pulmonary syndrome so that the child can get the transplant faster, and really before the development of the dreaded complication of portal pulmonary hypertension, where the pulmonary artery pressure can go above 25 millimeters mercury. This condition has a high morbidity and mortality, and fortunately is quite rare in children. In terms of interventions in non-sorotic portal hypertension, non-selective beta blockers are not recommended, and this is different from adults, and the reason given is that there's lack of prospective studies, there's lack of case control studies, and the problems to do with the adverse event profile of non-selective beta blockers in small children who may have asthma, who develop wheeze during the RSV season, during you know respiratory tract infections, so the bronchospasm just makes their life more difficult, and also in a small child with a big bleed, if they are unable to increase their heart rate to increase their cardiac output, it can be problematic if they reach medical attention late, so really in small children, strongly advised to avoid beta blockers, and in adolescents you know whose weight is sort of more than 40 kgs who are you know above 14 years, one may elect to follow the adult guidelines, and this seems to happen quite a bit in practice talking to other hepatologists. Endoscopic therapy for primary prophylaxis of varicyl hemorrhage has not been endorsed, and again the primary reason furnished for this is that when they looked at all the studies where primary prophylaxis has been done, and this was for portal hypertension secondary to cirrhosis rather than non-cirrhotic portal hypertension, there was no significant improvement in outcomes, and so really for small children definitely it's not recommended, but in older children, adolescents, again adult guidelines can be followed in terms of primary prophylaxis. What is uniformly recommended is endoscopic varicyl ligation for management of acute esophageal bleeding for secondary prophylaxis, and to be you know started six days after the acute bleeding episode, and to be continued every two to four weeks till the varices are eradicated. When the size of the child is really small, and the banding device cannot be loaded on the scope, then sclerotherapy is recommended, and I think when smaller banding devices become available, then naturally you know that would be the preferred method, but in the meanwhile sclerotherapy continues to be a modality that pediatricians use. TIPS transjugular intrahepatic portosystemic shunt, this is going to be the subject of the next talk, and he will address all the pros and cons throughout. Consensus that mesorex bypass should be used as a primary and secondary prophylaxis in extra hepatic portal venous obstruction in infants and small children, provided this favorable anatomy and surgical expertise. In this diagram you can see the superior mesenteric vein, the splenic vein joining together to form drained blood through the portal vein into the liver, but the, I'm sorry, this thing does jump, my apologies, but given that there is a thrombus, you can see this anastomosis that has been produced using a jugular vein conduit, which is connecting the superior mesenteric vein to the left branch of the portal vein, and this is allowing the blood to bypass the obstruction and go back into the liver, and this is in the rex bypass, rex recess, and this is really the most favored approach in pediatrics and small children, both for primary and secondary prophylaxis. Distal splenorenal shunt is not as physiologic, but it's definitely better than the non-selective shunts. Determination of which shunt should be performed is generally guided by the anatomy, by the local expertise, the site of the non-sorotic portal hypertension. I will stress that the rex bypass is only recommended when there's an obstruction. If there's damage in the liver, if there is hepatoportosclerosis or any other etiology of portal hypertension, rex bypass is not recommended. Dr. Iman, who is doing a talk on the rex bypass later on this session, will go into all of this in much more detail. One thing I would like to mention is that splenectomy is not recommended for the most part for management of portal hypertension unless there's splenic vein thrombosis, repeated splenic infarctions, and sometimes, you know, as an emergency when there's a massive bleed. The key takeaway points from this session are that extrahepatic portal hypertension is the most common cause of non-sorotic portal hypertension in children. Mesorex bypass is recommended for primary prophylaxis in extrahepatic portal venous obstruction. The beta blockers and primary endoscopic varicea ligation are not recommended in management of portal hypertension in children. Please note the caveats that I'd mentioned that in older adolescents, sometimes the adult guidelines are being managed, being