Good morning. I am Paul Tulavar, and my co-chairperson is Amanda Chaney. On behalf of the Clinical Practice SIG, I welcome you all for this session titled Common Challenges in Clinical Hepatology and Liver Transplant Practice. As the title indicates, we are covering a wide variety of topics during the next 90 minutes. We have five 15-minute talks during this session. This talk is a common problem we see in our clinical practice, hepatic adenomas. Dr. Jennifer Guy will tell how to diagnose and manage those hepatic adenomas. Two topics are related to liver transplant. Dr. Julie Heimbach will discuss the potential role of bariatric surgery in liver transplant patients, and Dr. Lisa Van Wagner will educate us how to optimize pre-transplant cardiac evaluation. Then, Dr. Stephen Congley will talk to us on the impact of coffee and cannabis on liver diseases. Adam Thomas will give the final talk on the management of prurities in people with chronic cholestatic liver diseases. After the last talk, there will be 10 minutes for questions and answers. If you missed this session, I hope not, the presentation will be available on demand for up to 90 days after the meeting. I invite the first speaker, Dr. Jennifer Guy. Thank you. It's my pleasure today to be with you to discuss the diagnosis and management of hepatic adenoma. My name is Dr. Jennifer Guy, and I'm a transplant hepatologist at the California Pacific Medical Center in San Francisco, and I serve as the director of the liver cancer and liver lesion program. I have no disclosures. Our learning objectives for today are to review radiographic and histologic diagnosis of hepatic adenoma, outline the molecular classification and its uses, and discuss management strategies in hepatic adenoma. Clinical features of adenoma include most commonly that patients present as women ages 20 to 40 years old, and there's a strong association with the use of oral contraceptive pills. Other risk factors include exogenous steroids, obesity and the metabolic syndrome, vascular liver disease, and rare genetic conditions. This information can include abdominal pain, incidental findings of a liver lesion on abdominal imaging done for another cause, or rarely can patients present with acute hemorrhage. Diagnosis of adenoma is based on a combination of clinical features, radiographic findings, and in some cases, molecular classification after liver lesion biopsy. MRI with hepatobiliary contrast agent is a radiologic modality of choice for adenoma. Here is an example of an adenoma on MRI, where you'll see arterial enhancement in the arterial phase. It will become iso-intense in the portal venous phase, and on the hepatobiliary phase, there is absence of retention of a hepatobiliary contrast agent, for example, gadazetic acid, which is known as IAVS in the United States, and PrimaVis in Europe. This is in contrast to focal nodular hyperplasia, which is often on the differential of a young woman who presents with a liver lesion, and often these women are on oral contraceptive pills as well. However, with focal nodular hyperplasia, you will see uptake of contrast on the hepatobiliary phase of imaging, and the image on the far right will be bright as if on the arterial phase as well. This helps us to delineate MRI findings of focal nodular hyperplasia versus adenoma. Additional features on MRI, which can be helpful in diagnosing adenoma, include here what we'll show in panel A and B for the human nuclear factor alpha-1 adenoma. Here you'll see diffuse homogeneous signal dropout on chemical shift T1-weighted sequences, also known as in-and-out-of-phase imaging, where due to the steatosis that characterizes focal nodular FNH alpha-1 adenomas, you'll see dropout of the images. This is important because, additionally, with arterial phase imaging, radiologists can diagnose the HNF alpha-1 adenoma by MRI in over 85% of the time. There are also findings on inflammatory adenoma, both on the T2 sequences and arterial phase as well. However, I won't be able to cover them due to time constraints here. An important caveat is that inflammatory adenomas can also, on occasion, retain EOVIS contrast. And so if you see a lesion that retains EOVIS, remember to go back to the clinical setting to think about, could we be considering here an inflammatory adenoma? Liver biopsy is indicated when the etiology of the liver lesion is indeterminate by radiology. For example, as we've discussed, if we want to be ruling out focal nodular hyperplasia or if inflammatory adenoma is in the diagnosis and EOVIS retention is seen, or if the lesion is presenting in a patient that may be older than what we clinically think, or if the lesion is growing in size. It also can be helpful in determining the risk of malignant transformation by applying the molecular subclassification, which we're going to review soon. I want to call your attention to these two slides. The first is map-like glutamine synthetase staining in a focal nodular hyperplasia. This is one way histologically we can diagnose FNH as compared to adenoma. The second slide is of diffuse nuclear glutamine synthetase staining in a beta-catenin exon 3 adenoma. I'll remind you of this finding in a few slides. Molecular classification for adenoma has really been pioneered by Jessica Zucman-Rose's lab in France, and it has allowed us to distinguish five main molecular subgroups, which are based on mutated signaling pathways involved in benign liver tumor genesis. These subgroups have specific risk factors, histologic features, immunohistochemical staining, and distinct biologic behavior. Overall, the risk of malignant transformation in adenomas is approximately 5%, but it's highly correlated with sex and molecular subtype. It is up to 40 to 60% in beta-catenin activated exon 3 adenomas and in adenomas in men. Let's delve a little deeper into the molecular classification of adenomas. This is a table from an excellent review in Liver International by Kopenhauer and colleagues. The first classification I'd like to call your attention to is in the green group, and this is the FNH human nuclear factor 1 alpha adenoma that represents approximately 35% of all adenomas. In this, 90% will have a biolelic inactivation of HNF alpha 1, an important pathway in glucose and lipid metabolism. In 10% of patients, they'll have a germline mutation, which is associated with mature onset diabetes of the young type 3. Histologically, these lesions will be full of fat, and on immunohistochemical staining, liver fatty acid binding protein will be negative as compared to the remaining liver, which will be positive. Importantly, the HNF1 alpha adenomas are mutually exclusive of the other subtypes. This is in contrast to the inflammatory adenoma that I'd like to outline next. The inflammatory adenomas are in the pink subclass on the graph, and they also represent about 35% of all adenomas. This is an activation of the JAK2-STAT pathway with the specific mutations located at the top of the screen. These lesions can be seen in people with obesity and metabolic syndrome, and on histology, they'll have inflammatory infiltrates, dystrophic arteries, and sinusoidal dilation. Immunohistochemical staining is positive with serum amyloid A and C-reactive protein, which are inflammatory markers that are upregulated in these lesions. This is an important caveat that I'd like to point out about inflammatory adenoma is that it does have overlap with the beta-catenin exon 7 and 8 activated lesions and the beta-catenin activated lesions on exon 3. The purple boxes show this overlap, and importantly, in inflammatory adenomas, 6% of them will have beta-catenin activation mutations in exon 3, meaning they carry an increased risk of malignant transformation. Let's focus now on the beta-catenin exon 3 mutated lesions, which are the blue subcategory. These lesions account for approximately 7% of all adenomas, and they're associated with increased risk of malignant transformation, as I alluded to a few slides ago. On histology, they can have cellular atypia, and on immunohistochemical staining, they will have that diffuse glutamine synthetase staining in the nucleus, which I showed you two slides ago. This is an important distinction between the beta-catenin exon 7 and 8 lesions, which do not have increased risk of malignant transformation, and they only have faint glutamine synthetase staining. The final pathway is the sonic hedgehog pathway, which represents about 4% of all adenomas, and it's notable because it has increased risk for bleeding. Let's turn now from adenoma diagnosis to adenoma management, and this is the current paradigm that I'd like to review with you. This graphic is from a review from Kate Kraus from the Annals of Surgical Oncology. The first thing we need to do when thinking about adenoma management is risk factor modification, and in that, I mean discontinuation of oral contraceptive pills and exogenous androgens, weight loss in patients with obesity and metabolic syndrome, and data shows that in those patients, for example, who discontinue oral contraceptive pills, about 60% of them will regress their lesions when followed for 6 to 12 months. Similarly, in those who are able to lose weight, approximately 30 to 70% of patients may indeed also show regression. The next part of the paradigm is to assess for the sex of the patient, and in men, all lesions should be resected regardless of size. There are many different pieces of data that would suggest this, but the one that I would like to refer you to is a population-based study in Denmark where biopsy-proven adenomas in their national database were followed, and up to 60% of men developed cancer. Therefore, all men with adenomas are recommended to be resected. For