Hi everyone and welcome to the ASOD practice guidelines workshop. My name is George Ioannou and I'm the chair of the ASOD practice guidelines committee. We have five presentations today on five upcoming ASOD guidelines and guidances. These are all new guidelines and guidances that were conducted in 2021. Some of them are already published and some of them will be published soon in hepatology and on our website. The first one is a guideline on non-invasive liver disease assessment presented by Dr. Richard Sterling. The second one is a guidance on nutrition, sarcopenia, and frailty presented by Dr. Jennifer Lai. The third one is a presentation on Wilson disease by Dr. Michael Shilsky. The fourth one is a guidance on primary sclerosing, cholangitis, and cholangiocarcinoma by Dr. Christopher Bolus. And finally, a guidance on palliative care in end-stage liver disease by Dr. Fasiha Kanwal. I wanted to remind everyone that all AASOD guidelines are available full-text on our website without requiring any login to all of our members and non-members alike. So please visit our website and download these guidelines and guidances to help with the management of your patients. I want to specifically thank all the members of the practice guidelines committee for their hard work in reviewing the guidance and guidelines that you are about to hear and also for all the other guidelines that were completed in the last two or three years. And specifically, I wanted to thank our AASOD staff liaisons, Audrey Davis-Aguino and Linae Sanders, who do all the hard work behind the scenes. As my three-year tenure as chair of the AASOD practice guidelines committee is ending this year, I wanted to take this opportunity to thank the AASOD governing board for this wonderful opportunity. During the last three years, we initiated or completed 17 guidelines and guidances. We also initiated guidelines for patients, which I hope you will see in the near future. And finally, I know that the practice guidelines committee is in excellent hands with the incoming new chair, Dr. Betsy Verna, and the new vice chair of the committee, Dr. Cynthia Levy. I hope you enjoy the next five presentations. Thank you very much. On behalf of the AASOD, I'm happy to present an executive summary of the non-invasive liver disease assessments, or NILDA, for hepatic fibrosis and steatosis and portal hypertension. The AASOD commissioned a diverse group of experts across multiple disciplines in the field of adult and pediatric liver disease to develop guidelines and guidance statements along with three systematic reviews. We focused on blood-based NILDA, imaging-based NILDA, and NILDA for clinically significant portal hypertension defined of at least 10 millimeters of mercury. The literature was reviewed between 1988 and June of 2021 to answer specific clinical focus questions in the PICO format. Several important clinical questions could not be answered by a systematic review due to sparse and or indirect evidence. Thus, a thorough narrative review was performed by the writing group to develop ungraded guidance statements. Recommendations were graded based on the quality of the evidence, balance of benefits and harms, patients' values and preferences, and the burden of testing, such as access and financial, and the feasibility of the recommended action. These recommendations, however, are still preliminary and have not yet been reviewed and approved by the AASOD Practice Guidelines Committee and Governing Board. We developed 15 PICO questions that resulted in 36 statements that will be included in three systematic reviews. Today is an executive summary of 12 of those PICO questions. The overall summary of the evidence of NILDA is that in recognition that liver histology is an imperfect reference standard, prior to considering a liver biopsy to assess fibrosis staging in patients with chronic liver disease, the AASOD recommends using blood and imaging-based NILDA as the initial test to detect significant to advanced fibrosis and cirrhosis. NILDA can be broken up into two types for fibrosis and steatosis. Blood-based NILDA includes both routine and proprietary or patented tests and algorithms, and imaging-based NILDA is separated into ultrasound-based and MR-based, looking for fibrosis via liver stiffness measurement and steatosis using controlled attenuated parameter for ultrasound and MRI, PDFF, or spectroscopy for MRI. There are, however, several limitations of NILDA that need to be kept in mind. Blood-based NILDAs can be affected by severe patic inflammation, splenectomy or thrombocytopenia not related to portal hypertension, active alcohol use, chronic kidney disease, and elevated bilirubin in the setting of hemolysis or Gilbert's. Imaging-based NILDAs can be affected by obesity, ascites, iron overload, obstructive jaundice, infiltrative disease, heart failure or Blood-Chiari Syndrome, as well as the non-fasting state. Our first PICO question was, in adult patients with chronic liver disease, including hepatocellular and cholestatic disorders, are blood-based biomarker panels versus liver histology as the reference accurate in staging hepatic fibrosis? The overall guidance statement for blood-based NILDA is that in adult patients with chronic liver disease, the AASLD recommends using simple and readily available blood-based NILDA tests over complex and expensive blood-based testing for the initial detection of significant to advanced fibrosis and cirrhosis, given their good diagnostic accuracy when liver biopsy is used as the reference standard. Genetic recommendations related to this PICO question were, in adult patients with chronic hepatitis B and C undergoing fibrosis staging prior to antiviral therapy, the AASLD recommends using blood-based NILDA to detect significant fibrosis, advanced fibrosis, and cirrhosis. Similarly, in adult patients with NAFLD, the AASLD recommends using blood-based NILDA tests to detect advanced fibrosis. And in patients with alcoholic liver disease or chronic cholestatic liver disease, the AASLD recommends using blood-based NILDA tests to detect cirrhosis, all for strong recommendations with moderate quality of evidence. Shown here in this table are blood-based NILDAs for detecting advanced fibrosis. Several blood-based tests are mentioned, including APRE, FIB4, the European Liver Fibrosis Test, and the NAFLD Fibrosis Score. Again, based on the specific disease, using lower thresholds gives the sensitivities between 69 and 83%. Using the higher thresholds, you have specificities that can exceed, often, 90%. For PICO question 2, we asked, is any blood biomarker panel superior to another for staging hepatic fibrosis? Here, we recommend that in those with chronic hepatitis C who require fibrosis staging before therapy, the AASLD recommends using simple, cost-effective, and readily available blood tests, such as APRE or FIB4 for the detection of significant and advanced fibrosis. In patients with NAFLD, we recommend using, again, simple, cost-effective, and readily available blood-based NILDA tests, such as APRE-RI, FIB4, or the NAFLD Fibrosis Score for the detection of advanced fibrosis, both with strong recommendations with moderate quality of evidence. In our next PICO question, we asked, is the combination of two biomarker panels superior to a single one for staging fibrosis? In patients with chronic hepatitis C, the AASLD suggests that the combination of APRE and FIBR test over either test alone for the detection of significant fibrosis or cirrhosis, and in those with NAFLD, we recommend using a combination of the NAFLD Fibrosis Score and FIB4 in identifying advanced fibrosis over a single test alone, both ungraded statements. The next PICO question asked, do serial blood-based biomarker panels accurately predict the natural history of progression of fibrosis or regression of fibrosis in response to therapy? Here, the AASLD does not suggest the use of blood-based NILDA tests to follow progression, stability, or regression, specifically not to be used in hepatitis B or C patients following therapy or in NAFLD, alcohol-associated liver disease, cholestatic or autoimmune disease following lifestyle or pharmacological interventions, all ungraded statements. Our next PICO question asked, are imaging-based tests accurate in staging hepatic fibrosis? Here, we say that in adult patients with chronic liver disease, the AASLD recommends using available imaging-based NILDA targeting liver stiffness for the detection of significant to advanced fibrosis and cirrhosis, given their good to excellent diagnostic accuracy. Specifically, in patients with chronic hepatitis B and C, undergoing fibrosis assessment prior to antiviral therapy, we recommend using imaging-based NILDA to detect significant fibrosis and cirrhosis. Similarly, in those with NAFLD, the AASLD recommends using imaging-based NILDA tests to detect advanced fibrosis and