followed. Endoscopic varicea ligation is recommended for management of acute variceal bleeding and secondary prophylaxis. Thank you so much for your attention. Hello there. I'm Paolo Ficoli. I'm an interventional radiologist at UCSF. It's my privilege to present this lecture on pediatric tips and what we know in 2020. Let me first start by thanking Dr. Biggins, Dr. Karikar for the invitation to speak at this session. I understand it's a unique session with both adult and pediatric providers, and so I'm very excited. My clinical practice spans both adult and pediatric patients with a focus in portal hypertension, and so hopefully I can provide information that's relevant to all the folks in the audience today. This is my disclosure, and let me just ... There we go. I start with the case. This is a patient I took care of a little bit more than a year ago with non-sorotic portal hypertension and acute uncontrolled variceal hemorrhage. She's successfully underwent a TIPS. In this context, I think there's no controversy over the role of TIPS as acute rescue therapy and really an acceptance of TIPS in this patient population as an inpatient transplant. The question we want to try to address today, at least with the available data, is, is this a viable long-term solution in pediatric patients with portal hypertension? Slightly different context there. Before we dump off into the data that exists at present, we should think about this. If we think about pediatric TIPS, if you look at this largest study of pediatric TIPS experience across three centers in 17 years, we averaged that about one TIPS is placed per year at tertiary pediatric centers. Contrast this with 30 to 50 TIPS placed per year in adult patients at tertiary centers. There's clearly a dearth of data and experience with regard to pediatric TIPS. We have to step lightly and just see what we know and think about what the future is, but with some humility. So the other piece is this idea that TIPS series span many years is critical because TIPS as it was practiced in 1990 is markedly different than as it's practiced in 2020. And so sprinkled throughout this lecture, I'm going to sort of go on some tangents that get into my wheelhouse, which are the technical aspects of TIPS. The first one is thinking about TIPS as a more effective shunt compared with what existed in the 1990s. So in 2004, this EPTFE covered TIPS stent graft was FDA approved, and this covering spans the hepatic parenchymal tract. Why is that important? Well, multiple studies have confirmed that the long term patency of these covered TIPSes is significantly better than those of the prior prostheses that were used, which were bare metal stents. And so with that context, what I've done is taken really the series that are published that include significant numbers of patients who've had this type of TIPS created. So this is really modern TIPS. This one series goes back to 1997. It does have a significant minority of patients who had these type of TIPS created, and you'll see that the data outcomes from that study tend to diverge from the other three studies. And so I'll present that as we go through this. So we'll sort of build through the different important outcomes related to TIPS towards answering the question of, is this a long term viable option in pediatric population? Beginning with the epidemiology, it's a busy slide, but what we can surmise and summarize from this slide is, number one, compared with adult patients, these diagnoses I think are not unfamiliar to pediatric practitioners, but a higher proportion of patients who undergo TIPS have non-sorotic causes of portal hypertension as compared with sorotic causes. And number two, the indication for TIPS in pediatric patients is much more frequently varices in control of variceal hemorrhage, and in fact control of acute variceal hemorrhage compared with adult patients in whom 40% of TIPS, 40 to 50% of TIPS are placed for control of diuretic refractory ascites. Another important point is that historically the presence of portal vein thrombosis or occlusion was considered a contraindication of TIPS. That is really not true in modern practice, and even in pediatric series this is reflected. So let's think first of all about technical success. It's not infrequently said that pediatric patients are smaller. Our tools are the same we use for adults. It stands to reason that we're less frequently successful in creating a TIPS in pediatric patients compared with adult patients. The data don't bear this out, and so all of these series have very high technical success rates that are near the expected technical success rates as set forth in the Society of Interventional Radiology Standards and Practice Guidelines that I've cited here. And with regard to patient size and how does this affect, all of these series skew towards patients who are 10 years and older, but all of them have