women, one of the things we can do is to break up the lesions by size. In lesions less than 5 centimeters, we can look for the HNF-alpha-1 factors on MRI. If those are seen, the recommendation is that we can follow these lesions because the risk of malignant transformation in lesions less than 5 centimeters is thought to be very low. In lesions that are less than 5 centimeters, we could also consider biopsy to identify those beta-catenin at exon 3 activated lesions in order to pursue surgery. As we know, regardless of size, if a patient has a beta-catenin exon 3 activated lesion, they should undergo surgery. In lesions over 5 centimeters, it's recommended that they go to surgery, and that's based on the solid bar, but you will see that there's a dotted bar there to consider biopsy in these lesions, and I'll refer to this in a moment. For those patients who are undergoing surveillance for their lesions less than 5 centimeters, a repeat MRI every 6-12 months is recommended with the consideration to stop imaging at menopause. I refer you to the Klopenhauer reference down at the bottom from the Journal of Hepatology in 2016, which reviews the fact that you could consider discontinuing surveillance after menopause. The ESL guidelines of 2016, also referenced below, suggest we could use ultrasound rather than MRI for surveillance. All the alternative approaches to the current paradigm. The first question I often get is, in lesions that are over 5 centimeters but are not beta-catenin activated, do these all need to be resected? What is the risk of rupture by size, age, subtype, and other variables? And what is the likelihood of these lesions regressing over time? These are questions that we need ongoing information, so we can maybe determine if there are indeed lesions over 5 centimeters that could be monitored rather than resected. An additional question that comes up is, are there alternative strategies for non-surgical candidates? There is very minimal data on ablation, so I won't speak to it here. But I call your attention to this systematic review by Von Musom, where they identified over 800 patients who had undergone a diagnosis of adenoma, and 151 of them were treated with transarterial embolization. 61 of these were for elective transarterial embolization. And in those, two-thirds of patients were able to avoid surgery. In all patients, regardless of indication, over 75% of patients saw regression of lesions with a complication rate of approximately 5%. Acute bleeding is known to have a more established treatment in transarterial embolization, though I would like to point out that the risk of bleeding is variable. We often quote that the risk of bleeding is up to 25% in lesions over 5 centimeters, but I call your attention to the review below by Rodriguez that looked and showed that indeed some patients with lesions less than 5 centimeters may be at increased risk of rupture. We do know that risk factors including tumor size, exophytic location, recent oral contraceptive use, recent lesion growth, and sonic hedgehog subtype are all increased risk factors for bleeding. Transarterial embolization is indicated in hemodynamically significant bleeding, and there was a retrospective study done by the Dutch Benign Liver Tumor Group where they identified 59 patients in their centers that underwent transarterial embolization for bleeding. Of those 23 patients for that indication as compared to elective indication, they showed that the majority of lesions regressed to less than 5 centimeters over time, and that the beginning size of those lesions that underwent arterial embolization was approximately 8.4 centimeters. 30% of the people that were followed did require surgery, and the overall complication for both emergent as well as elective arterial embolization was approximately 10%. Delayed surgery is recommended over urgent surgery if surgery is required, and this is because of decreased transfusion requirements, decreased hospital stay, and decreased morbidity. A word on pregnancy. This is a beautiful study, again done by the Dutch group, where they followed 51 pregnancies in women with adenomas of less than 5 centimeters. 25% or 13 patients had adenomas that grew, and you can see that on the graphic. The median growth was about 1.4 centimeters, and interestingly, 22% of lesions regressed. Only one patient required intervention, and this was with an embolization at week 26 because their lesion had grown from about 4.9 centimeters to over 7 centimeters. This pregnancy proceeded uneventfully without complication. In the whole cohort, there was no hemorrhage observed, and therefore, the authors recommend that women with adenomas of less than 5 centimeters can be followed prospectively during pregnancy with the low risk and minimal need for intervention. Their study looked at following with ultrasounds every 6 weeks starting at 14 weeks, though very few were able to undergo all ultrasounds. This suggests that we may be able to do an ultrasound at the beginning of the second trimester and third trimester when following patients with pregnancy. My take-home points are the following. MRI with a hepatocyte-specific contrast agent can distinguish between focal nodule hyperplasia, and the T1, T2, and arterial characteristics can help sub-classify adenomas. Beta-catenin-activated exon 3 lesions are at high risk for malignant transformation and should be surgically removed. The risk of bleeding is variable and needs more study. The blue box shows the management strategies, including surgery for beta-catenin lesions, all lesions in men, and lesions over 5 centimeters, and that transarterial embolization, though small numbers have been studied, suggests it's an effective alternative to surgery and that it can indeed reduce the size of the majority of lesions with a low complication rate. Thank you so much for your attention. Hello, I'm Dr. Julie Heimbach, Professor of Surgery and the Director of the Transplant Center and Ale Clinic in Rochester, Minnesota, and today I am delighted to speak to you about bariatric surgery and liver transplantation. I have nothing to disclose. Worldwide, the obesity epidemic is progressing at a rapid rate, and indeed the incidence of obesity has tripled since 1975, and currently in the United States, 42% of the adult population are considered obese with a BMI greater than 30. This does obviously have implications for the liver, and in most cases this just results in simple fatty liver disease, although it can progress to NASH and fibrosis. Fibrosis only happens in a minority, and from there it is possible that the patient will ultimately need to have a liver transplant, and you can see on the bottom the regression of fibrosis can result from weight loss. What does this mean for transplantation? As you can see here with the left-hand side of this graph showing the incidence of the U.S. population with obesity increasing over time, and the right-hand side of the graph showing, overlaid on that, the remarkable rise in the indication of liver transplant for NASH being noted in the registration counts. We also see on this very same graph the incidence of diabetes, which is also on the rise in the U.S. population. What does this mean for outcome of transplant? Well, although initial data suggested that patients with obesity had a worse outcome following transplant, more recent reports using OPTN data looking at the comparison of severely malnourished patients with BMI under 18.5 compared to patients with a wide range of BMI 18 to 45, and then the most severe obese patients with BMI greater than 45, essentially shows no difference for outcomes following transplant for the obese patients, although with the low BMI still being associated with worse survival. However, looking at the impact of obesity on long-term post-transplant outcomes, because we don't really just do transplant with the idea of achieving a one-year survival, the combination of both obesity and diabetes post-transplant is associated with inferior survival at five years post-liver transplant, and This is specific to those with both obesity and diabetes while those with just obesity or just diabetes had a similar outcome to those with neither of those conditions. We also know that outcomes following gastric bypass surgery do show evidence of long-term efficacy. This is showed on the top where the patients who are able to proceed to bariatric surgery over followed for 12 years, as evidenced in the top graph, have a durable weight loss. Indeed, half of them have an impact on diabetes with a 95 percent reduction in new onset diabetes in this cohort at 12 years, as well as a resolution of diabetes in 51 percent of the patients who had diabetes going into surgery, showing that this is effective in the long-term for weight loss. The control group in the bottom are those that were referred for bariatric surgery, but were unable to proceed because of insurance, and some of those ultimately crossed over once they were able to obtain insurance approval. We also know that weight loss has an impact on fibrosis, and this is an elegant paired biopsy study of 45 patients who were followed for a mean of 4.6 years with serial biopsies, and the 12 patients with bariatric surgery and the six more patients who had weight loss with medical management, who had a total body weight loss of greater than 10 percent were able to show fibrosis regression. This is also demonstrated in this series, or excuse me, this is a series of patients with bariatric surgery who have cirrhosis. This is not a transplant cohort, but rather patients, small study, 13 to 23 patients who underwent a sleeve gastrectomy or re-ygastric bypass. The authors found longer aura time and higher complication