cirrhosis, both strong recommendations with moderate quality of evidence. In those with alcoholic liver disease or chronic cholestatic liver disease, the AASLD suggests using imaging-based NILDA tests to detect advanced fibrosis and cirrhosis. Here, this was a conditional recommendation with low quality of evidence. Shown on this slide is a summary of imaging-based NILDA for the detection of advanced fibrosis. As you can see, for transient elastography, point shear wave elastography, 2D shear wave elastography, or MRE, across the various diseases using the thresholds as shown, there is excellent sensitivity and specificity. For our next PICO question, we asked, is one imaging test superior to another in staging fibrosis? In patients with chronic hepatitis B and C, ultrasound-based elastography methods have comparable, acceptable diagnostic accuracy for detecting significant or advanced fibrosis, and good to excellent diagnostic accuracy for detecting cirrhosis. In patients with NAFLD, ultrasound-based elastography methods have comparable, acceptable diagnostic accuracy for detecting significant or advanced fibrosis, and again, excellent accuracy for detecting cirrhosis. However, we do recognize that MRE is superior to ultrasound-based elastography for detecting significant fibrosis or advanced fibrosis, all ungraded statements. For our next PICO question, we asked, is one imaging test superior to a blood-based biomarker test? Here, the ASLD suggests that the choice of blood-based versus imaging-based NILDA should be based on local expertise, test availability, and test cost. There is insufficient head-to-head comparative data to support superiority of imaging-based compared to blood-based NILDA. Next, we asked, is the combination of an imaging test with a blood-based test better than a single test for staging fibrosis? Here, we found that in those with chronic hepatitis C with viremia, the addition of blood-based NILDA to ultrasound-based elastography does improve diagnostic accuracy for detecting advanced fibrosis. In patients with chronic hepatitis B, either immune tolerant or immune inactive, the addition of blood-based NILDA to ultrasound-based elastography does not improve diagnostic accuracy for detecting significant fibrosis, and in those with NAFLD, the sequential combination of ultrasound-based elastography to blood-based NILDA may improve diagnostic accuracy for detecting advanced fibrosis. All ungraded statements. Next, we asked, do serial imaging tests accurately predict progression of fibrosis or regression of fibrosis in its natural history or response to therapy? Here, we think that imaging-based NILDA can be used as supportive evidence of regression or progression of liver fibrosis, but found there is insufficient evidence to indicate that it can be used as a surrogate for liver histology. For the purpose of prognostication in patients with chronic hepatitis B and C, the ASLD recommends using imaging-based NILDA, which should be obtained before antiviral therapy, given the limited evidence associated with liver stiffness measurement with clinical outcomes once viral suppression or eradication is achieved. Of note, large reductions in liver stiffness measurement immediately following antiviral treatment for hepatitis B and hepatitis C should not be interpreted as fibrosis regression, and no absolute cutoffs for change following successful antiviral therapy have been identified. For our next PICO question, we asked, is blood-based or imaging-based NILDA useful for predicting the degree of portal hypertension based on an HVPG measurement? Here, we found that the ASLD suggests not using current blood-based NILDA or thrombocytopenia for the detection of clinically significant portal hypertension as they have poor diagnostic performance. Liver stiffness measurement can be used to exclude clinically significant portal hypertension due to its high sensitivity. Spleen stiffness can be used to predict clinically significant portal hypertension in those with suspected advanced fibrosis due to its high sensitivity. Liver stiffness measurement is not as sensitive or specific compared to HVPG for detecting higher levels of portal hypertension, and that liver and spleen stiffness measurements cannot accurately detect changes in HVPG and are not currently acceptable tools for following decreases in HVPG after treatment for liver disease. Next, we asked, in children, are blood-based biomarkers accurate in staging hepatic fibrosis? Here, we found in the pediatric population that the ASLD suggests the use of simple, cost-effective, and readily available blood-based NILDA such as APRE or FIFOR for the detection of advanced fibrosis, but in the pediatric population, there is currently insufficient evidence to recommend blood-based NILDA as endpoints to monitor changes in fibrosis over time. Lastly, we asked, in children, are imaging-based NILDA accurate in staging fibrosis and steatosis? And here, we found that in the pediatric population, imaging-based NILDA tests have both different disease-specific and fibrosis-staging thresholds than the adult population, and that in the pediatric population, it is not possible to recommend a single imaging-based NILDA over another to assess liver fibrosis or steatosis. Shown here is our general approach to how to use NILDA in clinical practice. On the top, step one is using blood-based or imaging-based tests, either alone or in combination, for the detection of fibrosis. On the bottom is the identification of steatosis by imaging, as we did not find blood-based NILDA for steatosis to be accurate enough for clinical practice. There still are several research questions, including the use of NILDA in primary care populations, underserved populations, using combinations of blood-based and imaging-based tests, utilization of novel techniques, such as artificial intelligence and machine learning, and longitudinal studies that will help better assess the natural history of disease, clinical outcome, and changes with therapy. Thank you for your attention. Hello. On behalf of my co-authors, I am honored to present the inaugural AASLD practice guidance on malnutrition, frailty, and sarcopenia in patients with cirrhosis. Our working group included these individuals with scientific expertise relevant to this guidance, but who first and foremost are clinicians who care for patients with end-stage liver disease and therefore understand the unmet needs in clinical practice. I am Jennifer Lai, Associate Professor of Medicine at the University of California, San Francisco. Here are my disclosures. This guidance document is intended to be a pragmatic reference for clinicians who care for patients with cirrhosis. It summarizes the evidence around factors contributing to malnutrition, frailty, and sarcopenia in this population. It also addresses the management of the clinical phenotypes, frailty, and sarcopenia in clinical practice based on evidence when available, and expert opinion to fill in the knowledge gaps. But it should not replace clinical judgment for an individual patient, but instead provide general guidance to optimize the care for most. Our guidance document is quite extensive, and I will not be able to review each of the 39 guidance statements. Rather, today I will provide you with our working definitions of malnutrition, frailty, and sarcopenia, a broad overview of the frameworks covered in this document, and finally, I will highlight key pragmatic tools and tips for management of these conditions in patients with cirrhosis in clinical practice. Prior to this practice guidance, consensus definitions for malnutrition, frailty, or sarcopenia had not yet been developed for patients with cirrhosis. As our first step, we achieved consensus around the theoretical definitions for these constructs. But recognizing the need for more pragmatic definitions to manage these conditions in clinical practice, as well as conduct research on these conditions, we developed separate operational definitions. Malnutrition is a clinical syndrome that results from deficiencies or excesses of nutrient intake, imbalance of essential nutrients, or impaired nutrient utilization. Operationally, we found it useful to consider malnutrition as an imbalance, either a deficiency or excess that, and this is the key point of the definition, that causes measurable adverse effects on tissue, body form, or function, and or clinical outcome. Frailty is a clinical state of decreased physiologic reserve and increased vulnerability to health stressors. Operationally, frailty is the phenotypic representation of impaired muscle contractile function. And finally, sarcopenia is a progressive and generalized skeletal muscle disorder associated with an increased likelihood of adverse outcomes, including falls, fractures, disability, and mortality. Operationally, sarcopenia is the phenotypic representation of