a minority of patients that are quite young and quite small. So I think technical success can be expected in both small and large pediatric patients. And when we talk about technical success, I want to talk about a couple of really technological advances in the past decade or so that have changed how we think about TIPS. First of all is the incorporation of the use of transplenic access to the portal venous system really has allowed us to treat patients with much, I think, greater success who have complex portal vein occlusion. So this patient's got cavernous transformation of the portal vein. This is an example from an adult patient with cavernous transformation of the portal vein. We're able to track through the thrombosed cord of the prior portal vein into the liver. And with that, we can actually target to create a systemic communication with the portal venous system and deploy a TIPS stent. And impressively, what we've found more often than not is that this thrombosed portal vein undergoes a positive remodeling process, becomes much larger, clot resolves, and we end up with something where we have much greater confidence that this can lead to long-term portal decompression. This has been studied in the pediatric population in this single center study of 44 patients who underwent transplenic access for a variety of interventions, 100% technical success rate of achieving transplenic access, and surprisingly to me, a higher than expected bleeding rate. I can share that our institutional experience, skewing towards adult for sure, we've actually not had yet a patient have bleeding requiring blood transfusion. So I do think that this is solidly in our armamentarium in a way that it was not a decade ago and really allows complex interventions in patients with complex portal vein occlusions or obstructions. The other important addition to our tool chest is intravascular ultrasound. So this is a catheter that can be placed through the femoral jugular vein and used to look into the liver and importantly follow and adjust a needle trajectory into the portal vein. This can allow less passes into the portal vein. My sense of this is that it allows greater operator confidence. It probably doesn't translate into higher technical success rates simply because the technical success rates are already quite high. What it does clearly result in though is less radiation dose during the performance of the tips and less contrast dose. And I would argue that if absolutely necessary, one can actually perform a tips with minimal or no contrast with the use of intravascular ultrasound. So I want to introduce the concept of hemodynamic success. Our audience may or may not be familiar with this, but the idea is that particularly when we're not treating acute varicella hemorrhage, but we're doing prevention or ascites control, what intra-procedural outcome can we monitor and try to achieve to predict long-term clinical success? Now, one of those is qualitative, the change in flow dynamics that one sees with injection of contrast. So this is pre-tips creation after access in the portal vein, filling of esophageal varices and a splenorenal shunt, and those are no longer filling. They're actually flowing in reverse after the creation of the tips due to the creation of a low resistance outflow circuit. More importantly, we can measure a direct portosystemic gradient and use that as an intra-procedural marker for success in this patient reduced by 50% to 7 millimeters of mercury. Now, this has actually been tied to long-term clinical outcomes, specifically esophageal variceal bleeding, where we know that if we achieve a portosystemic gradient less than or equal to 12 millimeters of mercury, it does occur, but very rarely that a patient experiences a re-bleeding event. And so in pediatric patients, all of these series show very high hemodynamic success rates, particularly modern series that more frequently use modern tips technique. There's a caveat to this, which is that's really validated. That hemodynamic success that we're targeting is validated in patients with esophageal varices. And this, and I studied adult patients, showed that in patients who underwent tips for acute variceal hemorrhage and their source of the bleeding was an isolated gastric varicea, the baseline portosystemic gradient was lower compared with patients who had esophageal variceal bleeding. So I just introduced this article as an introduction to the concept of the specific the specific amount of shunting and pressure reduction that we're trying to achieve is really dependent on the context of which a tips is being placed. So let's get to the meat of this first clinical and success, and then hepatic encephalopathy. When we look at clinical success defined in slightly different ways in each of these studies. If we look at the first three studies, they look at this over time, so that's critical. And