rates, but they were able to conclude in all five case series that the bariatric surgery was thought to be safe and also effective in patients with compensated cirrhosis. But in fact, we're actually talking about patients who are decompensated, who need a transplant, and what about this cohort of patients? This actually has been analyzed in this paper from UCSF, which is a single center analysis of 32 patients undergoing bariatric surgery, who actually had been referred for the possibility of liver transplant. These were still quite low mild patients with a mild of 12, the range was 11-13. The vast majority were Child A, although they did have some Child B. They were heavy patients with a BMI of 45. They had no deaths, although they had one leak. Ultimately, of this cohort of 32, they determined that 21 should be listed, although only 14 ultimately went to transplant. However, we need to know a little bit more about this. In fact, this is an interesting analysis where they looked at 78 patients with prior bariatric surgery who were referred to liver transplant. These were well-matched with 156 patients also referred for liver transplant who did not have bariatric surgery. What they looked at was the outcome from the time of the assessment and the listing to one-year post-transplant and they actually found intention to treat analysis. As you can see in the Kaplan-Meier curve, it would be lower for those with prior bariatric surgery versus liver transplant alone at 84 percent versus 90 percent one-year survival. They also noted death and delisting was higher for this cohort with prior bariatric surgery at 33 percent versus 10 percent as well as a lower transplant rate in this cohort. Another analysis, which was not intention to treat, but rather just post-transplant outcomes of 33 patients who underwent bariatric surgery and then were followed, matched 3-1 with those who had transplant that were not having bariatric surgery prior to transplant, but matched for all the other things like age, male, etiology, BMI, sex, date of transplant. What they found, in fact, was actually a very similar outcome to the patients that did not have bariatric surgery. These are two single-center analyses, one showing concern, at least, especially on the pre-transplant side of patients having a higher chance of falling off the wait list. These patients in the prior analysis did have higher rates of scleropenia as well. Another important thing to consider when we're talking about bariatric surgery and cirrhosis is the possibility of referral bias or publication bias where we typically don't write about things that don't work out as well. This is shown in the nationwide inpatient sample data from 1998 to 2007. This captures a large cohort of patients, 62 of which had bariatric surgery in the setting of decompensated cirrhosis, compared to nearly 4,000 who had bariatric surgery as compensated cirrhosis, or those with no cirrhosis, which was over 670,000. The in-hospital mortality for the decompensated patients was 16 percent versus 0.9 percent for compensated cirrhosis and 0.3 percent for those with no cirrhosis. This is a clearly unacceptable outcome, and this was published in 2011, actually was recently re-analyzed in a more recent cohort of patients between 2004 and 2016 and still demonstrating in-hospital mortality rate much higher at 1.8 for patients with compensated cirrhosis compared to 0.2 for no cirrhosis and 22 percent in-hospital mortality for patients with decompensated cirrhosis undergoing bariatric surgery. This is a critical message. Also found higher rates of operative complications in the cohort, both with cirrhosis and with decompensated cirrhosis. This analysis does not look at patients with cirrhosis, but it is a randomized trial, which is quite rare in surgery, and it looks at patients with NAFLD, who had a Roux-en-Gastric bypass compared to sleeve gastrectomy. What they found was that the patients were very similar at the one-year outcome with similar excess weight loss, but they found the patients undergoing the Roux-en-Gastric bypass had induced a higher INR and a lower albumin immediately after the surgery, compared to no change in those with the sleeve gastrectomy at one month. This was resolved by one year. However, they conclude that patients with NASH undergoing Roux-en-Gastric bypass are more susceptible to early transient liver dysfunction compared to those with sleeve gastrectomy. We also have looked at the outcomes post-liver transplant for bariatric surgery. Since we've clearly established that it's not safe to do bariatric surgery prior to transplant in patients with decompensated cirrhosis. This looks at after they've had the transplant, the meantime from transplant to surgery. In this particular case report, which was just seven patients undergoing Roux-en-Gastric bypass post-liver transplant. In this, at 2.6 years after transplant, what they found in the cohort of seven patients was that two patients died in the first year and one had to undergo reversal when having a Roux-en-Gastric bypass after liver transplant. These are very adverse outcomes in this cohort of just seven patients. Giving pause to the idea of Roux-en-Gastric bypass after liver transplant. But another report of 15 patients, more contemporary, 2014-2018, again, about two-and-a-half years after transplant. In this cohort of 15 patients, really had excellent outcomes with sleeve gastrectomy after liver transplant, with really the only difference being that the patients had a little bit more blood loss. Otherwise, everything else was quite similar in these two groups of patients. Very small numbers. Now, is there another option? Well, there is an option of combining liver transplant with sleeve gastrectomy at the same time. This is actually the approach we've adopted at Mayo Clinic. We do have a medical weight loss protocol, so non-invasive weight loss. But for those who are unable to achieve their weight loss goal prior to transplant and have a melt that's high enough to achieve transplant, we do offer the gastric sleeve resection combined with liver transplant. The reason we are opting for the gastric sleeve over Roux-en-Y, is that there is no malabsorption with this technique. The weight loss is more gradual, which is probably more optimal in the patient who is more medically complex. It is also a technically easier procedure. This is just some images interoperatively, and showing the newly transplanted liver and the concurrent sleeve gastrectomy. We've recently analyzed the outcome of this protocol in the more long-term. What this shows at the time of listing, the patients in the red are the ones with the higher BMI at listing. At transplant, those in the blue were able to achieve their weight loss goal, so they had a liver transplant alone, whereas those in the red still with a high BMI of over 45. Then at four months post-transplant coming down, and you can see at two years, actually those with a liver transplant and sleeve gastrectomy, able to maintain their weight loss, whereas those without that, had weight gain following transplant. This is just showing the exact same thing, but in this case, demonstrating the percent of excess body weight loss. I want to just highlight that 30 percent of those patients in the liver transplant alone cohort were able to maintain that greater than 10 percent total body weight loss, which is needed to reduce the risk of fibrosis, whereas a 100 percent of the liver transplant sleeve gastrectomy patients were able to maintain that. We also saw improvement in other parameters such as less diabetes, less hypertension, and lower triglycerides, and those combined procedure. From a practical standpoint, the most crucial aspect is to have a standardized approach including specific nutritional activity and weight loss goals for the medical non-invasive arm. Then following transplant, really close follow-up because excess weight loss and weight regain can happen following transplant and we also have challenges with reflux. Also, from a technical standpoint, the weight distribution and the presence of ascites is really important. The patient on the left, technically pretty straightforward, whereas the patient on the right with a lot of central obesity and no ascites, technically much more challenging. This just highlights, this is a recent and it's very small, but since this is on Zoom, you can probably look at it more closely at your leisure. What this shows is basically an approach to the patient with cirrhosis. Basically, if the goal is to achieve that greater than 10 percent total body weight loss to try and manage their liver disease in the most optimal way, if the patient has compensated cirrhosis and they're not sarcopenic, it could be assessed and potentially being offered laparoscopic sleeve gastrectomy. If the patient has decompensated cirrhosis, the question is, are they a liver transplant candidate? If so, you could consider bariatric surgery concurrent or following liver transplant. If they're not a transplant candidate, then really you don't have an option of bariatric surgery in this cohort and you need to optimize their medical management and their nutritional status. The key takeaways are that long-term post-transplant outcomes could be impacted by obesity and diabetes. Selected patients with compensated cirrhosis may be suitable for bariatric surgery. Bariatric surgery in decompensated cirrhosis is only feasible either concurrent or after liver transplant. Thank you very much for your attention today. Hello. My name is Stephen Conkley, and I'm a transplant hepatologist from the University of Calgary in Canada. I'd like to thank the organizers for the invitation to speak about cannabis, coffee, and