Hello, my name is Laura Kulik, and on behalf of my co-moderator, Dr. Sophia Jacob, I would like to welcome everyone to this year's SSLD Hepatology Updates. We have changed the format somewhat, and then we have decided to approach this from a multidisciplinary approach looking at some very challenging cases that we see in hepatology. This will include the use of newer therapies and HCC in the advanced state, including the potential for liver transplantation. We will then move to the approach and management of addictions in patients with chronic liver disease. And lastly, we will conclude with the use of tips, not only for common indications, but some of the more uncommon indications. I would invite you all to type in questions for our presenters, and I hope you enjoy these presentations. Thank you for attending. We will start with HCC as our first presentation. Hello, and thank you all for joining us today for the general hepatology update. I will be presenting today on evolving therapy for hepatocellular carcinoma. I have no financial relationships to disclose. This will be a case-based presentation, and in the context of a specific clinical scenario, I will review the staging systems for hepatocellular carcinoma, along with their limitations. I will then review our current treatment options and some of the recent advances in our therapies, and end with a brief overview of ongoing clinical trials. For our case today, we have a 55-year-old man with a history of hepatitis C-induced cirrhosis, prior decompensated with a variceal hemorrhage, though no episodes of recent bleeding and otherwise no history of ascites or portosystemic encephalopathy. Recent imaging demonstrated multifocal and bilobar HCC, with a total of four tumors ranging in size from 1 to 3 centimeters and a total tumor burden of 9 centimeters. Imaging otherwise demonstrates patent hepatic vasculature, and staging scans show no evidence of metastatic disease. The patient actively works as a carpenter with excellent functional status. I've listed his labs here for your review, and to summarize, the patient has a meld sodium of 12, child class A6, and an ECOG of zero. Prognostication of a disease is critical when planning therapeutic strategies, and while most solid organ tumors are staged using the TNM classification, due to lack of histologic data in the majority of patients diagnosed with HCC, as well as lack of important prognostic factors such as liver function in the staging system, several alternative systems have been proposed. I will not go into detail for each of these systems, but I note that the Barcelona Clinic liver cancer system has been the most widely accepted, as it not only accounts for tumor burden, but also takes into account a patient's performance status, as well as their liver function. It has been validated in a wide variety of patient populations, including European, North American, and Asian populations, and additionally, it assigns treatment based on prognostic subclasses to help aid in the management of these very complex patients. Here is a schematic representation of the BCLC staging system, and in our particular clinical case, where we have a patient with more than three tumors, without evidence of vascular spread or extrahepatic disease, well-preserved liver function, and excellent performance status, he would be classified as intermediate stage, or BCLCB, with a treatment recommendation of chemoembolization. There are several shortcomings and criticisms to the BCLC staging system, in particular for patients that have intermediate or advanced stage disease, and this is due to the wide heterogeneity of this population regarding tumor burden, performance status, degree of vascular evasion, and degree of metastatic spread. These variations really create challenges in understanding the true clinical benefit from our therapeutic interventions, and for this reason, a variety of subclassifications have been proposed dating back to 2012. These subclassification systems have actually shown differences in prognosis of the subgroups, but due to lack of external validation, no single subclassification system is formally recommended. This overall highlights the importance of multidisciplinary discussions, however, when coming up with the best individualized treatment approach for our very complex patients. In regards to HCC treatment, we really think of two categories, which include curative therapies and palliative therapies. Curative approaches include resection, ablation, liver transplant, and more recently proposed stereotactic body radiotherapy. Palliative therapies include local regional or transarterial therapies, systemic therapy, as well as radiation palliative therapy. Resection is curative therapy for patients that are in the very early stage or early stages of the BCLC system. Generally, we think about this treatment for patients that have a singular tumor, irregardless of tumor size, with a limiting factor being the quantity of the future liver remnant, which if too small, can result in postoperative hepatic insufficiency and death. Techniques including preoperative portal vein embolization or radioembolization can be used in patients with an insufficient liver quantity to induce contralateral hypertrophy, and this technique has really expanded the pool of potential resection candidates. Other ideal criteria include lack of clinically significant portal hypertension, which either can be measured invasively or using surrogate markers of platelet count and bilirubin. I note a very excellent five-year survival rate of 70%, but also importantly to note a very high risk of recurrence, and thus ongoing surveillance is essential. For our patient who falls into the BCLC-B category, but more importantly, due to the multifocal and bilobar nature, as well as the evidence of clinically significant portal hypertension, resection would really not be the best treatment approach. HTC really is a treatment field of transformation, and while I will not go into details about all of the studies out there, there have recently been challenges regarding the ideal criteria for resection candidates, and several observational and retrospective studies have demonstrated that patients with multifocal disease, vascular invasion, evidence of clinically significant portal hypertension may have similar survival outcomes, and even in comparative studies with palliative therapies may have overall improved survival. Again, no level one evidence exists to formally recommend expanded criteria for resection, but I think this is an area where we will see changes, especially in high volume and experienced centers. Ablation is another curative therapy in which there is direct tumor injury, either through chemical, thermal, or electrical damage, and this can be done either percutaneously or through surgical approaches. I have shown the four major ablative techniques here, and again, through advancements in these techniques, the safety and efficacy of ablation has significantly increased. Ablation is recommended as well for patients in the very early and early stages of HTC, usually when resection is not an option. Prior randomized trials had suggested resection had better overall survival compared to ablation. However, recent literature has shown that for patients that fall into the very early stage with lesions less than two centimeters in size, outcomes are similar to that of resection, and from a cost-effective analysis, ablation may actually be considered as first-line therapy. Tumor location is extremely important given the potential for surrounding thermal damage. Though I do note with techniques such as irreversible electroporation, which uses a non-thermal energy for tumor destruction, lesions, which now can be considered for ablation, have expanded. Resilience and survival is very similar to that of resection. Going back to our case, really due to the significant tumor burden and multifocality in our patient, ablation alone would not be the treatment recommended. I would briefly like to mention the combined ablation and chemoembolization has been a very hot area of interest, and the theory behind this is that the embolic effect from taste can result in reduction in hepatic artery blood flow and reduce cooling, and this results in improved thermocoagulation from ablation. Additionally, chemoembolization may result in peripheral portal vein damage, and this can expand the area of necrosis. Prior randomized trials demonstrated that combined therapy compared to ablation alone actually resulted in improved survival, especially for lesions greater than three centimeters in size, and in a retrospective trial comparing combined therapy to taste alone, a subset of BCLCB patients had an improved outcome. SBRT is an advancement in the technique of external beam radiation, and this allows for large ablative doses of radiation to be given in a very precise manner, sparing surrounding tissue. Prior studies had shown that SBRT was an effective therapy in patients with unresectable disease, including those with vascular invasion and for the treatment of metastatic disease. However, recent literature has suggested that SBRT has similar outcomes compared to other local regional treatments, and in a recent phase three trial compared to ablation, SBRT had non-inferior results and may actually be beneficial in lesions greater than three centimeters in size. There is also a strong area of interest regarding radiation in combination with immunotherapy, known as the star effect. And the theory is that radiation may actually augment intratumoral cell surface expression of immunogenicity markers, as well as increased tumor antigen release, which together result in the proliferation of tumor-specific T cells and immune-mediated cytotoxicity. Hepatocellular carcinoma is almost exclusively fed by the hepatic artery, whereas normal liver tissue gets its blood supply from the portal vein. These variations in blood supply allow for highly selective embolization of and cytotoxic drug delivery to the tumor while sparing normal surrounding liver tissue. Chemoembolization results in both cytotoxic and ischemic damage, whereas radioembolization is predominantly working by exerting internal radiation damage while having a very minimal embolic effect. This may be why TER is better for the use in patients that have portal vein thrombosis. The first randomized trials dated back to 2002 and showed a clear survival benefit of chemoembolization compared to symptomatic management in patients with unresectable non-metastatic HTC. And thus, for our patient with large tumor burden, this would be the treatment of choice. There are no formal recommendations regarding the choice of local regional therapy to use. However, conventional tastes and dentists, which differ in the suspension or delivery agent of chemotherapy, have shown that in trials, dead tastes may potentially have a more favorable side effect profile with reduced systemic toxicity. And in a phase two randomized trial comparing tastes and TER, TER showed improvement in time to progression with fewer adverse effects, but no change in overall survival. So going back to our case, in an ideal setting, the patient would be treated with local regional therapy, successfully downstaged, and be listed for transplant. However, this patient presented with bilobar and multifocal disease suggestive of intrahepatic metastases, and thus remains very high risk for both progression of disease or recurrence. Additionally, the presence of multiple tumors has repeatedly been associated with increased risk of transplant weightless drop-off. And so for our patient with such an aggressive