to summarize these complex data, what I would say is that clinical success, at least up to a time period of two years, is achieved in 75 to 100% of patients with pediatric tips. So it's an effective therapy, but not perfect. Probably this type of data is best represented with time to event plots. And I'll draw your attention to this, which is for secondary prevention, there's this sort of time-dependent decrement in clinical success. In other words, people do experience re-bleeding even with the presence of the tips. And just remember the shape of that plot, as I'll come back to that later. Now, the other key, really the Achilles heel of tips in portosystemic shunting is hepatic encephalopathy. And what these studies seem to show was that the rate of hepatic encephalopathy, particularly, again, this is the outlier study in all of these outcomes. So with modern tips, it seems that the rate of hepatic encephalopathy is lower in pediatric patients as compared with adult patients, 8% to 15%. Whereas in adult patients, we see 15% to 35%. And really the severity of overt hepatic encephalopathy seems to be less in pediatric patients compared with adult patients. That's great news. There's a big asterisk here, right? Is that with subclinical hepatic encephalopathy, how often does that occur and it's not recognized? And more importantly, what are the unknown long-term neuropsychiatric complications that ensue? Now I want to take another technical divergence because it introduced you to what modern tips in the 2015-on era really looks like. First, historically, when one places a tips, you select the shunt diameter, in 90% of cases, 10 millimeters, and the other 10% usually around eight millimeters, and you place the tips. And there had been a question of, if you only balloon dilate that tips to eight millimeters, are you creating a smaller shunt than if you dilated to 10 millimeters? And this nice retrospective study in patients who had had CT after tips showed that passive expansion of tips occurs over time. And so that stem graph that I showed you that was FDA approved in 2004 always achieves its nominal diameter. So we didn't really have much control over the diameter of the tips and the amount of portosystemic shunting. Now this is critical because really what we'd like to achieve is just the right amount of portosystemic shunting, enough to treat the complications of portal hypertension, but not so much to cause either hepatic or other end-organ injury. And so if one could control the diameter of the tips, we would have an outsize effect on the overall amount of portal shunting and really move towards a place, what we call precision tips, where we achieve just the right amount of portosystemic shunting for a given patient. This was, early on, this was achieved by the use of a balloon expandable stent and placing a tips through that. The balloon expandable stent constrains the tips and you can achieve diameter reduction at placement and one-way control where you can, at subsequent interventions, increase the size of the tips as necessary. This technique is probably not relevant anymore. Since 2007, the Viator has been modified to the Viator CX, which is the standard of care for tips placement. This constrains the tips to eight millimeters and it's only dilated, it only goes to nine or 10 millimeters if you expand a larger balloon of nine or 10 millimeters to that. So we now have standard of care, routine control of the diameter of a stent graft. We also have techniques now available to downsize tips and this adult patient was suffering from recurrent overt hepatic encephalopathy. By decreasing the diameter of this tips, I was able to increase the portosystemic gradient and qualitatively increase the filling of the intra-hepatic branches and her recurrent episodes of encephalopathy were controlled. So, we've talked about the critical factors of clinical success in hepatic encephalopathy. Let's talk about patency, which is the other critical question that must be answered if we think of tips as a long-term solution. What I'll show you in the next two slides is that there is a time-dependent decrement in the primary patency of tips. However, there is a long-term ability to maintain the patency of tips, secondary patency with secondary interventions. In this study, even out to eight years, granted a slow number, 100% secondary patency. And if you think about this, we have this time-dependent decrement in primary patency and this time-dependent decrement in clinical success. While not formally analyzed in any of these studies, it stands to reason that these are associated. And what this requires is a paradigm shift. So, if we're thinking about tips as a long-term therapy in pediatric patients, this requires an aggressive surveillance and secondary intervention paradigm to maintain long-term clinical success. The other question with regard to