others in liver disease for the clinical practice special interest group session as part of the 2021 AAASLD liver meeting. Here are my disclosures over the past two years. None of these are relevant to this talk. I'd like to start off this presentation by talking about cannabis. This plant has been used for about 4,000 years for its cloth and fiber, as well as for its psychogenic effects. Its use is increasing worldwide, including in the United States, with more territories and countries legalizing or decriminalizing this agent as time is progressing. There are three species of cannabis, sativa, indica, and ruderalis that produce different ratios of cannabinoids. Although the two most commonly discussed components of cannabis are CBD and THC, both cannabinoids, it is a very crude drug. It contains many components, including other cannabinoids, terpenes, and flavonoids. The flower or in the butt of the female is a source for consumed cannabis. There are a number of ways of consuming cannabis for either recreational or medicinal use. There's smoking, vaporization, and ingestion. With smoking, the butt is burned or heated when vaporized leading to rapid effect within minutes, higher blood levels of the cannabinoids and shorter duration of effect. Oral ingestion leads to slower onset of effect and is longer lasting with a lower peak level in general. In this image, the endocannabinoid system is illustrated showing the mechanism of action of how cannabinoids work. In point number 1, is a standard neurotransmitter released from a presynaptic neuron onto GABA receptors on the post-synaptic neuron. Endogenous cannabinoids, anitamide and 2-arachnidiol glycerol, after the G protein coupled cannabinoid receptors 1 and 2, known as CB1 and CB2 in presynaptic neurons in both the central and peripheral nervous system. CBD works by modifying the CB1 and CB2 receptors ability to bind to cannabinoids and is non-psychotrophic. There are a number of proposed medical indications for CBD through anti-inflammatory effects and mood modulation, although data for medical use is still emerging. THC is a partial agonist of both CB1 and CB2, and is considered the more psychotrophic of the components and has a psychoactive component. Differing strains have different CBD to THC ratios with indica having higher THC, and so is often used to help people sleep, and sativa has a higher CBD often used to make them more active. Given the differing effects of CBD and THC, I ask my patients to use cannabis either recreationally or medically, especially with those with advanced liver disease or cirrhosis, what the ratio of cannabis is, given potential implications with encephalopathy, which I'll discuss later, as well as with transplant considerations. How does cannabis work on the liver? CB1 receptors are considered profibrotic and are associated with steatosis and developing non-alkali fatty liver disease or NAFLD. CB2 receptors are upregulated in chronic liver disease and are felt to be more protective, although can increase steatosis. Other mechanisms of impact of cannabis on the liver include directly impacting fat accumulation through increased production, increased appetite, and reduced destruction of lipids. To start, the effect of cannabis on liver disease is not very well-studied with variable results. Frankly, further studies are required in this area. For hepatitis C, cannabis use is potentially associated with a higher risk of fibrosis with a three-study meta-analysis showing an odds ratio of 1.77, although there's a possible protective association seen in the later study of the National Inpatient Sample or NIS. Notable in the second study is that ICD-9 coding was used. For NAFLD, the data is limited. There was an NIS study suggestive of a lower prevalence of NAFLD in cannabis users, although this was not supported in a GWAS study for alleles associated with NAFLD or cannabis use disorders in Caucasians. However, for alcohol, there potentially may be a protective effect as seen with the NIS, as well as in a recent case control study published earlier this year. Although these administrative associations with NAFLD and alcohol-related liver disease are interesting, I would like to point out that there are some challenges with the NAS database, including coding issues for cannabis use as there are two states capturing the NIS or cannabis abuse and cannabis dependence. Further, using ICD coding for NAFLD is quite fraught with difficulty. For patients with cirrhosis, NAS analysis suggests that a higher rate of encephalopathy was seen in patients with cirrhosis secondary to hepatitis C, as well a higher rate of ascites in patients with NAFLD, including those with cirrhosis or without. This though, is in contrast to an analysis comparing inpatients in Colorado and Washington in two different years, 2012 and 2015, to represent the time frame where cannabis was legalized. Data came from state emission databases, which are used in the national inpatient sample. Cannabis use in this study was associated with lower rates of paternal renal syndrome and ascites, as well as a lower length of stay in hospital by 1.15 days. For myself, I encourage my patients with cirrhosis to be cautious about cannabis use. My biggest concern would be the risk of developing encephalopathy, given the psychogenic effects of cannabis on the brain, although I do acknowledge the data is limited for this question. Switching gears to liver transplantation, cannabis is not infrequently used either pre or post transplant, with data showing between 12-64 percent of patients using cannabis pre-transplant, and up to a quarter of patients using cannabis post-transplant. In one recent series from the University of Colorado, looking at use of cannabis post-transplant, almost 60 percent of people surveyed used cannabis five days or more a week of the cannabis users. The major reasons for use were anxiety, pain, and recreation, highlighting the need to ask all patients about potential cannabis use, and ensuring that other symptoms are managed preferably through non-cannabis-based methods, for reasons which I'll detail shortly. I would like to highlight a recent analysis from UCLA, looking at the impact of cannabis use on both patient survival and graft survival. In this study, there is no difference seen in either patient survival and graft survival at three years time between non-users, previous users, and current users. Throughout the published literature to date, there's been no significant difference in patient and graft survival. Key things to be aware of with cannabis use in patients post-liver transplant is the risk of invasive fungal infections such as invasive aspergillosis, and so the preferred method of use would be ingested, rather any inhaled methodology. As well, cannabis and THC interacts with tachylimus and so may lead to increased levels and toxicity due to inhibition of cytochrome p450 pathways. This position statement from the Canadian Association of Gastroenterology made a number of comments about cannabis and liver disease which I still, which I think are still take-home points for cannabis. Although there have been epidemiological association with improved outcomes with NAFLD and ALD in cannabis use, the data to me is insufficient to recommend its use for these patients. Cannabis is not recommended in patients with hepatitis C due to increased fibrosis, steatosis. There is a potential risk of hepatotoxicity with cannabis analogues and synthetic agents. And lastly, cannabis use is not an absolute contraindication to liver transplantation, but its use should be assessed on a case-by-case basis. In the context of other addictions, cannabis use is not recommended. I would like to shift gears now to coffee. There has been a growing interest in the impact of coffee on health, including liver disease, and so I'd like to briefly highlight our knowledge about this field. There are a number of potential mechanisms of how coffee may affect the liver summarized in this image. Steatosis reduction may occur via decreased fatty acid synthesis and increased fatty acid beta-oxidation, as well an increase in hepatic glutathione content may lead to reduced oxidative stress and hence less steatosis fibrosis. For fibrosis, other mechanisms may include inhibition of hepatic stellate activity by antagonizing adenosine A2A receptors and lowering TGF-beta as well as increased apoptosis. Last, hepatocellular carcinoma reduction may occur through up-regulation of nuclear factor like 2, increased ERK1 and 2 phosphorylation, which can increase apoptosis, as well as through alteration of the balance between detoxification and activating carcinogenic enzymes, resulting in reduced and slower tumor growth. A number of studies have looked at the potential association of coffee with liver disease. Cohort series suggest that patients with primary biliary cholangitis and autoimmune hepatitis consume less coffee than controls, but this was not seen in primary sclerosing cholangitis. For non-alcoholic liver disease, they've been conflicting meta-analyses with one suggesting a positive protective effect of coffee with NAFLD versus one showing no impact of coffee use on prevalence nor incidence with a non-statistically significant risk ratio. I feel these are thought-provoking studies but do require further replication analysis. A few studies have suggested the potential impact of coffee in developing chronic liver disease in the general population with a meta-analysis of six respective cohort trials suggesting a risk ratio of 0.62 for the dose-related response. More recently, an analysis of the NHANES database suggested a lower risk of having significant fibrosis as measured by translistography for values less than 