phenotype at initial presentation, consideration of early systemic therapy must be discussed. Systemic therapy is probably the most exciting treatment field, given marked advancements over the last few years, now with 10 FDA approved therapies for use. The four main classes include tyrosine kinase or multi-kinase inhibitors, which work by altering signal transduction of multiple pathways, including those that play a role in cell growth, differentiation, and cell death. VEGF inhibitors, which alter angiogenesis and modulate the tumor immune microenvironment. And our immune checkpoint inhibitors, which include programmed cell death one and cytotoxic T lymphocyte antigen four ligand inhibitors. Liver tumors really exploit the physiologic mechanism of immune checkpoint inhibition by expressing corresponding ligands in both their tumor and stromal cells. These medications block the interaction of checkpoint proteins with their ligands and prevent the inactivation of T cells, allowing them to have an anti-tumor effect. To briefly review our landmark inBRAVE trial, that was a phase three randomized controlled trial comparing serafinib to the combination of atezolizumab and bevacizumab for first line therapy showed that the latter combination had a significant improvement in overall survival and disease-free survival. This combination therapy is now considered first line in patients that can tolerate the medication. Notable contraindications for the use of bevacizumab include a history of cardiovascular disease thromboembolic disease, uncontrolled hypertension, and recent bleeding events. The American Society of Clinical Oncology recommends an endoscopy within six months of initiating this medication. Additionally, we need to use caution when using this medication in patients with autoimmune disease who are actively on anticoagulation or who have hepatitis B and C co-infection as these patients were excluded from the inBRAVE trial. Given that our new first line systemic therapy includes immunotherapy, we will constantly face a challenge whether it is safe to use this class of medication in patients who we hope to bridge for transplant. Due to the novelty of these agents, there is a lack of data. However, here I present six studies, mostly case reports of patients that underwent PD-1 blockade prior to transplant. I note that all but one patient who received two years of nivolumab with a minimal washout period of eight days did extremely well with no increased risk of rejection in the post-transplant period. And while I will not have time to go into specific details regarding the abundance of current clinical trials, many of which are phase three, I would like to stress the important role of immunotherapy, which is not only being studied for novel combinations of a systemic treatment, but also as both adjuvant and neoadjuvant treatments. Lastly, I note that novel targets, including natural killer cells and the chimeric antigen receptor T cells that will target glycogen three are also in study. So to summarize our case of a 55-year-old man with well-compensated liver, excellent performance status, and multifocal yet non-metastatic HCC, we would recommend local regional treatment as first line therapy. Should he be successfully downstaged and otherwise be considered a candidate, we would recommend liver transplant. Should you have an incomplete response or progression of disease, we would recommend multidisciplinary discussion to decide the use of future local regional treatment or initiation of adjuvant systemic therapy with consideration of risk and benefit in implementing immunotherapy in a young man we would ultimately hope to get to transplant someday. So key takeaways are that the BCLC system provides treatment based on prognostic subclasses, but does have limitations, especially with our intermediate and advanced stage patients. Multidisciplinary discussion is critical, as management of patients really requires an individualized approach and is not always so linear. And lastly, we anticipate changes in treatment, given the abundance of phase three trials that are ongoing. I thank you for your time. Thank you to the program chairs for inviting me to speak today, and also thanks to Dr. Jaffee for that excellent overview of HCC staging and treatment strategies. So as a reminder of our case that Dr. Jaffee went through, this is a 55-year-old patient with hepatitis C cirrhosis with portal hypertension with multifocal liver cancer involving both lobes with a total tumor diameter of nine centimeters and bland segmental portal vein thrombosis. So I wanted to shift gears a little bit from what Dr. Jaffee was discussing and really focus on how we can push the boundaries of liver transplantation for hepatocellular carcinoma. I'll touch on various selection criteria. I'll then move on to updates and downstaging and all comers outcomes. I'll briefly talk about this new idea of perhaps combining systemic therapy with downstaging in certain patients. And then finally, we will touch on portal vein thrombosis with respect to liver cancer and liver transplantation. So several years ago, when there were conversations about liver transplantation for HCC and pushing beyond the Milan criteria, a lot of it was focused on expanded criteria, specifically either using the UCSF criteria or the up to seven criteria. These are both mild expansions of tumor size and number beyond Milan criteria. But with that, we do know that we get a slight decrement in post-transplant survival. That being said, these are not really concepts that we use very much anymore, especially with relation to our patient who has a total tumor burden of nine centimeters. Because for one, in the United States, only patients within Milan criteria can get mild exception. But more importantly, there are many other potential markers or tumor biology that are just as important, probably as tumor size and number, that need to be explored when considering a patient's candidacy for transplant. Now, there's been many different proposed selection criteria, and I've listed about 10 here. Some of them are used in the deceased donor population and some mostly in the live donor population. But the main theme that emerges is that all of them use some form of combination of tumor burden, as well as biomarkers, often alpha-beta protein, but at times other ones such as DCP. And some of them have additional criteria that, for example, PET scan or tumor biopsy. And then each has a resulting expected five-year push and sun overall survival. So we don't have time to go into details on each of these. But I just wanted to highlight a few. For example, the Metro Ticket 2.0 calculator proposed by Mozzaferro and colleagues will give you HCC-specific survival based on the patient's alpha-beta protein, as well as the combination of the number of tumor nodules, some to the size of the largest nodule. So for example, our patient with what I'm assuming is about four lesions, with the largest being three centimeters, that sum would be seven. And their AFP is down here between 10 and 50. And so that would give us an expected five-year HCC-specific survival of about 85%, which most places would be comfortable with. Another way to look at this would be, these are proposed live donor transplant selection criteria that were recently proposed by Bengi and colleagues from Madanthan, India. And they found three different selection criteria that were particularly valuable for predicting recurrence-free survival. Specifically, AFP greater than 100, PET-positive liver tumors, and being beyond UCSF criteria. So again, kind of going with our patient. Our patient is slightly beyond UCSF expanded criteria. So that's an X. But their AFP is less than 100, so that's good. And so for example, if we had a mechanism to move forward with live donor transplant for this patient, we might have the patient undergo a PET scan. And if their tumors in the liver are PET-negative, then they would have only one poor prognostic factor and have an expected very good outcome after transplant. So this is a couple of examples of how we can use biomarkers and other features of tumor biology to consider a patient's candidacy for transplant. Now, with all that being said, in the United States, again, this patient that were been presented is not currently eligible for deceased donor transplant because they can't actually obtain mild exception as they're beyond Milan. And so we've really moved in the US to focusing on downstaging. And downstaging is defined as a reduction in the size of tumor using local regional therapy to meet acceptable criteria for liver transplant. We gauge the tumor response based on the radiographic measurement of the size of all viable tumors, not including the area of necrosis from local regional therapy. And one of the most important parts here is that downstaging really is a selection tool for tumors with more favorable biology that respond to downstaging treatments. And so that patient's more likely to do well after transplant. So in the United States currently, we have the Milan criteria, which remains the gold standard for mild exception. But if patients are beyond that slightly, then they are likely eligible for UNOS or national downstaging criteria. This is a slight expansion of tumor burden with the goal, as I said earlier, to use local regional treatments to get them downstaged to within Milan criteria. So, for example, our patient is somewhat beyond this, but if a patient had a six and a half centimeter tumor, then they would meet downstaging criteria. And if they receive treatments, then they could be downstaging to Milan criteria if that lesion was then under five centimeters. So in practice, what's the data look like? Well, this is our single center UCSF data from several years ago now that shows no significant difference in post-transplant outcomes in patients who are downstaged to within Milan criteria prior to transplant compared to patients who are always within Milan criteria. In a multi-center expansion of these results, we found very good 80% five-year survival in a cohort of over 100 patients who underwent downstaging at three centers in California. And then also in Italy, there was a downstaging randomized control trial where patients initially beyond Milan with partial or complete response based on M-resist were randomly assigned to either transplant or non-transplant therapies. And as you can see here, there's a significantly improved four-year survival in the transplantation group. So all of these studies are really showing us that downstaging is an effective therapy and leads to acceptable potions and outcomes. So this is a summary slide for downstaging criteria where patients would undergo local regional treatments for tumor downstaging with the endpoints being within Milan. That's when the patient can be listed with mild exception after the six month wait period. At any point along this cascade, patients can drop out due to tumor progression or liver related death, for example. Typically, we'll perform additional local regional treatments to maintain tumors within transplant listing criteria, and then pursue transplant with a five year survival, same as the Milan criteria without downstaging. And now, automatic mild exception is granted in the US as national policy. We also have a prospective multi-center, multi-region consortium evaluating downstaging called the Merits LT Consortium. We recently published over 200 HTC patients meeting UNOS downstaging criteria, showing a very high, almost 90% probability of successful downstaging. With no difference in the probability of successful downstaging or transplant between those