patency that comes up is as children enlarge and their liver gets larger, can we maintain patency? I think anecdotally, and this is not well studied, the answer to that is we are performing surveillance ultrasounds on these patients. So, it's possible to perform secondary interventions to elongate a TIPS to maintain long-term patency. And so, hopefully that addresses that concern. So, these are the data in terms of both who and why patients and pediatric patients undergo TIPS and what the expected outcomes are. If I summarize and synthesize that, what I would say is that TIPS is really, I think, well-established in the pediatric population with high technical and clinical success rates as both an acute rescue therapy and as a bridge therapy in select patients' liver transplant. But I would go further and say it's probably, based on the existing data set, reasonable as an intermediate and long-term treatment for pediatric portal hypertension with the caveats that, number one, this requires aggressive surveillance and maintenance in secondary interventions. And number two is, again, we don't know the long-term neuropsychiatric effects of subclinical hepatic encephalopathy. Of course, that is something that surgical portal systemic shunting potentially suffers from as well. And in my wheelhouse, technically, we're moving into an era of precision TIPS where we will hopefully be fine-tuning the amount of portal systemic shunting patients undergo, really towards the indication for which TIPS is performed. So thank you very much. It's really an honor to lecture at this meeting, and I'll stop there. Good afternoon. I'm John Emon. I'm a professor at Columbia University, and I have experience with liver transplantation and portal systemic shunt surgery. My expertise involves both children and adults, and so I'd like to share my experience with surgical approaches. I want to thank the ASLD for the privilege of the floor and the moderators for their kind consideration. I have no disclosures. The decision to introduce surgery into the mix for portal hypertension is primarily focused on non-serotics and especially children. In any case, patients are expected to have a long transplant-free survival. There are different types of surgical shunts that I will explain to you. There are shunts that restore portal flow to the liver. There are shunts that selectively try to preserve portal flow, and there are shunts that decompress completely and result in the least amount of portal flow and the greatest risk of impact on liver function over time. The restorative shunts, which would bring portal blood back into the liver in the presence of portal obstruction, can only be done when the liver biopsy is normal or the parenchyma is normal. Indications for treatment in portal thrombosis include varices, hypersplenism, which can be a big issue in children, ascites and congestive enteropathy, portal biliopathy, hepatic atrophy, and in children, growth retardation. Humanologic considerations enter into the picture since many people with portal thrombosis in fact have thrombophilias that are either due to chemical disturbances of the coagulation cascade or hematologic or myeloproliferative disorders. Anticoagulation may be indicated in the perioperative period but also in long-term maintenance. And vascular grafts that are anything other than the patient's autologous veins are usually a risk in these patients. So not early regenerative hyperplasia, a disturbance of regeneration that leads to abnormal parenchyma without dysfunctional failure, and also portal hypertension is a frequently encountered challenge that may or may not be associated with portal thrombosis. These patients generally can only be treated with decompressive syndromes. A typical MRI with the venous phase shows this enormous collateralization, a dilated bile duct, which we'll allude to in a bit, and the large collaterals along the lesser curve associated with portal hypertension and varices. This is an illustration of a very typical liver atrophy. This liver is only about 2 3rds the expected size with the expected giant spleen in a typical adult with portal thrombosis. This is a picture, a little hard to interpret, this is the base of the gallbladder, but large venous collaterals that cause biliary obstruction, which has different names, we call it portal biliopathy. Obviously cirrhosis leads to portal hypertension, but is only a suitable indication for surgical shunting in exceptional cases of good liver function, good expected long-term survival, and the inability to manage the patient endoscopically, interventionally, and then shunts come into the picture. Splenic embolization is intriguing alternative to control portal hypertension. We've used it in a variety of settings, and I'll show you a little data later on. This is an example of an MRI of a patient with a splenic artery embolization that reduces