9.5 kilopascals with three cups of coffee, controlling for sugar and diet with an odd ratio of 0.4, 95% confidential, between 0.2 to 1, p-value less than 0.05. For patients with liver disease, coffee may reduce the risk of cirrhosis. This meta-analysis from APT of nine studies, five cohort, and four case control with about 2,000 cases and 432,000 participants show that drinking two cups of coffee per day was associated with reducing the risk of cirrhosis in patients with chronic liver disease by about 50%. In addition to reducing the risk of cirrhosis, coffee might reduce the risk of pataclitic carcinoma in patients with chronic liver disease with an odds ratio of 0.69 reported in a meta-analysis of 20 studies. However, in this analysis, it was found that one cup of coffee was not enough with an odds ratio of 0.76 with the confidence crossing unity. With more coffee consumed, the risk of pataclitic carcinoma was reduced with an odds ratio of as low as 0.51 with three cups of coffee. That being said, distinguishing between the impact of etiology of liver disease cannot be done, so we cannot determine whether this would have more of an impact on viral hepatitis, autoimmune disease, et cetera. To conclude, the other component of my presentation, I would like to talk about silymarin as a representative of herbals in liver disease. This herbal agent is probably the one I'm asked most about in clinic by my patients. Silymarin is the active component of milk thistle with its mode of action being unclear, including possible antifibrotic effects, antioxidant effects, and stabilization of cellular membranes. Given that, what is the impact of silymarin on liver disease? A meta-analysis of seven trials showed that the ALT and AST were improved by 15 and 70s respectively. However, when shifting to more significant endpoints, the body mass index was not impacted unsurprisingly, and there was no data that can inform outcomes regarding fibrosis in this meta-analysis. Perhaps the most eloquent trial for silymarin was a randomized controlled trial looking at patients with hepatitis C who failed interferon and had an ALT of 65. Patients with decompensated cirrhosis, viral co-infection with hepatitis B or HIV, or use of silymarin within 30 days were excluded. In this three-arm trial, 154 patients were randomized, 52 to placebo, 50 to take 420 milligrams of silymarin, and 52 to take 700 milligrams of silymarin. Overall, this slide summarized the trial data after 24 weeks of treatment, showing that for the primary endpoint of reducing the ALT to less than 45, which I think is probably the easiest part to obtain for clinically relevant outputs, there was no statistical difference between arms. Other endpoints studied included a drop of ALT to 50% baseline, changes in ALT level, changes in hepatitis C RNA, or changes in quality of life factor also show no difference. As such, I highlight a quote from a nice review about herbals by Drs. Stickel and Helderbrand. So far, clinical studies analyzing the efficacy of herbals and the treatment of liver disease provide only moderate evidence. Future efforts ought to implement extensive methodological improvements to separate the real therapeutic value for unfounded hopes. Rigorous scientific testing along the principles of medicine is required for herbal medicine to become more than a fashionable trend. To conclude, cannabis likely does not harm the liver in patients with non-hepatitis C-based liver disease, although I'd be cautious of using it with patients with cirrhosis and the potential impact of hepatic encephalopathy. The data for benefit of liver disease is not yet compelling to me. As such, it's important to ask patients about cannabis use and clean their composition. There is growing data that coffee may be protective against fibrosis and hepatocytic carcinoma for patients with liver disease, with those dependence being seen. I would not go as far as some and suggest that everyone in the general population drink coffee, nor routinely prescribe it to my patients given potential intolerance, but rather would tell people to enjoy their coffee. Last, there is limited data for the use of silymarin in liver disease. It does not seem to cause harm, but its benefit is unclear. Herbals are frequently used in patients, and at this point, there's no great data for compelling efficacy, but further studies are required. Thank you very much for your attention in this presentation, and thank you again to the organizers for inviting me. Hello. I want to thank the organizers first for the opportunity to present here today. And over the next 15 minutes, we are going to discuss the epidemiology and timing of cardiac events after liver transplant, describe the impact of cardiac disease on liver transplant outcomes, and then we'll finally summarize an approach for detection of cardiac risk in our liver transplant candidates. Importantly, we are not going to address management issues of identified disease today. It's just unfortunately beyond the scope of the 15 minutes we have together. These are my disclosures, the most important of which is that I am not a cardiologist, so everything I say here today is coming from a hepatologist perspective. So I think it's important that before we talk about risk stratification for cardiac disease in liver transplant candidates, that we talk about what do we mean when we use the term cardiac disease in the context of liver transplant. So if you look at the American Heart Association definitions for cardiovascular disease, you'll see that it's a very broad definition. For cardiovascular disease and cardiopulmonary disease, it really falls within the Venn diagram in these three different circles here. And what we are going to focus on today is that green circle. We're going to focus on coronary heart disease, MI, revascularization. We're going to focus on heart failure risk and arrhythmia and cardiac arrest risk. So why are we even talking about this today? Why is this a part of the clinical practice, big programming? Well, it's because cardiovascular disease is now the leading cause of both early and long-term mortality after liver transplant. And if you look at this data from the Organ Procurement and Transplantation Network of 2002 to 2012, that cardiac disease accounts for 40% of all 30-day deaths. Now, this translates to a liver transplant cardiovascular mortality rate of about 1.2%. And just to put this into context, if you compare it to other surgeries, you can see that cardiovascular death from a liver transplantation is almost as high as that of a cabbage surgery. So what are the cardiac events that are happening after liver transplant? Well, it's important to note that most of them are actually non-ischemic in origin. If you look at the pie chart here on the left, you can see that the majority of events, nearly half, are due to either cardiac arrest or arrhythmias, particularly atrial fibrillation. About a quarter are due to heart failure, and a minority are due to thromboembolic events. This data has been replicated in other datasets. If you look at data from the nationwide inpatient sample over the past 10 years, you can see that hospitalization trends for dysrhythmia and heart failure have been increasing, while hospitalizations in the bottom two lines for stroke and MI have been decreasing over time. So when we talk about risk assessment, of course, it's really important that we think about the timeline of events that we are trying to predict risk for and how this changes over time after transplant. So in the immediate perioperative period, most of the events that we're seeing are a result of the stress of the liver transplant operation itself. We see acute decreases in cardiac output. We see a reasonably high cardiac arrest risk in this period, especially ventricular arrhythmias that underlie that risk, and we do see embolic events that happen in this immediate period. As we move into the early postoperative period, this is when we start to see that uptick in acute heart failure, particularly diastolic dysfunction or stress cardiomyopathies. We see an increase in atrial arrhythmias and that afib risk that we talked about, and a little bit of an uptick in stroke, particularly hemorrhagic stroke, often related to our antiplatelet anticoagulation protocols that we often are using for prevention of hepatic artery thrombosis. But as we move out of the early postoperative phase, sort of three months and beyond, and later after transplant, this is when we start to see the ischemia risk increase and atherosclerotic cardiovascular disease, which of course is related to all the increase in associated risk factors for ASCVD. That is a result of ongoing risks associated with immunosuppression, weight gain, and return to health behaviors that are associated with increased cardiac risk. This is another nice study that just highlights again the importance of having cardiac comorbidity going into a transplant and how this actually impacts mortality longer term after transplant. What you're seeing here on the y-axis are all the different sort of comorbid conditions that patients come into transplant with, from cardiovascular disease down to renal disease at the bottom. You can see that cardiovascular disease in the panels here, and these are separated by time frames within 90 days, 90 days to five years, and from five to 10 years, cardiovascular disease really has been the primary driver of all-cause mortality throughout all those time periods, with the exception of the early time period. Just below, you can see that it's congestive heart failure that is the highest driver of all-cause mortality. So our approach to cardiac risk mitigation, I tend to think of it in terms of sort