loss of muscle mass. Now, although we have developed separate operational definitions for these three conditions, we acknowledge that in clinical practice, they are interrelated and are often present and recognized simultaneously in an individual patient. With this in mind, we have proposed a conceptual framework to consider the relationship between these three constructs. Malnutrition is a major contributing factor that leads to the clinically diagnosable phenotypes of frailty and sarcopenia. Now malnutrition is not the only contributing factor. Other factors such as cirrhosis complications, other systems, physical inactivity, and environmental and organizational factors can also lead to these phenotypes independent of malnutrition. It is these two clinical phenotypes, frailty and sarcopenia, that ultimately lead to the adverse health outcomes that we so frequently see in patients with cirrhosis. Specifically, frailty has been associated with mortality independent of liver disease severity in various clinical settings, including the ambulatory setting as shown in this survival curve on the right. Change in frailty has also been associated with mortality independent of baseline frailty. Furthermore, frailty has been associated with outcomes other than mortality, including unplanned hospitalizations, recovery of physical function after liver transplantation, and overall healthcare utilization. Sarcopenia affects 30 to 70% of adults with cirrhosis and is more common in men than in women. It has been reported in 17 to 40% of children with end-stage liver disease. Like frailty, sarcopenia has been associated with adverse outcomes, including mortality before liver transplantation, as you can see in these survival curves in this figure on the right. A separate but related condition is sarcopenic obesity, defined as the state of decreased muscle mass in the setting of increased fat mass. Sarcopenic obesity has been observed in 20 to 35% of patients with cirrhosis and is independently associated with mortality. Given current trends in obesity, we will undoubtedly be seeing more of this condition in the future. Given the impact that frailty and sarcopenia have on health outcomes in patients with cirrhosis, it is critical to implement interventions early and often to prevent their development and progression. We have proposed in our guidance document a three-level framework for disease prevention and management, with each level representing different aims at different stages of disease, requiring increasing intensities of assessment and action in order to allocate relatively scarce resources of time and specialized care to those with the greatest needs in terms of frailty and sarcopenia. At the level of primary prevention, the aim is to prevent development of frailty and sarcopenia and delay its onset. This requires screening for malnutrition and routine assessment of frailty and sarcopenia. When patients begin to show signs of frailty and sarcopenia, secondary prevention is intended to diagnose these phenotypes early, initiate treatment promptly, and slow their progression. Assessment now requires evaluation for etiologic risk factors and more in-depth exploration of dietary preferences and barriers to exercise. If frailty or sarcopenia are severe or progressive despite intervention, intensive tertiary preventive efforts must be implemented with the goal of rehabilitating and reversing. Assessment should be repeated frequently to evaluate response to personalized interventions. This three-level framework forms the basis for three specific action-oriented guidance statements. All patients with cirrhosis should receive education, motivation, and behavioral skills support to reduce the risk of development of these conditions. A positive frailty or sarcopenia screen should prompt evaluation for underlying etiologic risk factors and the development of an ambulatory personalized management plan. Patients with progressive frailty or sarcopenia despite initiation of secondary prevention efforts should undergo more intensive nutrition and exercise rehabilitation under the direct supervision of a registered dietitian and certified exercise specialist. Now, in order to implement this three-level framework in clinical practice, routine assessment is key. We recommend systematic assessment of frailty and or sarcopenia in all patients with cirrhosis using a standardized instrument. Frailty testing may be particularly useful in the ambulatory setting and for longitudinal assessments to assess natural progression or response to treatment. Sarcopenia testing may be particularly useful for patients in whom administration of tests of frailty are not feasible or are impractical, such as in the inpatient setting, in acutely ill patients, or in very young children. In this guidance document, we have provided two tables that summarize the attributes of the standardized tools that have been studied in patients with cirrhosis to assess frailty or sarcopenia. After a thorough review of the literature, our working group felt that there are insufficient data to recommend the use of one frailty tool over the other. Instead, we recommend that selection of the frailty tool in clinical practice depend upon the relative need for efficiency versus objectivity with a certain clinical scenario. For sarcopenia, on the other hand, CT image analysis is recommended as the most consistent and reproducible method to quantify muscle mass in patients with cirrhosis, but given the risk of radiation exposure, it cannot be recommended for the sole purpose of muscle mass measurement. MRI has not been validated in patients with cirrhosis, but theoretically provides the same information on muscle mass as CT imaging. Let's move on to some select management strategies from the guidance document. We have organized our management strategies around the etiologic factors that contribute to frailty and sarcopenia in patients with cirrhosis. ASCITES leads to early satiety, reduced exercise capacity, and immobility. Some patients who have undergone TIPS placement display increased lean body mass and decreased visceral fat. Frailty and sarcopenia are both associated with adverse outcomes after liver transplantation. Frailty improves one year after liver transplant for most, but only about 40% meet criteria for robustness at one year after transplant. While approximately 30% of liver transplant recipients display improvement in muscle mass, up to 25% may develop new onset sarcopenia after liver transplant. Our guidance statements based on these data are that TIPS placement and liver transplantation for standard indications may offer an indirect benefit of improving muscle mass. There is currently insufficient evidence to recommend using frailty or sarcopenia as an absolute indication for or contraindication against liver transplantation. Systemic inflammation is associated with frailty and sarcopenia in patients without chronic liver disease, and systemic inflammatory markers are elevated in patients with NAFLD, chronic HCV, and alcohol-associated liver disease. Therefore, treatment of liver diseases associated with inflammation is recommended to improve frailty and sarcopenia. Weight loss may reduce disease progression and portal hypertension, but intentional weight loss leads to decreased lean mass and bone mineral density. However, this can be mitigated by resistance training. Therefore, if weight loss is medically required for a patient with cirrhosis, reduce overall caloric targets while maintaining protein targets based on ideal body weight. Caution is advised when recommending weight loss in a patient with decompensated cirrhosis, and it is essential that resistance training be recommended to reduce muscle loss. Patients with cirrhosis have increased total energy expenditure, leading to a catabolic state with relatively short fasts. Therefore, patients should minimize fasting time, particularly at night, with a snack given before bedtime and or upon awakening. Indirect calorimetry is the gold standard for measuring resting energy expenditure, but is not readily available in most practice settings. There is high inter-individual variation in measured versus predicted values of REE in patients with cirrhosis. A personalized nutrition prescription should be provided to patients who screen positive for frailty and sarcopenia. If indirect calorimetry is not available to calculate resting energy expenditure for this personalized nutrition prescription, predictive or weight-based equations may be used. Only about 30% of patients prescribed a low-sodium diet were adherent, and those who were adherent had 20% lower caloric intake. So for patients who cannot meet nutritional targets on a sodium-restricted diet, liberalization of sodium restriction should be considered to facilitate oral intake. Positive protein balance in patients with cirrhosis can be achieved