who first treatment was chemoembolization or taste versus those who received Y90. One important point though is that tumor understaging or patients beyond Milan criteria on X-Plant was actually quite common in over 40%. With the amount of tumor on their last imaging, an important significant predictor of X-Plant understaging. Now as a reminder, our patient has a total tumor diameter of nine centimeters with their multifocal HCC. So this patient actually is beyond UNOS downstaging criteria and would meet what we would call the all comers criteria, which allows for any number of tumors and no extra hepatic disease with a total tumor diameter greater than eight centimeters. So two years ago, we published single center data from UCSF showing quite poor intention to treat survival in this all comers cohort at 21% at five years, which was much worse than the UNOS downstaging group. One interesting thing we did find is that in the all comers, the probability of downstaging was directly related to the patient's initial tumor burden. So for example, in our patient who has approximately four tumors with the largest approximately three centimeters, they would fall into this blue line and have almost a 70% chance of initial successful downstaging. So that's at least one positive sign for our patient, as opposed to if they had much more tumor or larger tumors, then their chance of successful initial downstaging would decrease. We've also looked at this in the UNOS database, comparing patients who are always within Malone criteria, compared to UNOS downstaging patients as well as all comers. And one of the most important things we found is similar to our data from Merit's LT consortium that the rates of understaging or explant beyond Malone are quite high over a third. And in the all comers patients, 40% of them actually had tumor beyond Malone. Also in the all comers patients, we saw pretty high rates of microvascular invasion and macrovascular invasion. So, and in fact, the odds of understaging increased by 10% for each one centimeter increase in total tumor diameter on their last pre-transplant imaging. Now, when we looked at three year survival, we saw no significant difference between the Malone groups and the UNOS downstaging groups. However, we did see that the survival was still fairly good at 71% in the all comers group, but was significantly worse than the other two cohorts. So putting this all together, it does appear that there's likely an upper limit in tumor burden that exists beyond which successful transplant after downstaging becomes an unlikely goal. We see significantly worse rates of downstaging, intention to treat survival, more weightless dropout, and worse push and send survival for the all comers. So one of the questions that comes up often, especially recently with improved systemic therapies, is could adding these therapies in this population be helpful to improve outcomes? So this, we don't have time to go into the details of this plan clinical workflow, but this is something we're planning on doing within the merits LT consortium. Our patients who are in the all comers or maybe select UNOS downstaging patients would undergo treatments to achieve downstaging and then once that happens, we'd actually refer them to GI oncology to initiate systemic therapy. For example, if they're child PUA with no high risk varices, they may get a Tez OBEV. And with the goal to try to maintain them with additional local regional treatments as needed, to try to maintain them within Malone criteria. And we probably would try to stop systemic therapy about 12 weeks before transplant, and as long as they maintain target tumor stage, then they could undergo transplant. So this is one example of how we might be able to combine local regional treatments with systemic therapy. Now, switching gears a little bit, I wanted to note that the patient also had presumed bland segmental portal vein thrombus, and I wanted to take a minute or two to discuss that. So this was a study we did several years ago where we took almost 500 patients listed for transplant with HCC at UCSF. And we wanted to see the effects of portal vein thrombosis here. So we had about 60 patients with portal vein thrombosis and the rest without. And we did a blinded independent review of their contrast enhanced CT or MRI, with the goal of putting patients either into the bland or tumor portal vein thrombus category. What we found is that we found five criteria that appeared to help us to differentiate bland versus tumor portal vein thrombosis, and we call this the AVENA criteria. A is AFP greater than 1,000, V is for venous expansion. The E is for thrombus enhancements, along with neovascularity, and was the tumor contiguous or adjacent, A, with the portal vein thrombus. And we found that if a patient has three of these criteria, this really nicely predicts portal vein tumor thrombus with 100% sensitivity, 94% specificity, an area under the curve of 0.97. We also found that in patients who did have bland portal vein thrombus, they actually had pretty similar intention to treat survival compared to our patients who did not have portal vein thrombosis. Now the other question that comes up is, can we consider liver transplantation? Say this patient actually had portal vein tumor thrombus, can we actually consider liver transplantation? As a subset with segmental portal vein tumor thrombus actually can achieve a five-year potransplant survival of around 50 to 55% with or without local regional treatments. A recent multinational retrospective analysis of transplant after portal vein tumor thrombus showing complete radiographic response to local regional treatments such as Y90 in 30 patients actually showed similar 55 or so percent five-year survival. And found that if the patient's AAP transplants greater than 10, they have a significantly higher risk of HCC recurrence. And then finally, a recent pilot study applied Y90 for lobar or segmental portal vein tumor thrombus in 17 patients. And then listed the patient after complete radiographic response as well as after downstaging to within Milan with an AAP under 100. Only five of these patients are about 30% were able to undergo transplants after a median of two years from their Y90. Unfortunately, three of these five had pretty early tumor recurrence, but two of them were able to achieve long term survival. The overall five year intention to treat survival was 60% in the transplant group versus 0% in those who did not undergo transplant. But actually, 15 of the 17 or 90% failed the super downstaging experiment as either they were not downstaged, they had dropout after transplant listing, or they experienced HCC recurrence after transplant. So in summary, patients with tumor burden exceeding the EUNOS downstaging criteria must be very carefully selected for transplants. We should be considering additional local regional treatments, a minimum observation period before transplant, and perhaps more stringent AAP cutoffs. Perhaps with improved systemic therapies, we may be able to combine this with local regional treatments to improve intention to treat outcomes in such patients. The AVENA criteria can help characterize bland versus tumor portal vein thrombosis. And then finally, even with sustained portal vein tumor thrombus radiographic response after Y90, we still see relatively high risk for post-transplant recurrence, especially if the patient's AAP is elevated. Thank you very much. Hello and welcome. My name is Jessica Millinger and I'm an assistant professor in gastroenterology and hepatology at the University of Michigan, where I do clinical care and research of patients with alcohol-related liver disease. I'll be speaking to you about managing substance use in alcohol, THC, and other medications and drugs in liver disease. I have no relevant disclosures. The management of substance use and alcohol use disorder in liver disease is really becoming an important part of the care of hepatology patients. And this graphic really shows us why. The use of substances in the US is really increasing. And in the last year, as of the 2019 NSDUH data, 139 million people had used alcohol of some type. The next most common was tobacco and third was marijuana. And so what we're seeing is that as a consequence of this use, we're seeing alcohol use disorder really rise along with other substance use disorder. In this data, which is a 10-year survey that occurs about every five years performed by the NIAAA, what we find is that over that 10 years, rates of alcohol use disorder, which is the most severe form of alcohol use misuse, really rose across all demographic groups, but particularly amongst women, it went up by 80%. And in young people here, you can see a really alarming statistic. Nearly one in four young people as of 2013 had reported having an alcohol use disorder in the past year. So this becomes a real issue for us as liver disease doctors, as we see rates of ALD rise and rates of substance use in all of our liver disease patients rise. Marijuana use has also become much more frequent as legalization has really kind of been occurring in a wave across the United States. Marijuana is derived from cannabis sativa and cannabis indica, which are the two most common forms of the cannabis plant found in Central and South America. And two of the major active ingredients in marijuana, of which there are many forms of these two ingredients, are tetrahydrocannabinol, or THC, and cannabidiol, or CBD. THC is a partial agonist of the CB1 receptor, and CB1 and CB2 are the two main cannabinoid receptors in the body occurring throughout the body, but in the liver here, as you can see in the cartoon, really scattered across hepatocytes and multiple other cells in the liver. And as a consequence, the effects of marijuana on liver fibrosis, et cetera, have been somewhat difficult to pin down, with some studies showing that there were beneficial effects, other studies showing that there were negative effects on fibrosis. THC is responsible for the intoxicating effects of marijuana, whereas CBD, which has a very low affinity for CB1 and CB2 receptors, does not really have the same psychoactive properties as THC. So it's felt to be less addictive, though it does have some antioxidant and anti-inflammatory properties. And as a consequence, it's being used more frequently for pain control. I think many of us have seen some of these products likely emerging more and more on the market. But why does this matter? And often it's because ALD is really the number one reason for liver transplant in the United States. We have a wave of alcohol-related liver disease that's coming through our doors, even worse now after the COVID pandemic. But these patients rarely come with just an alcohol use disorder in addition to their liver disease. They're often coming with more than one psychological problem and substance use disorder. And what we can see here is that for patients who have had any alcohol use disorder in their lifetime, they're six and a half fold more likely to have another drug use disorder separate from the alcohol, four and a half fold more likely to have a nicotine use disorder, nearly twice as likely to have a mood disorder. So understanding this and understanding what lies underneath an alcohol use disorder is really critical. So that we understand the implications of maintaining long-term abstinence in our patients and getting them really connected. So why does this matter? It's because other substance use can actually trigger an alcohol relapse. So we know that for ALD patients, a relapse to alcohol use, particularly if you have cirrhosis or acute alcoholic hepatitis, is