of four key steps. We want to first assess global cardiac risk, and then we then want to evaluate prevalent cardiac disease, which we'll talk briefly about each of these. We want to treat then the modifiable risk factors for these diseases, and then importantly, we want to consider the potential implications of what we found in the setting of the liver transplant operation, and then of course reassess our risk over time. Risk is not static, it of course changes. I do want to highlight here that in this entire process, it's incredibly important that this is a multidisciplinary approach, and that we involve our colleagues both in cardiology and anesthesia in all discussions, and that we involve other specialists as clinically indicated. So in terms of our ability to assess for global cardiac risk, this is one tool that's available at the point of care called the CAR-LT score. It was something that we developed here at Northwestern. We looked at over 300 preoperative and perioperative variables, and you can see the variables that ended up in the final model are listed here on the left. This score is clinically available and freely available to anyone who wants to use it online. The website is www.carlt.us, and what it gives you is your one-year absolute predicted risk of your patient having a death or hospitalization related to a major cardiac event. Now, this score is not meant to make transplant decisions. It is meant to help inform risk-based discussions on a multidisciplinary level, and who we decide to transplant as a center of course is going to vary widely based on our accepted level of risk. Now, the second step is to assess prevalent cardiac disease, and we'll start off by talking about key principles for detection of coronary artery disease in this population, and what we know from the decades worth of data that has been accumulated is that the strongest predictors of significant obstructive CAD in this population are having greater than or equal to two traditional cardiac risk factors. The presence of NASH, which of course is a very important now-recognized independent risk factor for cardiac disease, particularly obstructive CAD, and the presence of renal dysfunction. So taking these things into consideration, we actually recently just conducted a national survey of liver transplant centers here in the US. That paper was just published in Liver Transplantation last month. We surveyed 117 of our transplant programs. We had about a 52% response rate. All 11 UNOS regions were represented, and we asked people, you know, what is your strategy for CAD risk assessment? Now, the majority of us are using some sort of a risk-based protocol, and you can see the cardiovascular risk factors that we're all using to determine who's going to get further testing here on the right. I think what's really interesting to note is that though there are some similarities, there are some significant differences. For one, age. There is a wide variation in the age threshold that we all agree or disagree is associated with cardiac risk. Some centers are using a threshold as young as 30, while other centers are not performing further testing unless patients are greater than age 70. I think the other interesting thing is that despite the growing body of literature indicating that NASH is an important predictor of obstructive coronary disease, just over half of us are using NASH as part of our risk algorithm, while many of us are not considering NASH as a cardiac risk factor. A minority of centers are using a universal non-invasive testing, meaning that they're ordering, you know, dobutamine stress echocardiographies in everybody. That's really a minority of centers at this point. Why is that? I think this is encouraging. Much of our older literature and actually our older ASLD guidelines had recommended consideration of dutamine stress echocardiography in the majority of patients to assess for CAD risk or vasodilator testing. However, there's been a huge body of literature now over the past decade that has shown that these tests have very poor sensitivity and negative predictive value in this population, and you can see the point estimates listed here. That's been something that I put together from just the body of literature that's been published, and a lot of this has to do, right, with the physiology of end-stage liver disease. These patients have chronic vasodilation. They have chronotropic incompetence. They're not able to mount an appropriate stress response. I think what's more promising in terms of the tests that we might see increased use of over the next couple of years are cardiac PET CT, sorry, PET scanning and fractional flow reserve by coronary CT angiography. As you can see here, these have excellent sensitivity approaching 90 percent with excellent negative predictive values as well in the general population, and cardiac PET in particular is very nice because it isn't associated with renal injury as many of our other testing modalities are. In 2021, it's really out with the old and in with the new. Stress testing alone for detection of significant CAD is not a good modality and also is not good for preventing prediction of event risk in most liver transplant candidates. The new recommendation is really for coronary angiography, whether it's invasive or non-invasive as the evidence-based standard for detection of significant CAD and events in this population. So, what are the tests that we have available to us in terms of anatomic imaging? Of course, we're all very familiar with invasive coronary angiography. That's really the gold standard for coronary artery disease detection. It is safe despite coagulopathy and renal dysfunction and, of course, allows for simultaneous revascularization. But coronary CT angiography, you can see here, has excellent negative predictive values of near 100 percent. And importantly, to note, in end-stage liver disease, the nephrotoxicity is actually slightly lower than invasive angiography, though, of course, there are contraindications to performing the procedure and some of our patients just may not be able to tolerate this, so that's important to keep in mind. So, just turning to heart failure for a couple of minutes, I just want to highlight the fact that there have been new criteria published within the last year and a half finding cirrhotic cardiomyopathy using newer contemporary echocardiographic criteria, which have been listed here. And what I want to point out is that this is a really nice study that was published by Manhall Izzy and the Mayo Group this past year that shows that using these criteria for cirrhotic cardiomyopathy really is predictive of who is likely to survive free from cardiovascular disease after transplant. And persons who had cirrhotic cardiomyopathy had a nearly two and a half increased hazard of decreased survival after transplant, so these criteria have predictive value. Now, how do you evaluate for the presence of cirrhotic cardiomyopathy apart from obtaining baseline transthoracic echocardiography? Despite the fact that stress imaging does not potentially have a role for CAD risk assessment in most patients, there is likely a very strong role for stress imaging for the detection of who might have cirrhotic cardiomyopathy, and I think we're going to see more and more data over the next couple of years supporting the potential role of DSC for this purpose. There's been a lot of interest in contractile reserve, right, looking at how does the patient actually mount a stress response, and the absence of that appropriate stress response is a marker of cirrhotic cardiomyopathy. CPET testing, six-minute walk test, parameters that can be detected on cardiac MRI, which I've listed here, have all been associated with different thresholds and adverse outcomes after transplant, so the literature is still early. I think these are going to be things that we're going to be seeing used more and more to help us differentiate these very high-risk populations. So a few words on arrhythmia risk assessment. ECG really should be obtained in all of our candidates in order to identify disturbances in the heart rhythm and conduction abnormalities, and then, of course, there's been a lot of controversy, particularly in the role or lack of role in QT prolongation as a predictor of cardiac risk after transplant. And I think there's been a nice study that was published by Anup Koshi and the group out of Australia and Melbourne Health that showed that QT prolongation does play an important role when you're talking about perioperative cardiac risk. So that very early period, QT prolongation is important. Now, of course, there are things we can do in order to potentially reduce that risk, investigating causes like electrolyte disturbances, changing medications that can further prolong the QT. And so this isn't something to be ignored. And it can be very important in sort of the immediate perioperative period. The other, I think, large thing that has increased in our recognition of the role that it might play in adverse cardiac outcomes is the role of atrial fibrillation. Of course, I showed you earlier, it plays a huge role in sort of the proportion of events that happens early after transplant and increases peri-transplant cardiac risk by up to fivefold. And so talking with anesthesia about ways that we can reduce the intraoperative risk for AFib, minimizing volume when we can, trying to minimize catecholamine surges when able to, those are things that we could do to potentially stabilize and reduce risk a little bit for AFib. So just some final words using valvular heart disease risk assessment. Transthoracic echocardiography should be obtained in all of our candidates, not just to attest by