at 1.2 grams per kilogram of body weight per day. Patients with cirrhosis hospitalized with hepatic encephalopathy randomized to a low-protein diet versus 1.2 grams per kilogram per day displayed no benefit in terms of resolution of HE, but harm in terms of accelerated loss of total body protein. A meta-analysis of supplementation with branched-chain amino acids in adults with cirrhosis demonstrated no benefit in terms of improvement in nutritional parameters. Although one small pediatric study demonstrated improved anthropometrics with a branched-chain amino acid enriched nutrition support versus a standard formula. Based on these data, recommended daily protein intake for adults with cirrhosis should be 1.2 to 1.5 grams per kilogram of body weight per day for pragmatic reasons we recommend using ideal body weight based on height. Protein intake should not be restricted in patients with hepatic encephalopathy. There is insufficient evidence to support branched-chain amino acid supplementation in adults. Physical activity-based interventions improve muscle function, muscle mass, and quality of life in patients with cirrhosis, and improvement in frailty has been associated with lower rates of mortality. While data on optimal duration, time, and type of exercise are lacking, activity-based intervention trials have ranged from eight to 64 weeks and have typically included a combination of aerobic and muscle-strengthening activities. Studies have shown that activity-based interventions are safe in this population, but should be adapted to reduce risk of falls and injury. Based on this information, physical activity-based intervention should be recommended to all patients with cirrhosis. Intervention should include a combination of aerobic and resistance exercises, and reassessment with a standardized tool is necessary to determine response and to tailor the intervention based on response. And finally, I wanna call to your attention two toolboxes that we developed to facilitate diagnosis and management of frailty and sarcopenia in patients with cirrhosis that summarizes pragmatic methods to implement our guidance statements within your day-to-day clinical practice. In conclusion, malnutrition, the imbalance of nutrients, leads to the clinical phenotypes of frailty, the loss of muscle contractile function, and sarcopenia, the loss of muscle mass. Frailty and sarcopenia are prevalent in both adults and children and strongly associated with adverse outcomes. The three-level disease prevention and health promotion framework can be used to tailor resources based on an individual patient's risk for and severity of frailty and sarcopenia. At the primary and early secondary levels, we recommend use of the diagnostic and management toolboxes in your day-to-day clinical practice. But if severe or progressive despite intervention, then we recommend co-management with a registered dietician, certified exercise physiologist, and or health behavior specialist. Thank you for your attention. Hi, my name is Mike Shilski, and as chair of the writing committee for the ASLB 2021 guidance, a multidisciplinary approach to diagnosis and management of Wilson disease, it is my honor to present on behalf of the writing committee. These are my disclosures. In 2003, I had the opportunity to, along with my colleague, Eve Roberts, to put forth the first ASLD practice guidelines on Wilson disease. As an adult hepatologist, it was wonderful pairing with Eve, who represented the pediatric viewpoint very well. And we felt we had a very complete and complementary writing group. In 2008, only a short five years later, we were called upon to add some updates to our prior guidelines. However, since then, it's gotten a lot more complicated. And so we thank our guidelines committee for sharing our vision in expanding our writing group, not only to include other hepatologists, Carl Heinz Weiss from Heidelberg, Anil Dhawan from King's, Jamie Hamilton from Hopkins, but also to represent the multidisciplinary care model for Wilson disease patients. We expanded the group to really include other disciplines that touch upon the care for our patients with Wilson disease. So on the bottom row, we have pictures. You'll see Paula Zimbrian to the left, Mary Kay Washington, Jeff Bronstein, and Anne-Marie Rivard. And these represent colleagues who have expertise in psychiatry, pathology, movement disorders for neurology and dietary management of patients. Now, this is importantly now a guidance and not a guideline. So when this appears in writing, it will not include the standard grading format that we had previously, but it will represent the advances in the literature, a thorough search and include expert opinion. And this is expert opinion as agreed upon by all the various different disciplines and members of our writing group and the committee. For this new guidance, we've included a number of new figures and tables. We've updated all the algorithms for diagnosis. And for reference, we have included scoring using the Leipzig score, which is a diagnostic score for Wilson disease for some of the elements as part of the algorithm for reference. We have inserted in determinate into the algorithm. And this was something that was through a shared discussion with Eve Roberts and Eve was brave enough to admit that we got to points where we had difficulty deciding. And we generated corresponding checklist tables to go through to aid you in that diagnosis in really carefully looking back through the algorithm and helping make the best decision. And this really was a major difference from before. We also have included a new figure regarding stage of disease dependent approach to thinking about the therapy for Wilson disease and new tables to discuss mimic diseases that overlap with the phenotype for Wilson disease that we may sometimes need to consider, as well as treatment targets for each of the available therapies. There also will appear supplemental tables that include dietary advice, the Leipzig score, as well as the new Wilson index in units that are more applicable to those working in the United States and Canada. We also have new features and definitions and we included an expanded pathology section. There is substantially enhanced neurology, psychiatry and dietary sections. We've also given a lot of thought to what actually constitutes asymptomatic versus symptomatic since we define many of our initiation of therapy upon which category of patients there are. We also include a section on acute liver injury for patients that may not have full acute liver failure, recognizing that some of these may be treatable and include the use of the prognostic scoring in evaluating some of these patients, as well as a separate section on defining intensive treatment for these individuals. Now, we've also given great thought to what constitutes treatment failure and when people should consider altering their therapy or performing further diagnostics. And we've also come upon finally, in terms of monitoring, a de-emphasis of the old formula for non-celluloplasmic proper and we'll discuss that in a few moments. This is an example of one of our new enhanced algorithms. And as you can see, you still need some basic information to get in. And this includes recognition of whether there's liver disease or other algorithms for neurologic patients, whether Kaiser Fleischer rings are present or absent, a value for seruloplasmin and a urinary copper. Let me show you two examples about how we may approach this as we take this through sort of parts of the algorithm. If we have a patient who has a moderate reduction or a normal seruloplasmin and a modest increase or a higher increase in urinary copper, we still may wanna go forward and do a liver biopsy. And the results from that would either give us a normal liver copper, in which case it would drive us towards further testing with genetic mutations for ATP7B. However, the results would probably lead to either patient being heterozygote or non-affected by Wilson disease, or on the other hand, lead to a diagnostic value of 250 micrograms per gram or above for the liver copper, in which case the diagnosis is established. However, if we move to the liver biopsy and we come up with that intermediate value of liver copper, then we may certainly need genetic testing. And if we find two disease-specific mutations, then it's easy and we've established diagnosis. If, however, we end up with one mutation only or no mutations detected, we have to really rethink it. And this is where the gray zone comes in. And so that patient may be a carrier or it may not be Wilson disease at all. Then we label this as potentially problematic or indeterminate. Now to approach these particular gray zones in our diagnostic algorithm, we have put forth checklist of table that has four separate sections. And here's an example of one section. This particular