quite literally deadly. If you drink after you have a diagnosis of cirrhosis or ALKEP, you are much more likely to die of liver-related complications. But if you're using other substances like opioids, other drugs of abuse, cannabis, those also can predict a relapse and predict a return to heavy drinking. And that's what this large study using the combined study data, 1,200 subjects who were in a randomized trial of alcohol use treatment, did not have liver disease but did have alcohol use disorder found. They found that in those who had heavy drinking, that having used opioids, having use of other drugs or cannabis made you more than twice as likely to go back to heavy drinking within three months and to have a faster time to heavy drinking day. So we do care very much about other substances and it's critical that we pay attention to other substances as hepatology providers. Understanding what a use disorder is, a substance use disorder is, is critical. It's not just that someone is using or even how much they're using. It's combined, it's, it's really diagnosed by building up a number of symptoms and you can see mild, moderate to severe is based on the number of symptoms you have. In really four categories, loss of control, severe psychosocial consequences, physiologic dependence, which includes craving, tolerance, and withdrawal, and then loss of function. Being able to diagnose this is gonna, is really critical and requires talking to your patient. Understanding also what types of substance use treatment are out there is really critical, so you can talk intelligently to your patient about the options that they have. This is the list of some, this is not all, but these are some of the most commonly used ones here in the United States. Many patients are aware of residential treatment or inpatient treatments and Alcoholics Anonymous or 12-step groups, but may not be aware that there are a lot of one-on-one counseling techniques, including 12-step facilitation to help them if they're in 12-steps, as well as other mutual aid societies like 12-step, but which don't use that modality. So, things like Smart Recovery, Refuge, or Celebrate Recovery. Also, medications are an important part of substance use treatment, particularly for opioid use disorder, and those can be critical as well. And it's important to know about those things so you can discuss them with your patients. When you're diagnosing alcohol use, you really wanna use the Audit C, which is a three-question, quick, easy test, survey that you can give either electronically or by paper. In this study of transplant patients who'd been transplanted for ALD, a hepatologist who asked found 20% of patients who were drinking, but the addition of the Audit C in a blinded fashion found another 15%, and an addiction specialist found an additional 5%. So just doing the Audit C, we found more alcohol use, and if we find the alcohol use and the substance use, we can intervene. Alcohol biomarkers are critical, and testing for tox screens for your patients, for other drugs as well, using urine drug screening is important, but there's less data on that in the ALD population. Alcohol biomarkers, on the other hand, are recommended, highly tested in liver disease patients, and recommended by both the ASLD and the ESL societies. There are indirect and direct biomarkers, indirect being things like aminotransferases, the mean corpuscular volume, GGT levels. These are not specific to alcohol use. They are not direct metabolites of alcohol use, and they are significantly less sensitive and specific for alcohol use, compared to the direct biomarkers, which are breakdown products of ethanol metabolism themselves. So blood alcohol levels that get alcohol about 12 hours back, urine ethyl glucuronide and ethyl sulfate, which get alcohol use about three to five days back, and then phosphatidyl ethanol, or PETH, which gets alcohol use about two to three weeks back, have emerged as some of the more commonly used and better tested alcohol biomarkers. And in direct comparisons in ALD patients, this study by Anderson Streichert in 2017 showed that the sensitivity and specificity was the best for phosphatidyl ethanol, as well as positive and negative predictive values kind of across the board. Urinary ethyl glucuronide, again, which gets alcohol use about three to five days back, was also highly sensitive with a good positive predictive value and a good negative predictive value. So certainly those have emerged to be some of the more commonly used ones, but they should be used and should be discussed with your patients ahead of their use as well. So a very common model for behavior change is the trans-theoretical model of change, which has patients going from pre-contemplation through contemplation to preparation, action, and then maintenance. And as we think about how to help our patients in substance use, it's important to know where people are in this cycle, because we have different interventions that we can do. So if they're in more of a contemplation phase, this is really where you wanna think about motivational interviewing and getting people through that ambivalence, helping them change, helping them see. Some of the pros of change might be better than the cons, that it might be better for them to stop or reduce their alcohol use or their substances. When they're preparing and starting to take those small steps, we really wanna encourage them, support them. And then when they are ultimately to have changed their behavior, we wanna teach them how to strengthen that commitment and do some relapse prevention planning. Liver disease can be an important motivation for behavior change. So giving patients liver feedback on the severity of their liver disease, as in this study, and then combining that with an audit score. What they found was that those who were in the highest category of liver disease, who had the yellow-red score on their liver checkup, were much more likely to decrease their alcohol use as measured by an audit score than those who didn't. So this can be a really powerful way of combining the work that we do with liver disease and giving patients that liver-related feedback, in addition to some alcohol use feedback right there at the bedside. And that by itself can have an impact. But one of the major problems we have is really getting our patients to engage in substance use treatment. As we talked about before, many times these patients are very complex. They have multiple substance use disorders. They might have mental health conditions underlying those substance use disorders. They may be traumatized, and trauma-informed care often has to be used and should certainly be thought about with these patients. So getting patients to connect with and kind of overcoming their ambivalence, not necessarily maybe about alcohol cessation, but about alcohol treatment engagement, can often be where we really need to put our efforts. And really, it can be tough. Patients have a lot of barriers, from here in the U.S., insurance barriers to logistical barriers, just getting to the appointment, finding a mental health provider, to attitudinal barriers, feeling like they don't need treatment or feeling stigmatized. Rates of treatment are low in this group. And in alcohol-related cirrhosis patients, only about 10 to 15% of patients get alcohol use treatment in the year, six months to a year after their initial diagnosis. So a lot of work needs to be done in this area. But what you can do at the bedside is, in addition to everything we talked about, really know where to find treatment for your patients. And I'm going to show you two websites that I think are critical that you should really have bookmarked in your clinics. And this is the SAMHSA Treatment Locator. This is the website here. When you go to this website, what you'll find is a place where you can put in your zip code, and it will pull up treatment providers, substance use and mental health treatment providers in your area. So here I put in Ann Arbor, and this is kind of what pulled up. And what I often, what I will do for my patients is put in their zip code and maybe print out the list for them to take with them and to call. So a really important, very important tool. The second tool that's good to bookmark is the Alcohol Treatment Navigator through the NIAAA, and this is the website here. This includes the link to the SAMHSA Treatment Locator, but also includes a lot of other information about alcohol use disorder, what kinds of treatments are available, who might need what kind of treatment, how to personalize it, what you should ask, what you should look for in a provider. So a lot of really great information there. I highly suggest people use that. With respect to motivational interviewing, this is a really powerful thing that you can do for your patients. And learning how to do motivational interviewing is not so much about techniques as about practicing the spirit of really being in collaboration with your patient, meeting them where they are, accepting their objectives, accepting them and having compassion for them, and really getting, working on evoking change from within the patient as opposed to what we often do, which is tell people what to do, try to scare them, you know, into changing. And we really want to be moving more towards using motivational interviewing, which has been around for decades and is highly effective to help patients who are ambivalent move towards behavior change. Make sure that we are not getting ahead of them when we're discussing change. So patients that can slow their commitment, we should really be listening, inviting people to inform us of their doubts and their concerns, maybe the reasons why they're not sure they're ready to adhere to the recommendations that we're discussing. And then definitely we want to be conveying optimism and focusing on their strengths, their successes, you know, conveying optimism that they can succeed, and remembering that change is not linear and it can really happen at any time. And I've certainly seen this in my clinic as well. The final thing I would suggest is that you familiarize yourself with the 12 steps. Many of our patients are in 12 steps in Alcoholics Anonymous or other substance use 12 step based groups. And it can be very helpful if they have someone in their medical team that knows the lingo and knows how to talk about that with them. So maybe consider attending an open 12 step meeting, an open AA meeting. Know where to find the meetings. So aa.org is the Alcoholics Anonymous website, and that could be helpful to find intergroups. There are a lot of virtual meetings going on right now for patients who maybe can't leave the home or don't want to. Maybe read the big book. Familiarize yourself with the approach. The big book is the text, the classic text of AA. And know the role of the sponsor as well and what that person does for the patient in 12 step. So finally, just to summarize, the epidemiology of substance use is changing in the U.S. and in liver disease patients, but screening for and detecting substance use and alcohol use is key. Helping your patients connect with treatment is very key, and motivational interviewing is useful and a vital tool for our ambivalent patients to help connect them to the treatment that they need to really save their life. Thank you. My name is Brian Lee, and I'm a transplant hepatologist at University of Southern California. My research is specifically focused on how to improve health for patients with alcohol associated liver disease. I have no disclosures, and we'll start by discussing pharmacotherapy for alcohol use disorder, AUD, and