ventricular function, but also valvular function, assess and screen for pulmonary arterial systolic pressure and of course, for pericardial effusion. It's important to remember that the high output state of end-stage liver disease does complicate an accurate assessment of valve severity, particularly of aortic stenosis. And so again, it's really important to work with our cardiology colleagues who understand the physiology of end-stage liver disease and have these patients volume optimized to really assess what the potential role is of the identified valvular heart disease and how that might tolerate or not tolerate the stress of a liver transplant surgery. So step three is to treat the modifiable cardiac risk factors. We've talked about these briefly, just to also highlight frailty has become an increased recognized risk factor, not just for all-cause mortality, for cardiac outcomes in particular. So this is another important thing to consider in the risk profile of patients. And then of course, we need to consider the risk that we have identified in the setting of the stressful liver transplant surgery itself. And where our threshold for risk falls for each of our centers is of course going to determine on our own center experience with cardiovascular risks, our volume, our team dynamics, patient factors and adherence, what factors are modifiable that we can actually change to reduce risk and what are our current center outcomes and how much can we tolerate? So there are of course, a lot of unanswered questions still in this field. What's the optimal interval for repeat risk assessment? How often should we be repeat testing or repeat assessing risk factors? Are there actual differences in cardiac outcomes based on the differences in our center protocols? And so there's been some nice papers that have come out over the past two years or so where some centers are actually starting to publish their protocols, which I commend people for doing, but now we need to actually link those protocols to cardiac outcomes and see, does someone actually have a better protocol? And then are we actually doing the right thing for our patients? Importantly, what's the most cost-effective approach? And can we personalize our approach to cardiac risk? Can we actually identify which patients need which tests that are gonna best predict outcomes and do this in the most cost-effective way? So our take-home points today are that cardiac disease is the leading cause of morbidity and mortality after transplant. And that cardiac event risk, it changes over time after transplant. And it's really important that our risk assessment considers both the short and the long-term risks. In 2021, anatomic imaging is required to accurately assess CAD risk in the majority of candidates and new criteria for cirrhotic cardiomyopathy needs to be considered in the risk profile for cardiac risk prediction, given the high rates of heart failure after transplant. Finally, a dedicated multidisciplinary team involving not just hepatology and transplant surgery, but cardiology, anesthesia, and other specialists is really critical to improving clinical outcomes in high-risk candidates. I thank you for your time, and I very much look forward to your questions. Good morning, and thank you for joining us at the Clinical Practice SIG. Today, I wanna talk to you about the management of pruritus. I wanna extend a thank you to Drs. Tulavath and Dr. Chaney for inviting me to speak. My name's Arul Thomas, and I'm a transplant hepatologist at Georgetown University in Washington, DC. I have no disclosures. So pruritus in liver disease is a debilitating and disabling condition. It affects up to three-fourths of patients with cholestatic liver disease, and it's associated with sleep deprivation, exhaustion, fatigue, and depression. Overall, as providers, particularly in hepatology, this is an issue that's brought up often at the end of a busy clinic visit, and it's super frustrating to hear because we know how difficult it is to manage and how difficult it is for patients. My goal today is to go over the basics of pruritus in liver disease and give you some tools from the medical toolbox that you can use to help manage this, and hopefully you'll see that most pruritus in liver disease can be successfully managed and you can successfully improve the quality of life of your liver patients. So instead of running to a corner and crying and being frustrated, which is often what I do, I think it's important to stop, take control, and get the facts about pruritus. One is to ensure, are you dealing with the right disease process? Pruritus in liver disease often occurs from an impairment of hepatocellular and cholangiocellular bile formation. It's very rare in common liver diseases like NAFLD and alcoholic hepatitis. Second, make sure your location's right. In liver disease, pruritus occurs in the limbs, often in the palms and soles, typically. We also need to think about timing. Liver patients classically describe a circadian rhythm of itching, worse in the evening and the nighttime. So check that when you're interviewing your patients. And then look for other skin complications, excoriations, folliculitis, purigonodularis, and lichenification can all occur. I remember seeing a patient who was newly referred to me with elevated liver enzymes who had this purigonodularis, and I immediately began thinking about a dermatology consult and a separate condition, and I should have spent time asking about pruritus and working backwards to solve that condition first. One of the main frustrations with pruritus is that there's many clues to why it occurs in liver disease, but no unifying theory. We know that there are classic pruritogens and that these pruritogens can affect transcription networks and intracellular signaling, particularly in the central nervous system, that affect how patients perceive itch, but we don't have one unifying theory as to how that occurs. We know bile salts, which affect our act on farsanoid receptor X, as well as transmembrane G protein coupled receptors, can signal transcriptional changes in intracellular signaling that can cause the sensation of pruritus. We know lysophosphatidic acid and its enzyme autotaxin can work to activate the neuronal system and particularly also in satellite glia cells and may actually correlate with bile salts. Interestingly, autotaxin as a substance is the only substance directly linked to intensity of pruritus. So bile salts, bilirubin, opioid level, none of those things actually match directly with the level of pruritus that a patient can feel except autotaxin. Endogenous opioids can modulate the central nervous system as well as serotonin, substance P, and as well as other yet to be determined mechanisms may also be at play with pruritus in liver disease. As we talked today, a lot of the research in this field is done from primary biliary cholangitis and thankfully some of that work can be applied to all cholestatic liver diseases. And I am indebted to Drs. Duhl and Kremer who wrote an excellent concise review about pruritus and liver disease in 2019, which is a great resource for further information. So in addition to the frustration about the lack of understanding about why pruritus definitively occurs, there's also frustration about many treatments and no best choice. And I think that's just the reality. And I think it helps to group the potential mechanisms of actions of treatment to help understand which to use for your patient. One potential mechanism is to eliminate potential pruritogens from the enterohepatic and body circulation. This is how anion exchange resins work like cholestatamine. Second mechanism is to modify metabolism of potential pruritogens in the liver and or intestine. This is how the antibiotic rifampin works. We can also modulate central itch and pain pathways. These pathways are often mediated by opioids and serotonin. And this is why opioid antagonists and SSRIs may work. And changing itch perception locally in the skin may be an attractive option to treat. And this is how UVB phototherapy works. Today, I wanna go over a stepwise approach to managing pruritus in liver patients. But the hallmark of this is to start on the lowest step, which is simple, and that's supportive care. Patients often don't wanna hear about this because it seems basic and they want immediate help, but it's really important to emphasize this first. Emollients to moisturize skin is very important. Oatmeal extract supplements may help with this as well as emollients with one to 2% menthol. Keeping fingernails trimmed is very important. And use of cold water after warm situations because warm situations like a hot bath may exacerbate itching. And liberal use of cold water may help with treatment as well as in nighttime settings. Moving on to the stepwise approach, again, we start at the base here with general recommendations here of some good supportive care, and then work our way up to these middle steps here with a first-line agent of cholestyramine, second-line agents of rifampin, naltrexone, sertraline, moving up to fibrates. As we get up in these higher steps, this is a more murky area for traditional clinical practice. You can talk about things like MARS, phototherapy, plasmapheresis, and of course, liver transplantation. These are not great options to discuss in a standard clinic visit. Certainly, liver transplantation is attractive for patients with intractable paritis. But now with the National Liver Review Board, it's difficult to get MELD exception narratives approved for quality of life. And of course, there's no standard MELD exception for paritis. One key point here is that antihistamines are largely ineffective. I was