one is looking at the accuracy of laboratory tests. And we talked about for each particular item, the specific issues in terms of understanding whether the test is valid or not or whether other testing is needed. And then actions about how to go about looking for that determinate value. And so you can see here, we looked at cerebral plasma, urinary copper, liver copper, as well as discussing the genetic analysis. And there are three more sections that go through this in a very detailed fashion. Next, we talk a little bit in terms of treatment and look at treatment with respect to the stage of the disease. Shown here is a timeline for the natural history of Wilson disease in an untreated patient. On the left of the timeline is the early phase when the patients may be asymptomatic and moving towards the right when they're developing more liver disease and more neuropsychiatric disease and ultimately liver failure and death may occur. Now, in the early phase of disease, prevention is really the treatment goal. And then when patients are symptomatic, we approach it slightly differently. But again, it's with the aim of reducing and then later preventing recurrence of symptoms. And then when you have a very unstable patient, further down the line, that's when we consider rescue therapy or the intensive therapy that's needed to try to rescue that individual if they're not going to undergo liver transplantation. We also have discussed better definitions for asymptomatic versus symptomatic, again, because we've defined some of our choices of therapy based on that. And here we've started to include concepts of whether organ damage is present or not, irrespective of whether the patient is actually manifesting clinical symptoms. And we think this is an important distinction and may help us define this a little bit more carefully going forward. And importantly, we've gone through each of the therapies and also defined treatment failure and not only define that, but also talk about what to do next in terms of approaching these individuals, whether it's changing therapy or exploring whether or not there are other secondary problems going on in that individual. Now, we've also broken down the scoring systems into two different sections, one related to diagnostic, and we will discuss a little further the Leipzig score. And again, we've taken that and incorporated that as well into the algorithms more for reference for those who like to use that preferentially. And then importantly, we've added a little more emphasis on the prognostic scoring system or the New-Wilson Index, in the past also called Modified Maser Index, and really thought about its use not just in a single moment in time, but potentially sequentially and serially so that we can look at an individual and decide which path they're going upon, whether or not medical therapy may be possible or whether we're headed definitively towards transplantation. And in the supplemental part of the manuscript will be this table, which includes the New-Wilson Index in units that are more commonly used in the United States. And lastly, we have moved towards a de-emphasis of the old formula, non-ceruloplasmin-bound copper using the estimate of total serum copper minus the ceruloplasmin times 3.15, which was always a fudge factor to give us the approximate amount of copper in the protein. However, this is a problematic formula when considering that most of the ceruloplasmin determinations are done immunologically, and we have very great difficulty in getting it in a significant proportion of patients, this to represent the accurate amount of copper that is in that protein, and many individuals had either a zero or negative value for something that is impossible in that setting. So therefore, we are welcoming new assays, although we have not, do not have these commercially available. There are now publications that recognize that there are better ways of getting to an accurate determination of ceruloplasmin-bound copper. The first publication back in 2020 came from Chris Harrington's laboratory, and they are shown in this figure are the peaks where you can see under the arrow of ceruloplasmin in a patient with Wilson disease and a larger peak in the graph below with a patient that doesn't have Wilson disease, and then using ICP male spec on these peaks that are separated by liquid chromatography, a very accurate determination of the copper in the ceruloplasmin protein can be made. Similarly, another manuscript has come forth in 2021, and that's by Ward Dietrich and colleagues, and in this method, it's similar to the Harrington method in that this uses a modified liquid chromatographic method that isolates the ceruloplasmin copper and similarly uses the ICP male spec for its determination. Using that methodology, we present in one of the posters, number 1548, that the validation of this method using controls as well as patients with Wilson disease from the trial called the QA trial. So, in summary, we have made a lot of advances, and in particular, the inclusion of this multidisciplinary writing group is really revolutionary, and for that, we have a special thanks to our Guidelines Committee, and in particular, our chairs, George and our embedded member, Anjana, who shared our vision and allowed us to move forth to produce these new extraordinary guidances, and we always like to remember to thank Audrey. Audrey has actually been working with Eve and I on the original guidelines going back to 2002, and a special thanks to you for all your assistance to us and to the Guidelines Committee. So, thank you very much, and we hope you do enjoy these. On behalf of my co-authors, it's a pleasure to present the ASLD guidance on primary splicing cholangitis and cholangiocarcinoma. This is an update of the 2010 guidance statement on primary splicing cholangitis and is the first to include cholangiocarcinoma. I'm the Lena Valente Professor-in-Chief of the Division of Gastroenterology and Hepatology at the University of California, Davis. These are my disclosures, and please note these recommendations are still preliminary and have not yet been approved by the ASLD Governing Board. Primary splicing cholangitis. PSC refers to a disease of the bile ducts resulting in segmental strictures and dilations of the intrapartic and extrapartic bile ducts. Distinguished PSC from its variant form, sometimes it is referred to as large duct PSC. The variant forms include small duct PSC in which there are typical histologic features of PSC, but in the presence of a normal cholangiography. These patients may progress over time to large duct PSC. Patients with PSC may also present with features of autoimmune hepatitis, a term called PSC-AIH overlap. Importantly, there are no established criteria for the diagnosis of PSC-AIH overlap. Because PSC is diagnosed in the presence of strictures, on imaging, the quality of MRI used for cholangiography is extremely important. Minimal criteria include T2-weighted MRCP with 3D MRCP using 1-millimeter slices, though 2D MRCP is adequate in many situations. Rank-mode imaging should be achieved with non-contrast T1-weighted and T2-weighted axial imaging. The use of contrast may be helpful in certain situations, but may not be required in all. Defining strictures of the common bile duct and hepatic ducts has evolved over time. Previously, a dominant stricture was defined as a stricture in the common bile duct of 1.5 millimeters or less, or less than 1 millimeter in the hepatic duct seen on ERCP. However, in clinical practice, dominant stricture has come to mean a stricture of the common bile duct or hepatic duct leading to changes in clinical status. High-grade stricture has recently been defined as a reduction in the lumen of the common bile duct or hepatic duct of more than 75 percent on MRI. In collaboration with colleagues at ESOL, the writing group has defined the term relevant stricture to refer to strictures of the common bile duct or hepatic duct, which may or may not achieve these criteria of dominant stricture or high-grade stricture, but in which worsening cholestasis or cholangitis occur. Unlike primary biliary cholangitis, autoantibodies and PSC are not diagnostic. Importantly, serum IgG4 levels may be elevated in up to 15 percent of patients with PSC and lead to confusion with the diagnosis of IgG4 sclerosing cholangitis. Notably, high levels of serum IgG4 over 5.6 grams per liter is highly specific for IgG4 sclerosing cholangitis. In individuals with intermediate levels of IgG4, an IgG4 to IgG1 ratio of less than 0.24 has a high negative predictive value for IgG4 sclerosing cholangitis. Liver biopsy has a limited value in PSC except to make the diagnosis of small duct PSC or concurrent autoimmune hepatitis, and although they are typical and compatible features of PSC, these are neither specific nor sensitive for the diagnosis. Therefore, the