alcohol associated liver disease, ALD. When we discuss pharmacotherapy for AUD, we typically think about FDA and non-FDA approved medications. FDA approved medications include acamprosate, naltrexone, and disulfiram. Non-FDA approved medications include gabapentin, baclofen, and topramerane. Highlighted in red are acamprosate, naltrexone, and gabapentin, which are preferred agents in ALD, the reasons for which we'll discuss. Topramate is not commonly used in ALD and will not be discussed. In general, the national landscape of AUD pharmacotherapy, specifically in ALD, is understudied. There was a recent VA study, which does provide some insight, which assessed over 35,000 patients with cirrhosis and an index diagnosis of alcohol use disorder from 2011 to 2015. They found that only 1.7% received FDA approved pharmacotherapy for AUD. Patients receiving pharmacotherapy had lower MELD and comorbidities, suggesting provider concern regarding potential adverse effects in sicker patients. The rate of death and of hepatic decompensation was significantly lower with those receiving pharmacotherapy versus no AUD treatment. The study concluded that pharmacotherapy for alcohol use disorder may improve survival for patients with ALD, but is rarely prescribed. Medical professionals have found to have limited knowledge of a pharmacotherapy for AUD, so we'll go through each of these agents one by one. We'll start with acamprosate. Acamprosate is a GABA agonist, which blocks protracted withdrawal symptoms and promotes abstinence. The dose is 666 milligrams orally, three times per day. There's a dose reduction with kidney disease. Randomized clinical trials show more efficacy on maintaining abstinence rather than a reduction of heavy drinking base. Acamprosate is a glutamate receptor antagonist, so theoretically it could increase risk of encephalopathy, but a small study of 12 patients with cirrhosis found no increase in subclinical encephalopathy. There's no hepatic metabolism and is well tolerated, and for these reasons, it's often thought to have the best safety profile among all pharmacotherapies for patients with ALD. Acamprosate is best used in patients with ALD who have already achieved sobriety, to maintain sobriety. Naltrexone is an opioid antagonist, which reduces alcohol-associated euphoria and reinforcing effects, and that's working on the reward pathway, which is in contrast to pharmacotherapies that modulate the GABA pathway. The dose is 50 milligrams orally per day. A longer-acting injection does exist, but is not commonly used in ALD. Randomized controlled trials show more efficacy with reducing heavy drinking and cravings rather than the strict abstinence, which is in contrast to acamprosate. Naltrexone has an added benefit in ALD in that it concomitantly provides relief for cholestatic pruritus. Naltrexone interacts with opioid agonists, so can't be used in patients prescribed opioids for chronic pain. About 1% of patients will develop elevated liver function tests at three times upper limit of normal, but this typically resolves even with continuation of the drug. However, there is an FDA-approved FDA black box warning for fatal hepatotoxicity, which is very rare, but has been reported. Naltrexone is thought to be best used in patients with ALD who are still drinking. Disulfiram is the next FDA-approved medication. It acts as an alcohol deterrent. Disulfiram inhibits acetaldehyde dehydrogenase in the metabolism pathway of ethanol as outlined in the figure on the right. The accumulation of acetaldehyde causes an acute sensitivity within five minutes of alcohol ingestion. These unpleasant effects deter the patient from consuming alcohol. Acute liver injury occurs at a rate of 1 per 10,000 treatment years, which is considered common in relative terms. With well-described reports of fatal hepatotoxicity, disulfiram is not recommended for our patients with ALD. So those were the FDA-approved medications. We'll now move on to non-FDA-approved medications. Gabapentin has emerged as a promising agent to treat alcohol use disorder and ALD. Gabapentin binds to the brain calcium channel in alpha-2 delta-1 site. This site is upregulated in chronic alcohol use and modulates GABA pathways. Gabapentin is theorized to treat AUD by blocking protracted withdrawal symptoms from alcohol abstinence and preventing relapse. The targeted dose in clinical trials is 1,200 milligrams daily, so it started at 100 milligrams three times per day and titrated up to a maximum of 400 milligrams three times per day. Gabapentin is randomly excreted, so dose reduction may be necessary with kidney disease. A recent randomized clinical trial published in JAMA Internal Medicine included 90 patients with AUD reporting current or prior alcohol withdrawal symptoms and randomized them to Gabapentin versus placebo. We found that in this population, specifically selected as patients that might benefit the most given Gabapentin's theorized mechanism of action in blocking withdrawal symptoms, there was significant benefit in terms of no heavy drinking days and total abstinence. Gabapentin has no hepatic metabolism, so Gabapentin, although not FDA-approved, is used in clinical trials for AUD and is safe in ALD, potentially best in patients with current or past withdrawal symptoms. A special note is that Gabapentin does potentiate opioid effects, so it does have some abuse potential and was recently classified as a Schedule V drug. Baclofen is another agent used off-label to treat AUD and is a GABA-B receptor agonist. The dose is 10 milligrams orally three times per day, and dose reduction is needed with renal disease. This is the only medication that was assessed in randomized controlled trial, specifically in cirrhosis, from Italy published in The Lancet in 2007, involving 42 patients with cirrhosis, which showed a higher proportion achieving and maintaining abstinence with Baclofen versus placebo. However, more recent larger U.S. studies and meta-analyses show no efficacy in abstinent days or heavy drinking. Additionally, there is concern regarding potential higher risk of encephalopathy from Baclofen due to some dependence on hepatometabolism. So, while Baclofen is endorsed in the current ASLD guidelines due to the early positive data, more recent negative data and potential risks limit Baclofen's use in ALD. Key takeaways are that AUD pharmacotherapy studies, specifically among patients with severe liver disease, are lacking and represent an area of high research need. Pharmacotherapy for alcohol use disorder in ALD can be feasible, safe, and appears to improve clinically important outcomes, especially in combination with behavioral therapy. The use of pharmacotherapy for alcohol use disorder in patients with ALD is endorsed by ASLD clinical guidelines. While multidisciplinary care with addiction specialists is desirable, this may not be feasible for all patients with ALD for a variety of reasons, and hepatologists should learn to prescribe pharmacotherapy for AUD. Campylase, particularly in those who are already sober, naltrexone, particularly in those who are still drinking, and gabapentin, particularly in those that pass our current withdrawal symptoms, are the preferred agents in our patient population and should be considered after discussion of risks and benefits with patients. So, we'll now move on to substance use policies and liver transplantation. The United Network for Organ Sharing, UNOS, and national organizations like ASLD provide general recommendations, but in the end, transplant centers have autonomy and flexibility to determine their own selection policies related to substance use. Not surprisingly, there's significant variability in selection policies related to substance use. In a national survey that was administered in 2013, 41 percent of centers required statements of abstinence to be eligible for transplant. Fifty-five percent of centers excluded patients with methadone use. Seventy-two percent of centers excluded patients with recreational marijuana use. Since that survey, attitudes regarding recent substance use and transplant have changed dramatically in recognition that with careful patient selection and management of substance use, excellent peri- and post-transplant outcomes can be achieved. Policies related to alcohol have seen some of the most changes. Many patients with ALD were not eligible for transplants due to the six-month rule, which was an arbitrary suggestion in 1983 provided at an NIH consensus meeting, where a patient with ALD is required to have six months of abstinence from alcohol to be eligible for transplant. Since then, there have been a number of studies which show that six-month rule is an unreliable predictor of post-transplant relapse. In parallel, studies have shown that medical recovery after referral for early transplant, meaning without a mandated period of abstinence for ALD, is rare. And for alcohol-associated hepatitis specifically, prognostic models predict short-term outcomes with high accuracy, especially the male-male joint model. There are now data to inform early transplant policies. The original ACCELERATE study was a multi-center study published in 2018, which included 12 centers and 147 patients who underwent early transplant for ALDCAP, meaning no required period of sobriety for transplant eligibility. The median period of abstinence pre-transplant was 55 days. It needs to be emphasized that these patients were very carefully selected. They had no prior diagnosis of chronic liver disease or prior diagnosis of ALDCAP. They all also underwent rigorous evaluations by transplant social workers and addiction specialists. Regardless of the short duration of sobriety, the expectation remains of a commitment to lifelong abstinence after transplant. One-year survival is 94 percent and five-year survival is 83 percent, which compares to the predicted six-month survival without transplant at less than 20 percent. Rates of alcohol use were similar to historic U.S. transplant cohorts in alcoholic cirrhosis. Sustained alcohol use after transplant was the strongest predictor of death. The main conclusion was that early transplant for severe ALDCAP is feasible and can be life-saving. As a result of data showing several transplant outcomes in carefully selected patients with recent alcohol use, there's been a considerable shift in guidelines related to alcohol policies and transplant, including ACG, ASLD, and ASLD clinical guidelines recently endorsing early transplantation in carefully selected patients with ALD. When should you refer a patient with ALD for early transplant? If a patient meets clinical criteria, which I define as allele score above 0.45 with severe ALDCAP or meld above 25 with decompensated ALD and without other serious comorbidities, and they meet psychosocial criteria, which I define as decompensation of liver disease the first time, meaning no alcohol use after a diagnosis of ALDCAP and or cirrhosis, strong commitment to lifelong abstinence, and strong social support, then these are the patients that should be referred early for transplant. They should be referred as early as possible as the survival benefit of early transplant is lost quickly with delays. We'll now move on from alcohol to other substances. In regards to marijuana, the most recent ASLD guidelines state that while some programs exclude patients with active marijuana use from transplant, this remains controversial. Potential risks of marijuana in the transplant population include data, although inconsistent and conflicting, whether marijuana increases liver fibrosis among hep C, unsterilized cannabis has resulted in lung infections, and cannabis can