disappointed to hear this too because when I started out, I always leaned to this first because it was a stressful clinic setting. And this is something you readily think about and can readily offer a patient. But as we all know, patients with particularly decompensated cirrhosis giving these sedative agents, they're just generally not a great step and they don't have much efficacy in paritis. And so today I want to go over some of these other agents, hopefully by going over them, they're more fresh in your mind and you can provide more efficient and efficacious care when dealing with paritis. So let's start by talking about some of these agents and let's begin with colostyramine. So colostyramine is an anion exchange resin. On the positive side, there is small non-placebo controlled trials that show efficacy over two weeks. It's relatively easy to obtain this medication and simple to dose. Usually I start with four grams twice a day and work my way up. Negatives are this medication interferes with absorption of other medications. And there's this issue of having to dose it at least four hours away from other medicines. And patients with chronic liver disease, this isn't a great option because they're often on so many other medicines. There's also not a strong clinical effect from colostyramine. And of course there's patient issues, taste, bloating, abdominal discomfort, malabsorption of fat and fat soluble vitamins that may affect your use of this medication. Moving on to rifampicin and rifampin, these antibiotics induce several hepatic and intestinal biotransformation enzymes and transporters. The key effect here is this alters the metabolism and excretion of potential proteins such as bile acids. And these drugs probably compete with hepatic bile acid uptake as well. This is why we can often see an increase in serum bilirubin when patients are on this drug. And it can affect also the intestinal and skin microbiome which may have a positive effect in treating pruritus. Positives of using rifampin is that there's randomized placebo controlled data that show efficacy in doses between 150 and 600 milligrams per day. And there is a strong clinical effect in treating pruritus by using these agents. The negatives are hepatotoxicity, there's a well-described drug-induced liver injury that can occur from these agents while that rate is likely low. It's certainly something our patients with chronic liver disease cannot afford to have. Other drug-drug interactions can occur and of course also discomfort from nausea, loss of appetite and the benign but still annoying complication of orange urine. Serotic patients also need particular care when on this medication to dose them very low and of course to keep a very close eye on hepatotoxicity. Moving on to naltrexone which is a new opioid antagonist. Positives here is that there are some small placebo controlled trials that show mild efficacy. The negatives if your patient has chronic pain, this really is not a good choice for obvious reasons. It can also be a breakthrough phenomenon where a patient is on this drug and still can recur with pruritus while on medication. Therefore, dosing may require a break period which is difficult to do in a clinical setting and headache, nausea, vomiting and dizziness can also sometimes be seen for patients on this medication. Moving on to sertraline. Sertraline is an SSRI. It has a moderate itch reducing effect in a single placebo controlled trial. It has a very attractive positive and that it can also concomitantly be used for depression. I've taken advantage of this when treating certain patients with pruritus. The negatives are in the liver world. The data is limited to sertraline and paroxetine only. There's not a class specific data in liver on using any SSRI for pruritus. And high doses are often needed somewhere in the range of 75 to 100 milligrams which I'm usually not comfortable starting a patient with that high. I usually start much lower and work my way up. Insomnia, agitation, change in appetite can all occur on this medication. And of course, serotonin syndrome, particularly with a drug interaction with a medication such as tramadol. So you have to pay very close attention to what other medicines your patient is on. Phenofibrate, so we're working our way up the stairs there. Phenofibrate is an attractive choice. And when I confess, I don't often think of enough when treating pruritus. A phenofibrate is a PPAR agent and it works to alter intracellular transcription factors. There's data from Europe on PBC in patients in the BES-ERSO randomized placebo-controlled trial in retrospective analysis showed a reduction in pruritus. It's important to keep in mind in this trial, the median baseline pruritus in patients was low. More recently, the Fitch trial was published that showed an improvement in moderate to severe pruritus using bezofibrate in patients with PBC, but also PSC and secondary sclerosing cholangitis. So definitely an agent we should be thinking more of when managing cholestasis-related pruritus. Positives, again, is a randomized controlled data from PBC. It's relatively well-tolerated. The negatives are you have to use caution when dosing for cirrhosis. So again, we've looked at this stepwise approach. I strongly recommend starting with the basics first, keeping the skin moist and working your way up the stairs with these agents that we've described. Take two to four weeks per step, sometimes longer to adjust dosing within each class, for instance, with cholestyramine. I want to make two other important points. Ursodiol is well-known to have an anti-cholestatic effect in PBC, but has a limited antipyretic effect. So when you're treating patients in PBC, don't expect to have a double treatment effect from using ursodiol. Make sure you treat the pruritus separately. And I've also had personal experience using THC, dronabinol, and marinol for patients with chronic pruritus and liver disease. This is a controlled substance, which makes it a little challenging to prescribe, and also dosing needs to be watched in patients with chronic liver disease. But I have had success treating pruritus with these agents as well. Advanced treatments are outside the scope of most clinical settings, but you need to think about if medication management doesn't work. UVB phototherapy could be used, nasobiliary drainage, endoscopic approach, and plasmapheresis. These are treatments I've thought about, but haven't actually used readily, and I think the same may be for most providers taking care of liver patients. There are future treatments we may see stateside. One is a capilloid receptor agonist. Earlier, I talked about mu-opioid agonism causing itching, and then antagonizing that receptor with naltrexone can reduce itching. Here, agonizing the kappa opioid actually can inhibit itching. And in Japan, there's an agent nalfurofene, which has been used successfully to treat pruritus and liver disease. And then a second class of agents called ileal bile acid transporter inhibitors. These medications break the enteropathic cycle of reabsorption of bile acids. They increase the excretion of bile salts in the feces. And in PVC, there's data that these agents reduce bile acid and autotaxin levels. The FDA just recently approved maralixabat for allergial syndromes. We may see more options to use this class of drugs in the United States to treat pruritus and liver disease patients. The key side effect we need to watch out for are bile acid-associated diarrhea. So in summary, pruritus is a debilitating condition in chronic, mostly cholestatic liver diseases. It's debilitating for patients and often also for the providers that care for them. I think spending time to think about the multiple theories behind the pathogenesis, whether it's bile salts, endogenous opioids, lysophosphatidic acids, serotonin, and thinking about your patient individually and what medical tools you can use will help you to be successful to treat pruritus. Supportive care with good skincare is super important to emphasize at first, and then using a stepwise approach, as we discussed, for pharmacologic therapy. Lastly, I think having a positive, open mind about tackling this problem is more than half the battle. Rather than retreating and avoiding the problem with the patients to talk about it openly, make educated guesses about what agents you can use and try them. I think you'll find your patients will be very satisfied and can reach an improved quality of life with this condition. And hopefully you as a provider will also feel the same way caring for them. So again, I thank you for joining us at our clinical practice SIG program today, and I appreciate your attendance. So thanks again. Thank you. Hi, on behalf of the clinical practice SIG, I would like to thank you all for joining this portion of our conference. We've had some amazing speakers to talk through some really important topics as far as clinical practice goes. As part of our clinical practice SIG, our mission is to promote the practice of hepatology in the community practice center. And I believe that we were able to accomplish that with the amazing speakers that we had today. So thank you so much for your time and enjoy the rest of the conference. I want to thank everyone for attending this session, especially the speakers for their scholarly talks. I also want to thank them for the time and effort they have put in these talks. I hope you had a wonderful discussion and hopefully we will meet again in person next year. Thank you.

Cannabis use

Liver disease

Encephalopathy risk

Liver transplant

Coffee benefits

Pruritus treatment

Bile issues

Cholestyramine

Sertraline

Capillary receptor agonists

Quality of life improvement