diagnostic approach to PSC should include a high-quality MRI, and when strictures are found in the absence of secondary causes, a diagnosis of primary sclerosing cholangitis can be made. If the images are normal, then a liver biopsy should be considered to rule out small duct PSC or an alternate diagnosis. In cases where the imaging is equivocal, if the scan is optimal, then repeating a scan in one year or considering liver biopsy is reasonable. If the scan is suboptimal, then consideration should be given to referring the patient to an expert center for repeat imaging. Staging of disease in PSC can be difficult because liver biopsy has limitations due to the sampling variability associated with the heterogeneous fibrosis that occurs in PSC. More recently, baseline and change in liver stiffness by transient elastography or MR elastography have been associated with hepatic decompensation and other clinical events. The liver stiffness may be affected by transient biliary obstruction. Several prognostic models have been developed over the recent years, including the Amsterdam-Oxford model, the UK PSC, PRESTO, and SCOPE models. They all use a variety of different endpoints and timeframes and include different populations in their model development. However, they all have excellent accuracy in the 5-10-year timeframe. Therefore, risk stratification in fibrosis staging should be done at diagnosis of PSC and regularly during follow-up. Clinical risk tools can be considered for this purpose, but specific probabilities of events should be interpreted with caution in the individual patient. Liver stiffness measurement is currently the preferred method for estimation of fibrosis in PSC. Liver biopsy is not recommended for fibrosis staging in clinical practice. There currently is no proven therapy for the treatment of primary sclerosing cholangitis, but two medications deserve attention, including ursodeoxycholic acid and oral vancomycin. UDCA has been extensively studied and consistently shown to improve alkaline phosphatase. A normalization of alkaline phosphatase, or GGT, in children, or the reduction to less than 1.5 times the upper limit of normal, are associated with better survival. And UDCA withdrawal is associated with increased symptoms, liver biochemistries, and myelospore. However, there's no evidence for a reduction of clinical outcomes in any trials. There are also potential risks with high dose or so, including increased risk of adverse events in colorectal neoplasia. Therefore, in patients with persistently elevated alkaline phosphatase, or gamma GT, UDCA in divided doses of 17 to 23 milligrams per kilogram per day can be considered for six months and continued if there is a significant reduction in alkaline phosphatase, or GT, and or symptoms improve. In contrast, oral vancomycin studies are limited to one randomized controlled trial in adults and conflicting case control studies in children. There's no established dose, and there are potential risks for selection of vancomycin microbes. In the largest study to date from the Pediatric PSC Consortium, listing for liver transplantation was not significantly different between patients treated with oral vancomycin, ursodeoxycholic acid, or no therapy. Therefore, currently, there is insufficient evidence to recommend the use of oral vancomycin outside of a clinical trial. The risk of cholangiocarcinoma in PSC is higher in males, those with a dominant stricture, and concomitant IBD. Lower risk is associated with a diagnosis less than 20 years of age, and cholangiocarcinoma is rare in children and those with small duct PSC. Surveillance has been associated with a better five-year survival, and MRI may be superior to ultrasound in asymptomatic patients, though there are concerns of MRI, including repeated gadolinium injections and its cost. CA199 has low sensitivity and specificity for cholangiocarcinoma. Cholangiocarcinoma and gallbladder cancer surveillance should be performed annually and include abdominal imaging, preferably by MRI, MRCP, with or without serum CA199, and surveillance is not recommended for patients under 18 years of age or with small duct PSC. PSC patients with IBD are at higher risk of colon cancer compared to the general population, as well as patients with IBD without PSC, particularly in those under the age of 40 years of age. They more frequently have endoscopically invisible dysplasia, more rapidly progress from low-grade to high-grade dysplasia, and colorectal cancer can occur in children with PSC and IBD and is greater in those diagnosed with IBD before the age of six years. Therefore, ileocolonoscopy with biopsy should be performed in patients with a new diagnosis of PSC and no previous diagnosis of IBD. In patients without IBD, subsequent ileocolonoscopy should be considered at five-year intervals or whenever symptoms suggestive of IBD occur. In patients with PSC in whom IBD is diagnosed, high-definition surveillance colonoscopy with biopsy should start at age 15 years and be repeated at one- to two-year intervals to evaluate for colonic dysplasia. For surveillance of biopsy-proven invisible low-grade colonic dysplasia, chromoendoscopy is required. Liver transplantation is indicated for any PSC patient with decompensated cirrhosis. In addition, MELD exception points may be assigned for patients with recurrent cholangitis if they meet the criteria of cirrhosis and at least two admissions to the hospital within a one-year period for acute cholangitis with a documented bloodstream infection or evidence of sepsis, including hemodynamic instability requiring vasopressors. Select patients may also be candidates for MELD exception points for cholangic carcinoma. Recurrent PSC occurs in approximately a third of patients transplanted, and the diagnosis can be difficult. Risk factors for recurrent PSC include male sex and a number of other transplant-related risk factors. Whether pre-transplant colectomy is protective has yet to be completely established. Therefore, liver transplantation should be considered in all PSC patients with end-stage liver disease and selected patients with recurrent cholangitis, intractable arthritis, and hepatobiliary cancers. Patients with elevated liver enzymes after transplant should undergo histologic and cholangiographic assessments to distinguish recurrent PSC from allograft rejection or biliary complications. And now on to cholangiocarcinoma. Cholangiocarcinoma can be divided into three separate groups based on the location of the lesion, including intrapatic cholangiocarcinoma, perihylar cholangiocarcinoma, and distal cholangiocarcinoma. There have been potentially actual mutations identified in each type of these cancers. For intrapatic cholangiocarcinoma, a third are diagnosed incidentally on imaging, and while CA19-9 is not specific for cholangiocarcinoma, elevated levels over 1,000 are associated with metastatic disease. Imaging is useful, but it can be challenging to distinguish cholangiocarcinoma from HCC, and there are no established imaging features that can be used to make the diagnosis of intrapatic cholangiocarcinoma. Therefore, intrapatic cholangiocarcinoma diagnosis requires histologic assessment of a core biopsy. Treatment of intrapatic cholangiocarcinoma is surgical resection and adjuvant capcitabine. The median survival following resection is 40 months, with five-year overall survival of 25 to 70 percent. In the randomized controlled trial of capcitabine, improved median survival was achieved versus observation following surgical resection. Historically, there have been poor outcomes following liver transplantation in patients with intrapatic cholangiocarcinoma, with recurrent free survival of only 18 to 25 percent after five years. However, retrospective analysis has identified that incidental solitary intrapatic cholangiocarcinomas of two centimeters or less are associated with a five-year overall survival of 65 percent, and therefore may be an option for some patients. Local regional therapy is frequently used for intrapatic cholangiocarcinoma, but there are no randomized controlled trials comparing the efficacy of different forms of local regional therapy. In contrast, Hylar obstructions can be imaged by MRI and MRCP and have high sensitivity and specificity for distinguishing benign from malignant causes. In addition, positive biliary cytology or biopsy confirm a diagnosis of perihylar distal cholangiocarcinoma, though conventional cytology has low specificity. This, however, can be enhanced with fluorescent in situ hybridization. Importantly, fine-needle aspiration, either percutaneous or EUS-guided, of a lesion should be avoided in patients who are potential liver transplant candidates, as tumor seeding may occur. However, fine-needle aspiration of lymph nodes may be advisable to include patients as transplant candidates. To achieve mild exception points for liver