cause increased hypothalamus levels as a CYP3AA inhibitor. Despite these potential risks, there's been many developments to support liberalizing marijuana policies. First, there's been strong societal legislative shift in recent years. Marijuana is now decriminalized in 32 states across the United States. Some states, including California, have made it illegal to deny organ transplant due to medical marijuana use. Second, recent observational large single-center data show no differences in weightless mortality or post-transplant mortality among marijuana versus non-users. Thus, transplant centers are likely to face increasing pressure to liberalize marijuana policies given recent societal legislative shifts and emerging data showing good clinical outcomes despite active marijuana use. In terms of clinical tobacco, the ASLD guidelines state that there are compelling reasons to prohibit all tobacco use in transplant candidates. Cigarette smoking carries several negative effects in the transplant population, increasing risk of cardiovascular events, hepatic artery thrombosis, post-transplant malignancy, infection and mortality. In the 2015 national survey, 38% of transplant centers excluded active smokers. In a 2010 to 2017 study at the University of Michigan, they implemented a policy prohibiting all tobacco for transplant listing. This prohibited policy resulted in more denials of smokers, increased the time to listing for smokers presumably because they needed time to become abstinent, but did not impact the total proportion of smokers listed for transplant. So, in summary, tobacco cessation should be strongly encouraged in all transplant candidates and recipients, but how to implement policies that achieve that goal successfully is unclear. We'll now move on to methadone and prescribed opioids. Many with end-stage liver disease have a history of illicit opioid use. Methadone maintenance is a treatment to prevent relapse to illicit opioid use. It's a form of opioid substitution therapy. The ASLD practice guidelines state that methadone-maintained patients should not be denied transplant based on methadone use alone, and expectations of methadone reduction or discontinuation should not be a requirement for transplant listing. Studies show that methadone-maintained patients may require more intraoperative anesthesia and post-operative analgesia, but they may also require an increase in methadone dose post-transplant. Non-methadone opioid use for pain has risen significantly since these practice guidelines were published, and there's now a high prevalence of opioid prescription among patients with cirrhosis, estimated to be around 24 to 54 percent. There's a dose-dependent association of weightless opioid use with poor post-transplant outcomes, including graft failure and death in observational studies, but conclusions and implications for clinical practice are limited by potential confounding. Despite this widespread use and potential implications for graft and patient outcomes, national guidance for chronic non-methadone opioid use and transplant practice is lacking. So, key takeaways for substance use policies in transplant are, first, recent alcohol, tobacco, marijuana, and methadone are not absolute contraindications to transplant, and excellent post-transplant outcomes can be achieved with careful selection. There are gaps in guidance regarding chronic prescribed opioids. This is generally not a contraindication, but is associated with worse outcomes, so more data are needed. There's a gap in guidance regarding recent illicit drug use, and this is generally a contraindication at most transplant centers. All patients should be encouraged to remain absent from alcohol and tobacco, and to enter therapy and counseling if relapse occurs, but policies to achieve this are variable and may not exist at many transplant centers. More transparency and alignment regarding substance use policies across centers may help to reduce disparities in access to transplant and transplant outcomes. So, thank you for your attention. Hello and welcome. I'm Paolo Piccoli. I'm an interventional radiologist at UCSF. I'm Justin Boyki. I'm a hepatologist at Northwestern University. And as a team, we'll pass with covering the topic of TIPS, expanding indications in cirrhosis management. And thank you to Dr. Tkulik and the organizers of the LIVER meeting for inviting us for this lecture. Next slide. These are our disclosures. And I think for this audience of hepatologists, of course, the underlying pathophysiology of portal hypertension and cirrhotics is a basic, but what's critical is to think about the concept of the pressure gradient between the portal venous system and the systemic venous system as the driver of these complications of portal hypertension. And then to understand that the purpose of creating a TIPS is simply While we won't get too technical in this lecture, some of the cases really focus on advances in technique in TIPS over the past decade or so. And so, it probably makes sense to do just a little bit of TIPS 101. How is a TIPS created? Well, we want to connect the systemic venous system to the portal venous system. And so, we access the internal jugular vein, navigate to the portal venous system, and then we connect the systemic venous system to the portal venous system. And so, we access the internal jugular vein, navigate to the hepatic vein, and advance the needle from the systemic venous system, the hepatic vein, into the portal vein. After using our catheters and guide wires to stabilize that access, we deploy, let's call it a neovessel, a TIPS stent graft, spanning the hepatic parenchymal tract and thereby decompressing the pressure in the portal venous system. Now, the other point I want to make and becomes relevant as we think about TIPS and outcomes is we're trying to achieve clinical outcomes that, in the case of acute variceal bleeding, might be immediate, but often are intermediate or long-term outcomes. And yet, we have only certain indicators of immediate outcomes during the procedure. What are those? One are subjective flow dynamics. In the image on the left, prior to TIPS creation, there is retrograde flow through the IMV in the coronary vein, filling varices near the vestibular of the stomach. And on the right, the flow in those vessels is now antigrade for the TIPS. And quantitative, we can take the pressure gradient between the systemic venous system and the portal system and 14 millimeters mercury prior to TIPS creation and reduce down to 7 millimeters mercury following TIPS creation. For today's talk, we're going to talk about the use of TIPS in a contemporary setting. It's going to be case-based discussion. We'll briefly review some of the traditional indications as well as an update to one of the approaches, particularly in the management of ascites, as well as we'll discuss some of the emerging uses of TIPS, both in portal vein thrombosis and reconstruction, as well as the utilization of TIPS, potentially before abdominal surgery. So it's important to recognize that the traditional indications for TIPS, again, have been variceal bleeding, or for the management of refractory ascites or hepatohydrothorax. Just briefly, TIPS for variceal bleeding, of course, covers the entire gamut of variceal bleeding, whether it's a rescue TIPS for variceal bleeding that's failed endoscopic band ligation, salvage TIPS for uncontrolled bleeding, or even earlier preemptive TIPS in patients who have a significantly high risk of re-bleeding after their first index bleed, as well as for the management of bleeding gastric varices. In the interest of today's talk, though, we're going to discuss the TIPS for the use of management of ascites and some updates in the utilization of new stent technology, as well as management of patients. And what I want to highlight here is that our ASLD guidance, unfortunately, is a little bit outdated in that it just recommends the utilization of TIPS for refractory ascites or ascites refractory to diuretics. The European guidance is a little bit more updated in the sense that it recommends the use of a small caliber stent. But again, this was evolving guidance in the setting of also evolving TIPS stent technology, which we'll discuss here in a few moments. More recently, Palavan and I, as well as 30 other participants, spanning the gambit of interdisciplinary approaches of all the patients or of all the providers who care for patients with cirrhosis, we underwent a consensus conference to create a guidance statements in the utilization of TIPS. And this is a fairly extensive iterative process utilizing existing literature, as well as expert opinion. And as a result of this guidance and recent publication, we put forth recommendations for indications of TIPS, as well as procedural considerations, as well as care for after TIPS, some novel indications for the utilization of TIPS, and as well as management of complications after TIPS. So just to highlight, particularly as it relates to TIPS for the use of ascites, we got a little bit more granular in our guidance and our recommendations, particularly to consider TIPS for ascites in patients who have or require more than three large volume paracentesis within a one-year time period, despite adequate diuretics. We recommend the use of controlled expansion TIPS, which we'll discuss here shortly, particularly to start with the initial diameter of eight millimeters. We also recommend to reassess patients within four to six weeks after placement of the small caliber TIPS. To really then consider, one, is the patient responsive to the TIPS at that diameter, and or do they need further TIPS expansion or dilation? As a result of this approach, we can then defer surveillance TIPS ultrasounds in the future. So we'd like to start out with a case, specifically one of my patients who was a patient with alcohol-associated cirrhosis who had diuretic refractory ascites with a very enlarging peri-umbilical hernia with associated skin changes. His diuretics were complicated by the fact that he had worsening hyponatremia and hypotension despite maximal therapy. And again, he's requiring weekly large volume paracentesis. He's currently undergoing transplant evaluation. He's in the process of undergoing alcohol counseling. As you can see here, his traditional MELD score is 13. And again, the MELD sodium has risen in the setting of hyponatremia. This image here highlights a small nodular liver, as well as surrounding large volume ascites. And you can see his hernia is so large that it's actually expanding outside the window of the CT scan itself. So this case offers opportunity or a platform to discuss the evolution of TIPS technology. I think too often we think of TIPS as the same thing it's been since the 1990s. Perhaps you all are familiar with the evolution in TIPS technology and really the sea change in the early 2000s, where the use of an EPTFE covered stent graft, and you can see that the hepatic parenchymal portion, the image on the right is the part that would be the covered stent graft, offered much better longer term patency of TIPS compared with the previously used bare metal stents. A key point though in that evolution is that these stent grafts, regardless of whether they were dilated during the procedure to eight millimeters or 10 millimeters, if you place a 10 millimeter stent graft as illustrated in this nice study from UIC, the TIPS always self-expanded over time to 10 millimeters. So we achieved one degree of portosystemic shunting regardless of the technique used once you select the tip stent diameter. So the sea change you may not be as familiar with is the replacement of