portal flow. And in our experience, large splenic artery ligations will reduce the portal flow by a third. Anatomic surgery is appealing because it can be focused, adapted to the disease, and lead to a maximum effort to preserve portal perfusion, which is hard to do with the tips. We'll discuss this a little later in the case presentation. And we use pressure and flow measurement to confirm the extent and severity of portal hypertension and the effect of our shunt. So shunts can be divided grossly into preserving shunts. This is the meso portal, or the REX shunt, which brings fresh portal and spondylic blood, or mesenteric and spondylic blood, into the left portal circulation. And this is a splenorenal shunt, a classic, which the distal part of the circulation is shunted, whereas the portal vein is kept intact. This has mixed results over time, depending on the state of the liver. Diverting shunts would be such as a side-to-side or a central splenorenal shunt, or else a diverting meso cable. We use a variety of structures to replace veins. Ideally, the jugular vein, it's long, it's elastic, and it moves in both length and diameter to adapt to the needs, as well as cryopreserved femoral veins, which don't last very long. Allograft veins from transplant donors and patches or tubes of Gore-Tex and Dacron do not generally stand the test of time, and shunts and tips are better than that. Here's an example of a cryopreserved vein. They look very nice, but their duration is generally a year. Here are some pictures of shunts. This is a classical meso cable shunt. We used to do these before there were tipses back in the 80s and 90s. This is a dissection of the mesenteric vein, the duodenum, the cava, and then the large Dacron shunt, as described by Dropanis back in the 60s. These are venous interpositions, which you can do here, splenic veins interposed to the renal veins using the adrenal vein directly or the adrenal vein as an interposition. The adrenal vein is often dilated in severe portal hypertension. This is another view of a Dacron meso cable shunt. The duodenum's here, the vena cava's not in view. Here's another alternative. This is a Gore-Tex or PTFE, which can be used for shunting, but again, not suitable in most portal thrombosis patients because of thrombophilia. Distal splenorenal shunt, here's an example. This is actually using the adrenal vein, but the end of the splenic vein is dumped into the renal vein. And in theory, anyways, the portal vein is preserved. This most dramatic operation was described by Jean de Ville. It's called the Rex shunt or meso-Rex shunt. And the recesses of Rex is the terminus of the left portal vein. And here's how we do it. First of all, there needs to be a little bit of imaging. This is a carbon, actually a venous return phase that shows the large dilated collateralized mesenteric system. A direct puncture of the portal vein. We actually don't do this anymore. We can usually depend on the MRI, but a direct puncture with carbon dioxide can give you a beautiful portogram. This is the dissection. Here's the round ligament, which is attached to the umbilicus. If you follow the round ligament into the left lobe of the liver, it becomes a vein. Here's the lumen. This is another lumen. The discovery of the Rex remnant is not always possible, but most of the time we find a nice vein. You can see beautiful shimmering vein endothelium here. So this is the outflow. This is where the graft will drain. And then this is the inflow. This is the end of the splenic vein, right where it meets the superior mesenteric vein. And then the portal veins obliterated in here. And so we have a long distance here. This is like six or seven centimeters in this child. And we are able to place a large, beautiful jugular interposition graft. Here's another illustration of it. This is the upper anastomosis into the liver. You can see it comes out from behind the stomach. And it originates here where the splenic veins, the pancreas right there, the splenic vein and the mesenteric vein meet. Here we're below the pancreas. Most of the time we do this operation above the pancreas. Here's another example of an interposition in place. And sometimes we can use a natural vein and just swing it up nearby. This is a giant inferior mesenteric vein. All of these things are confirmed with portal flow measurements, as well as pressure measurements. So we can confirm the flow. A normal flow in the portal vein should be about one cc per gram of liver or a thousand cc's for a thousand gram liver, which is a normal size or a medium sized liver. And so if the portal flow achieved approaches at least half a centimeter per gram of tissue, we're usually going to be fine. This is an example after surgery. This is actually three months later. The liver has regenerated from a thousand grams to 1,600 grams. It's dramatic. Here's another example of a Rex shunt