transplantation, Hylar cholangiocarcinoma patients must demonstrate a malignant-appearing Hylar stricture on cholangiography, and at least one of the following. Biopsy or cytology results demonstrate a malignancy, a CA-19-9 greater than 100 in the absence of cholangitis, aneuploidy, or Hylar mass less than or equal to 3 centimeters in radial diameter. Surgical resection is preferred for perihylar and distal cholangiocarcinoma in those with early-stage disease and preserved liver function, but this is associated with high mortality and poor outcomes after surgery, even with adjuvant capsidabine. Liver transplantation is an option for select patients with perihylar cholangiocarcinoma meeting very strict criteria. This involves neoadjuvant therapy and can result in overall survival of 65% and recurrence-free survival of 78% at five years following liver transplantation. However, there is a high dropout rate prior to transplant, though this is lower among patients with PSC and cholangiocarcinoma. Systemic therapy for cholangiocarcinoma includes first-line gemcitabine and cisplatinin. Second-line therapies include Folfox, which has demonstrated marginal improvement in meeting overall survival. More recently, two agents have been FDA-approved for the treatment of cholangiocarcinoma with FGFR2 fusions. Immunotherapy has shown limited efficacy. Therefore, in patients with unresectable cholangiocarcinoma, the treatment should follow the following algorithm based on the location of the cholangiocarcinoma and includes liver transplantation for those with higher cholangiocarcinoma and a single legion less than three centimeters, or those with intrapartic cholangiocarcinomas less than two centimeters, which can be referred for liver transplantation following a research protocol at select centers. So the key takeaways from the ASLD guidelines on PSC and cholangiocarcinoma include obtaining a quality MRI and MRCP for the diagnosis of PSC with liver biopsy reserved for select cases. Prognostic models and liver stiffness can be used to restratify patients. UDCA use is supported, but not oral vancomycin. Cancer surveillance should include annual imaging in patients with IBD, annual colonoscopy, and there are updated MELD exceptions for recurrent cholangitis. For cholangiocarcinoma, intrapartic cholangiocarcinoma requires histology for diagnosis, but perihylar cholangiocarcinoma does not. Do not perform FNA of perihylar cholangiocarcinoma if the patient has a potential liver transplant candidate, and there are also updates to MELD exceptions for perihylar cholangiocarcinoma. Thank you for your attention. Hello, my name is Fasiha Khanwan, and I will be talking to you about palliative care in patients with decompensated cirrhosis reviewing the recent ASLD practice guidance. I am a physician scientist with a federally funded research program focused on risk stratification and healthcare delivery of patients with chronic liver diseases, including patients with cirrhosis of the liver and hepatocellular carcinoma. I do not have any financial relations to disclose. As we know, patients with decompensated cirrhosis have a poor prognosis. In this recent study that followed over 100,000 patients with cirrhosis, the two-year mortality was as high as 20%, and it rose to about 50% at five years. As you can see on the right-hand side of your slide, the overall disease trajectory in cirrhosis is a progressive downward course with declining health, increasing symptom burden, and frequent hospitalizations at the end of life. Although liver transplantation can be curative, very few patients are ever listed for or receive transplantation. Collectively, these data underscore the high need for palliative care for patients with cirrhosis and their caregivers, but we also know that these needs are frequently unaddressed. The ASLD guidance for palliative care for patients with cirrhosis aims to meet this clinical need. Palliative care is a multidisciplinary, specialized medical care that addresses the physical, the spiritual, and psychosocial needs of patients with serious illness, as well as their caregivers. The benefits of palliative care are increasingly recognized across multiple disease states and also for patients with decompensated cirrhosis. These are the eight core domains of high-quality palliative care, and I will focus on most of these during my talk, including the physical, the psychological, social, spiritual, and cultural aspects. I'll also talk about care of the patient at the end of life and caregiver support. But before I do that, let me just talk a little bit about the different definitions and the conceptual distinctions between them. Specialty palliative care is the care delivered by specialists with advanced palliative care skills, such as board-certified palliative care physicians or nurses, social workers, pharmacists. Primary palliative care describes care that's aligned with the principles of palliative care. It's patient-centered, communication-focused, focuses on symptom management, and it can be delivered by any medical professional. Advanced care planning, it's a component of palliative care that involves a longitudinal process of medical decision-making for patients and their families over the course of their in-laws. It includes identifying surrogate decision-makers, in-laws education, prognostic disclosure, and documenting goals of medical and end-of-life care through advanced directives. Hospice is different than palliative care. It focuses exclusively on comfort rather than disease-directed curative treatment, and it includes only individuals with a life expectancy measured in months. Given the high burden, mortality, and morbidity burden in patients with cirrhosis, palliative care can be provided to patients with decompensated cirrhosis at any stage of their illness. Evaluation for unmet palliative care needs and specialty palliative care consultation should be considered for all patients with decompensated cirrhosis. There is a shortage of specialty palliative care providers, and given that, hepatology clinicians, especially those with long-term relationship with patients and families, can play a key role in delivering primary palliative care. Disease-directed care, such as thinking about liver transplantation, liver transplantation evaluation, and listing, does not preclude palliative care delivery or consultation. Advanced care plan, as I mentioned, is an iterative process, and it should start with the diagnosis of cirrhosis, and it should preferably occur prior to hepatic decompensation and loss of decision-making capacity that is seen with hepatic encephalopathy. Due to the poor prognosis of our patients, many individuals with decompensated cirrhosis that we see in our clinical practices qualify for hospice benefits, and we should always keep that in mind. This can help support patients and their caregivers. Caregiver support is critically important, and it should be provided across the trajectory of liver disease, end-of-life care, and after the patient's death. Let me briefly touch upon the psychosocial, spiritual, and cultural aspects of palliative care before I shift on to symptom management. Psychosocial, spiritual, and cultural aspects, they are understudied in our patient population. In general, an interdisciplinary, person-centered approach is recommended when addressing these potentially sensitive topics, and it is important to be aware of the local resources that we can leverage. These resources could be identified through ongoing conversations with our colleagues in the social work, pharmacy, patient navigation services, and pastoral care whenever available. Financial considerations. They should be assessed when providing palliative care, as they can contribute to a burden on patients and caregivers. Thinking about social work referral, earlier on, especially in patients with unmet psychosocial needs. Involving chaplaincy, spiritual, and pastoral care from the hospital or from the community can help address spiritual distress that many of our patients experience. Medical teams should also ensure that there are trained individuals who are available to facilitate communication regarding these psychosocial issues in the language preferred by the patients and their families. Symptom management is a core component of caring for patients with decompensated serosus who often suffer from multiple, often interrelated symptoms. A recent systematic review found that many of these symptoms, they co-occur, and they are common. The most frequently reported symptoms being pain, breathlessness, muscle cramps, sleep disturbance, depression, anxiety, and sexual dysfunction. I'll touch upon most of them in the next five minutes. Because often not all symptoms can be addressed in a single clinical encounter, it is important to create an approach to track and prioritize symptoms. It is also important to