that stent graft with what's currently in use, the Biotor controlled expansion stent graft. And here there's an external compression sleeve around the tip stent graft. This TIPS stent graft will only expand to eight millimeters on its own. Beyond that, balloon dilation beyond that will determine how large it is. It can be an 8-millimeter tips, a 9-millimeter tips, or a 10-millimeter tips. For this audience, this is probably very straightforward. The concept here is that we'd like to achieve as much portosystemic shunting as possible to reduce the complications of portal hypertension, while at the same time limiting the amount of portosystemic shunting to diminish the risk of hepatic dysfunction, hepatic encephalopathy, and right heart strain. The ability to control a tip-stent graft diameter from 8 to 10 millimeters is huge. Why? This is an oversimplification of the true physiology, but if we apply Purcell's flow dynamics equation, a difference in an 8-millimeter tip-stent graft and in 10-millimeter tip-stent graft is two-and-a-half-fold difference in flow through the tips. This allows us a tool in the goal towards the precision tips, just the right amount of portosystemic shunting for a given patient. In this patient, they actually underwent creation of an 8-millimeter tips, reduction of the portosystemic gradient significantly down to 6 millimeters of mercury, and most importantly, resolution of ascites. This case is important because it highlights two main things. One is how to best manage a patient after tips with ascites, especially with controlled expansion. One of the things I want to highlight here is the use of diuretics after tips placement, particularly what to do with the dose and the current dose. Particularly in patients with ascites as well as peripheral edema, it is important to maintain their current diuretic dosing if they can tolerate that. Particularly with patients with ascites alone, those are situations when we would want to reduce the diuretics by a dose of approximately 30 percent. The goal of continued diuretics after tips is really to achieve a negative sodium balance so our patients can continue to diurese and remove extra fluid and, again, result in resolution of ascites. In clinical practice, we recommend that patients have clinical follow-up within four to six weeks to then have reassessment of edema and ascites. We will often permit them one large-volume paracentesis within this time period, again, because it can take four to six weeks to achieve a total body negative sodium balance. However, if patients are requiring more than one large-volume paracentesis or they have ongoing tense ascites at the time of clinical follow-up, that's the situation when we want to recommend a tips revision with stent dilation from 8 to 10 millimeters. When you apply this approach to managing our patients with ascites, you can then defer routine tip surveillance ultrasound because you're really going to make decisions on revision based on the clinical appearance of the patient. This recent study utilizing controlled expansion tips placement with an index diameter or initial diameter use of 8 millimeters really highlights the fact that 92 percent of patients will actually achieve a portosystemic gradient reduction below 12 millimeters of mercury. With that approach, we can have a large portion of our patients being free of hepatic encephalopathy or even higher grades of hepatic encephalopathy as low as six percent. Again, it does a fairly significant job at controlling tense ascites with only a handful or a low percentage of patients actually requiring a stent revision in the future. This really highlights the fact that in order to manage our patients after tips placement for ascites, we want to consider those criteria as I recently suggested as far as for dilation up to 10 millimeters. There is important to acknowledge that some patients, however, will can have complications with portosystemic shunting even at 8 millimeters. The patients who have more than three episodes of hepatic encephalopathy or have recurrent hepatic encephalopathy despite maximal therapy, those are situations when one should consider stent reduction or even stent occlusion. Let's talk a little bit more now about some emerging indications, particularly portal vein thrombosis, as well as utilization of tips prior to abdominal surgery. This is a patient from my institution who has reasonable liver function in the setting of autoimmune hepatitis and primary biliary cirrhosis and is diagnosed with a new right colonic adenocarcinoma with surgery planned. She does have a complication of portal hypertension, have diuretic refractory ascites, and undergo paracentesis once a month. This is the patient's imaging. There's the right colonic mass, not particularly large varices in the region of the mass. She does have some ascites, and you can see the edge of the cirrhotic liver. After undergoing tips creation, in this case with 10 millimeter dilation, she had significant radiant production down to 9 millimeters of mercury. It raises a question because this comes up, what is the evidence underpinning the preoperative creation of tips in someone who's undergoing non-transplant abdominal surgery? Credit to Dr. Patrick Norfolk, who led this evidence review with the Alta Consensus Conference. The truth is the quality of the evidence is not high. There are only two studies out there that actually have control arms, one historical and one concomitant, and the outcomes were not particularly impressive. No difference in overall survival. There was in one of these studies less ascites perioperatively in the tips group, although interestingly, the tips group actually had a higher blood transfusion requirement than the non-tips group. I think the take-home point is it's unclear if this is beneficial in terms of patient mortality or outcomes, and the existing evidence is insufficient to render a strong opinion on that point. With that in mind, based on the limited evidence, again, an individualized patient approach is really important. As an example of how we approach this at our institution, we consider if a patient actually has a current indication for tips, that would be a reasonable approach to placing a tips before abdominal surgery. Two other factors that we consider is one, does the patient have clinically significant ascites that's present currently, which will again impair wound healing afterwards, knowing that likely production of ascites will increase after abdominal surgery, or does the patient have large varices that are within the field or within the surgical field of the surgeon, again, which could compromise the ability to successfully perform the surgery. Really, we consider those two approaches. Again, it's very individualized on a patient-to-patient basis as well in close discussion with the surgeon. Now, we'll transition to the topic of portal vein thrombosis, beginning with a case from my institution of a patient with decompensated cryptogenic cirrhosis treated HCC and portal vein obstruction. Importantly, this patient was planned for a living donor liver transplantation with a segment of portal vein that comes with the donor liver will be particularly short compared to orthotopic liver transplant. The reason to pursue tips in this patient was to allow portal vein to portal vein anastomosis, although this patient did indeed also have diuretic refractory ascites. This is pre-tips imaging showing extensive portal vein obstruction that is occlusive and extends to the portal splenic confluence, a short distance into the splenic vein and a little bit larger distance into the superior mesenteric vein. Once upon a time, this would have been considered a pretty significant relative contraindication to the creation of tips. This has changed quite a bit in the last decade, which is the reason to include this case in this topic in this presentation. These are images from our institution. We obtain now access into the portal venous system via the spleen. On the left is a needle in the splenic vein branch within the spleen. The next image is after we've achieved further access with a catheter injecting contrast. You can see significant filling of a splenorenal shunt and just a nubbin of the splenic vein filling towards the spine. What we're able to do now is recanalize across the occluded splenic and portal vein and achieve access into the intrahepatic portal vein branches. Once we've achieved that, we can put a lasso or a snare up through that access and via systemic venous access in the internal jugular vein, we can now pass a needle from the hepatic vein towards this target, close the snare and pull ourselves down and achieve access or communication between the hepatic vein and the occluded portal venous system. Here's an image of contrast injection after achieving that through and through access. We can then create a TIPS with an unstented extra hepatic main portal vein portion. We reduce, of course, systemic gradient. We dilated this to TIPS to 10 millimeters, but most importantly, this patient had a brief delay in their transplantation because COVID recovered, but you can see pre-transplant on the left, there's a large caliber, nice looking and long length extra hepatic unstented main portal vein that allows in the image on the right, this is post-transplant imaging of portal vein to portal vein anastomosis for the surgeon. Excellent. To go back a little bit, it is important when you're faced with a patient with portal vein thrombosis to identify the etiology and this really hinges on whether the patient has cirrhosis or no cirrhosis. In cirrhosis, portal vein thrombosis can be very common just in the slow blood flow state of the portal vein. It is important, however, to exclude HCC or pedocellular carcinoma because it can often present with tumor thrombus. Contrast enhanced imaging is important to exclude that. In patients without cirrhosis who present with portal vein thrombosis, this is an entirely different etiology or nature and is often driven by a procoagulable or hypercoagulable state. It's important to consult with our hematology colleagues as well as really mandatory to check for a JAK2 mutation as this can often be the only presenting sign or symptom of this myeloprolific disorder. This area of portal vein thrombosis and management is an evolving landscape and there's by Dr. Northrup and colleagues recent ASLD guidance that provides a lot more clarity in this realm, particularly at approaching patients with cirrhosis versus non-cirrhotic etiologies, as well as incorporating considerations if the patient is listed for liver transplant or not. Again, it's also important to now clarify at least the definitions of portal vein thrombosis as there has been a varying amount of nomenclature throughout the literature, both for clinical practice as well as for research practice. To briefly highlight that, though, it's important to note that there's both intrahepatic main portal vein as well as portal vein and tributary involvement of portal vein thrombosis. The current categorization of degree of occlusion either includes less than 50 percent, greater than 50 or complete. In patients with acute portal vein thrombosis who have cirrhosis, we have to think about one, what are our goals of therapy and what are our long-term goals particularly? In patients who have less than 50 percent occlusion of the portal vein, those are patients who actually will have spontaneous resolution within 40 percent. It is important, however, if there's intestinal ischemia to treat or anticoagulate. It's also important to consider anticoagulation particularly if that patient is a liver