after a period of time. You can see this is the intrahepatic portal vein. This is the Rex shunt coming from the end of the mesenteric vein. This person has actually had her spleen removed. Rick Superina has published the largest series in the States, probably in the world, from Northwestern Children's Hospital in Chicago, and showed comparing Rex shunts, where you restore portal flow to shunts where you divert it, the platelets generally get better. The spleen size usually stays about the same, but the INR gets better when you restore portal flow, whereas it does not get better when you divert it. The ammonia goes down, whereas it goes up when you shunt the patient. Growth is better. So ideally, whenever possible, the portal flow should be restored. This is our own data with 40 preserving and 24 diverting shunts. One thing I wanted to show you, the baseline liver with portal thrombosis is only about 2 3rds the size of an expected liver, either calculated or controls from live donors. And of course the spleens are enlarged. When we do the preserving shunts, we see between a 25 and 40% increase in the liver volume. The spleen doesn't change much, whereas when you do a diverting shunt, the liver stays the same, but the spleens get smaller. The platelets improve more after a preserving shunts, but the INR gets worse after a diverting shunt and the bilirubin goes up frequently after a spleen ligation shunts. We have started to combine splenic artery ligation with the shunt to further decrease and optimize and prevent the portal flow. And you see, this is in live donor surgery. When you, before ligating the splenic artery, the portal flow is about a liter in this patient. It falls to about 700 CCs and the arterial flows improves. This is called the buffer response that's been described by Lout and other liver physiologists showing that the liver auto-regulates its blood flow relative to the artery and the vein. Our experience is that the portal flow modulation reduces portal flow usually by between 10 and 40%. Our effect of spleen reduction is variable, which is why we started adding splenic artery ligation to our shunts. So in summary, surgery has a role in management in liver patients anticipated to have a lung transplant-free survival and is probably the treatment of choice in children with portal thrombosis and normal biopsies. Thrombosis causes atrophy that is restored, as I showed you. Interdisciplinary management helps you select the patients and do the best job. And unfortunately, from a biological point of view, this is clearly in the understudied population. Thank you very much for the privilege of sharing our data. Good afternoon, this is our final presentation of the controversies in diagnosis management of non-sorotic portal hypertension in children and adults. My name is Scott Biggins. I'm from the University of Washington, and I'll be presenting a case highlighting features of monitoring and management in non-sorotic portal hypertension. I have nothing to disclose. Our case is a 16-year-old male with autosomal recessive polycystic kidney disease, or ARPKD, with congenital hepatic fibrosis. He initially presented as a neonate with palpable masses in the flanks. He's now diagnosed with ARPKD bimolecular diagnostics. He lives in rural Arizona, about three hours away from an advanced care hospital. He's doing quite well in school. There's no history of cholangitis or GI bleeding, but his parents are worried about his risk for GI bleeding, particularly given his distance from an advanced care hospital. On physical examination, he's alert, well-developed adolescent male. Vital signs are normal, no hypoxia. His height is 50th percentile. His weight is 50th percentile at 60 kilograms. He's got bilateral dull flanks. His abdomen has no prominent veins. He's in a large spleen, measuring 14 centimeters below the costal margin and firm. He's got an enlarged left lobe of the liver that is otherwise uniform and firm, and a liver span of 12 centimeters. No detectable ascites. His CNS, cardiovascular, and respiratory examinations are unremarkable. Laboratory studies show a CBC remarkable for thrombocytopenia with platelets at 150,000. Liver function tests show a normal bilirubin, direct and total, AST, ALT, normal. GGT, alkaline phosphatase, normal. Total protein, albumin, and INR, also normal. His creatinine is mildly elevated at 1.2 with an EGFR of 60. Otherwise, the CMP is normal. Echocardiogram is unremarkable with a normal right ventricular evaluation and normal RVSP. No evidence of pulmonary hypertension. His triple-phase CT scan is notable for perisoftial varices, enlarged left lobe of the liver, dilated extra-hepatic duct, splenomegaly with a spleen-splan span.

ARPKD

congenital hepatic fibrosis

16-year-old male

neonate

genetic testing

rural area

GI bleeding

thrombocytopenia

splenomegaly

perisplenic varices

portal vein thrombosis