transplant candidate because we want to preserve portal vein patency. In our patients who have a fully occlusive or nearly occlusive portal vein thrombosis greater than 50 percent, anticoagulation is recommended. In fact, if patients are considered for liver transplant, recommendations or guidance do favor TIPS placement for portal vein reconstruction. It is important in patients who have fully occlusive portal vein thrombosis to remember that they are at risk for portal hypertensive complications including varices and ascites. It's important to evaluate and manage those appropriately. In patients with chronic portal vein thrombosis, particularly our cirrhotic patients, new guidance actually recommends deferring anticoagulation because there is a very low chance that that is a patient who will have recannulation. Of course, if the patient has an underlying hypercoagulable state and cirrhosis, that's an individualized discussion and often does require ongoing anticoagulation. Again, in a patient who has cirrhosis who is not being considered for liver transplant, it's important to manage their portal hypertensive complications including banding of varices or use of non-selective beta blockers and consider TIPS with portal vein recannulization or reconstruction if they have portal hypertensive complications that are refractory to medical care such as bleeding varices or uncontrolled ascites. Again, in our cirrhotic patient who is being considered for liver transplant, as was our case before, TIPS with portal vein reconstruction is recommended to be considered. This just highlights data from our group that initially published TIPS with portal vein reconstruction prior to patients or for patients who were listed for liver transplant to really demonstrate that patients had successful recannulization with minimal complications as related to their liver transplant in the end with only one patient actually requiring an interposition graft at the time of liver transplant. We want to also highlight a specific case in this situation where a patient who had a traumatic splenic injury that was resulting in complications of splenic vein thrombosis after splenectomy who was treated with warfarin for six months but unfortunately did not have recurrent abdominal imaging. He then presented several years later with imaging consistent with chronic portal vein thrombosis with cavernoma as well as large ascites that presented in the setting of variceal bleeding requiring banding. His course was further complicated for lower extremity DVTs requiring, of course, anticoagulation that were quite extensive. In his situation, TIPS with portal vein reconstruction was pursued in order to reduce his variceal bleeding future complications as well as permit ongoing anticoagulation. As we can see here, he has obliteration of the portal vein as well as demonstration of actually some mild to moderate ascites as well. From a technical perspective, this is a variation on a theme. It can be quite difficult to obtain access to intrapartic portal vein branches in patients with extensive portal vein obstruction, but my colleagues at Northwestern were able to successfully do this to recanalize the portal vein. In this case, the snare is from a different direction but the same concept of target, that snare from a systemic venous access with a needle. Embolize, in this case, a patient is acutely bleeding the inflow to the varices and create a TIPS with a nice result. In this case, only with mesenteric venous inflow and no mesenteric venous inflow to the prior splenectomy. Let's just actually highlight data that we recently published on the utilization of TIPS with PBR in non-sorotic patients similar to our example from just earlier. Key things to highlight here is that a large majority of these patients have a hypercoagulable state with up to a third actually having a JAK2 mutation. At time of presentation, their symptoms or manifestations oftentimes or more often than not were variceal bleeding or formation of large varices. Interestingly, up to two-thirds of these patients actually had significant abdominal pain associated with their portal vein thrombosis. Again, the access or approach was really significantly different than the traditional approach, whether it was utilizing transplenic or transhepatic approach as well. As we can see here that both the primary patency, which was defined as no subsequent TIPS revisions versus the overall patency, which was patients who required a TIPS revision in the future, were quite excellent, particularly in the long-term. This just highlights that, of course, this is an invasive procedure that can come with complications. We do note that in patients, a fair amount of these patients up to a third actually had some degree of TIPS stenosis or TIPS thrombosis. Again, this was actually more common in patients with hypercoagulable disorders. It is often important to continue anticoagulation after TIPS, particularly in patients with idiopathic causes. We have to also acknowledge that there is risk with transient encephalopathy or hepatic encephalopathy due to the shunting nature of the TIPS. While these are small numbers, it's important to counsel our patients as potential complications. Just to round out the discussion of non-sorotic portal hypertension due to extra hepatic portal vein obstruction, this is a case from my institution in a slightly different approach we took. She had suffered post-operative extensive portal vein thrombosis, did not have an intrinsic hypercoagulable state, and had really significant complications of portal hypertension, had had varicella hemorrhage, and was getting banded every three to six months, actually had portal-to-portal or really mesenteric-to-portal collaterals that were obstructing her bile duct requiring internal plastic biliary stenting to relieve jaundice, and had ascites that when accumulating in her abdominal hernia was painful. She had been referred to my institution for consideration of a surgical shunt. I saw her in combination with my transplant surgeons. This is her pre-TIPS, or pre, sorry, intervention imaging showing obstruction at the portal splenic confluence. What you see at the hepatic hilum is a collateral. The extra hepatic portal vein is obliterated with no recognizable extra hepatic portal vein. On the right, you see a plastic stent within her bile ducts with surrounding varices, no collaterals. I won't beat this too much, but again, we used transplantic access, very hard to really understand what the way home is into the liver. In this case, we use adjunctive trans-hepatic access into the intra-hepatic left portal vein branches. Ultimately, without belaboring the point, what we did here was just a variation. We created a portal vein reconstruction by stenting from the splenic and SMV into the main portal vein, but not creating a TIPS. While the data set was impressive that was presented in the prior case, there is this question in my mind. This same patient, 18 months out, patent intra-hepatic portal veins, good-looking liver, patent stents decrement in her splenic volume by 50% and resolution of all of the portal hypertensive complications. While there is a limited literature on this concept of portal vein reconstruction without TIPS, I do think it will be an interesting discussion over the next decade, probably driven by both anatomic factors and intrinsic patient factors, hypercoagulable or not, who undergoes portal vein reconstruction versus who really requires a portal vein reconstruction with TIPS in a setting of non-sterotic portal vein thrombosis. Thanks, and I'll hand it over to Justin for conclusion. Really, we want to highlight today the expanding landscape of TIPS, particularly as it relates to new TIPS stent technology with the utilization of controlled expansion. This provides us with a little bit more discrimination and, if you will, precision TIPS, where we have more ability to control the portosystemic gradient. Again, we've highlighted that this really gives the treatment team a high degree of control, particularly as it relates to ascites afterwards by minimizing the risk for hepatic encephalopathy. We talked about some expanding indications for the utilization of TIPS, including portal vein thrombosis, both in sterotic and non-sterotic patients, as well as portal vein reconstruction without the use of TIPS, as well, is something to consider. Again, we reviewed some of the limited data, however, as it relates to TIPS and the use of prior to abdominal surgery and how this really requires an individualized approach, but there is a potential use in permitting our patients to undergo abdominal surgery. With that, we'd like to thank the organizers and the moderators for this invitation to be able to present an area that we're both very, very interested in. Thank you again. Hello, I am Simona Jacob. I am co-chair for this session together with Dr. Laura Kulik. I'm a hepatologist and associate professor of medicine at Yale University and the Connecticut Health Care System. I'll be giving the closing remarks for this year's general hepatology update. I have nothing to disclose, and I would like to start by thanking our speakers for their outstanding presentations, highlighting that multidisciplinary management is essential for the optimal care of our patients with advanced liver disease and or liver cancer. As hepatologists, we must work closely with our colleagues from various fields of medicine, surgery, psychiatry, and we have to keep learning new skills to better serve our patients. For our first presentation, Drs. Jeffy and Mehta showed us that we continue to push the boundaries of HCC treatment in many ways. HCC staging becomes fluid and downgrading allows access to potential curative therapies. Liver resection or local ablation or liver transplantation may benefit patients not previously considered candidates for these treatments. More systemic therapies are available, used as combination regimens or adjuvant, new adjuvant to resection, ablation, transarterial treatment, or liver transplantation. We have now more options for HCC treatment in patients with portal vein thrombosis. In our second presentation, Drs. Mellinger and Li showed us the importance of diagnosis and optimal treatment of substance use disorders in our patients with liver disease. We must continue to advocate for building local expertise and multidisciplinary teams to increase the access to addiction medicine services for our patients. For our last presentation, Drs. Coley and Boyke showed us the expanding indications for TIPs. They summarized the latest recommendations in ascites management using TIPs, such as controlled expansion TIPs, starting with a small caliber of stent and dilate as needed, earlier use of TIPs after only three large-volume parasyntheses within one year, and no need for routine ultrasound every six months for surveillance of stent dysfunction. They also discussed the need for an individualized approach on TIPs prior to abdominal surgery in patients with ascites. Last but not least, we learned about several benefits of TIPs for portal vein thrombosis, either acute or chronic, in patients with or without cirrhosis, or prior to liver transplantation. My co-chair and I hope you enjoyed these excellent presentations and would like to thank you for attending the 2021 ASMD General Hepatology Update.

hepatology updates

challenging cases

newer therapies

hepatocellular carcinoma

liver transplantation

HCC staging

curative therapies

palliative therapies

substance use disorders

alcohol use disorder

transjugular intrahepatic portosystemic shunt

TIPS procedures

multidisciplinary approaches