identify and manage the underlying causes of symptoms when possible. Often, the first approaches to symptom management may be non-pharmacological, such as behavioral intervention, physical therapy, or other modalities that could potentially address multiple symptoms. Between 30% to 80% of patients with serosus report pain, and the etiology could be divided into liver-related, mechanical pain, inflammatory pain, or non-liver-related pain. Pain requires a systematic approach that starts with assessing and treating reversible causes, such as individuals with localized pain, knee osteoarthritis. It should be first addressed with local, rather than systemic, therapies. A certain amount of N, 500 milligrams every six hours, with titration to a maximum dose of two grams per day, is the preferred first-line pharmacotherapy for pain in serosus. Systemic NSAIDs should be avoided in patients because there are multiple studies that show the deleterious impact of NSAIDs due to risk of renal injury, bleeding, and worsening of ascites. Opioids, they are not effective in the management of chronic pain, and patients with liver disease are among the group with the highest risk of opioid-related adverse events. However, in some instances, opioid use may be necessary. And when necessary, they should be approached with caution. Low-dose oxycodone or hydromorphone can be started in select cases on an as-needed basis, and they should be titrated to effect. It should be done in combination with pain management experts. Ascites, the most common complication of serosus, and specific recommendations in this population, including use of large-volume parasitic disease, or LVP, they're covered in the relevant ASLD practice guidance. LVP requires multiple visits to the hospital, and it can be burdensome, especially towards the end of life. TIPS, which is another option in patients with the refractory ascites, but many patients are not candidates for TIPS due to hepatic encephalopathy, cardiac conduct indications, or high male scores. Recent studies, they have evaluated the feasibility and safety of longer-term abdominal drains, and automated low-flow ascites pumps in patients with the refractory ascites. For example, there's a recent review of 18 studies, including over 170 patients, over 170 patients, who were not candidates for liver transplantation, and they were treated with long-term ascites drains for palliation, showed that these drains had a low rate of non-infectious complications, and overall, spontaneous bacterial peritonitis rates were also less than 15%. Most of these instances were managed medically, with the drains left in place. A recent randomized control trial also demonstrated feasibility of long-term drains in TIPS-ineligible patients with comfort-focused goals. Given these data, abdominal drains may be an alternative to serial large-volume paracentesis for patients with refractory ascites who are transplant and TIPS-ineligible, and whose goals are comfort-focused. However, more comparative effectiveness research is needed before recommending this approach. A recent study of low-flow pumps in 30 TIPS-ineligible patients identified improvements in quality of life and nutritional status, with no serious adverse events related to renal dysfunction, at least in the first few weeks post-insertion. However, these pumps are not yet available in the US or Canada, and we need to wait for more data. Given the prevalence of difficulty breathing and shortness of breath, patients should routinely be assessed for the presence of dyspnea. Non-pharmacological therapies should be used first to manage dyspnea when possible, and they include use of a fan, supplemental oxygen even for non-hypoxic patients, and mindfulness exercises. Pharmacological interventions for dyspnea may include opioids and anxiolytics, which may be employed, but with careful consideration of risks, patient goals, and prognosis. Muscle cramps are very common and burdensome in patients with cirrhosis. While the precise etiology is unclear, alterations in nerve function, energy, and plasma volume and electrolyte depletion may contribute. Checking serum electrolytes levels and repleting potassium, magnesium, and zinc when low is the first step in management of muscle cramps. Small open-label studies have evaluated use of taurine as a treatment for muscle cramps in cirrhosis with resolution of cramps in 30 to 40% of patients over four weeks. And these findings were confirmed in a small randomized controlled trial as well. Vitamin E has had mixed effectiveness in treating cramps in small studies of patients with cirrhosis. Muscle relaxants such as Beclafen have also demonstrated efficacy, at least in the short-term trials of patients with cirrhosis. Beclafen, up to 30 milligrams per day, led to at least partial resolution in more than 90% of users after three months of use. There are other small studies that have demonstrated preliminary effectiveness of albumin infusion, alkanidine, and zinc in managing cramps, but more conclusive data are needed. Half patients with cirrhosis experience sleep disturbances and clinicians should evaluate and treat underlying causes such as hepatic encephalopathy, pruritus, obstructive sleep apnea, and restless leg syndrome when these are present. Mindfulness-based stress reduction therapy and cognitive behavioral therapy can be considered in patients with cirrhosis and disordered sleep. Short-term use of melatonin, three milligrams, or hydroxyzine, 25 milligrams nightly can improve sleep quality in patients with child class A or B cirrhosis, but data on long-term use of these medications are limited. And while chronic use of benzodiazepines should generally be avoided in patients with decompensated cirrhosis, specific circumstances may warrant their use, such as anxiety, especially at the end of life when comfort is the main priority. Fatigue is among the most frequent and distressing symptoms in patients with cirrhosis. There's several studies, at least in patients with child class A and B cirrhosis that have found that physical exercise can help reduce fatigue. Stimulants have been successfully used for fatigues in other patient populations. However, a randomized controlled trial, defenil, in patients with PBC, did not find any significant impact on fatigue. Given that, we recommend a multidisciplinary approach to addressing fatigue that could include evaluation and treatment of contributing factors, providing behavioral education, and recommending physical activity. As I mentioned, there are insufficient data to support the use of stimulants to treat fatigue in patients with cirrhosis. Pruritus, again, are common and burdensome symptoms in patients with cirrhosis from all etiologies, although it affects patients with cholestatic liver disease disproportionately. Our suggested approach to pruritus is to start with non-pharmacological options, use of moisturizing creams, avoiding hot baths, harsh soaps, and using loose-fitting clothes and cool, humidified air. Cholestyramine is a first-line treatment for pruritus. There are alternative agents, including low-dose naltrexone, rifampicin, and sertraline, but these agents require careful titration, especially for our patients with decompensated cirrhosis. Treatment of sexual dysfunction, it could be conceived as pharmacological and non-pharmacological approaches. First, medications such as beta blockers or substances such as alcohol that can cause sexual dysfunction should be removed when appropriate. Underlying conditions that can contribute to sexual dysfunction, such as depression and diabetes, again, very common in our patient populations, they should be managed. Thinking about pharmacological treatment, using phosphatidase trace inhibitors is a potential option. There is one small study of Tadalifil in 25 men with cirrhosis, and erectile dysfunction found that over a four-week period, this medication was safe and efficacious. There is an ongoing trial of Tadalifil for patients with cirrhosis that should add to this literature, but in the meantime, these data are important in forming our recommendations. Before I wrap up, a few key points about the end, about the care at the end of life. Hospice is a patient and caregiver-centered approach for the end-of-life care that is underutilized in patients dying with cirrhosis. In addition to the current criteria for hospice, epidemiology teams may consider using male score at the cutoff of 25, 21 or above, or child abuse score of more than 12 to determine when patients are prognostically appropriate for hospice. These are the patients with the estimated survival of six months or less. Providing caregivers with information about imminent death may help support decisions aligned with patient's prognosis, such as anxiety at the end of life when comfort is the stated priority. And just to wrap up, palliative care is a multidisciplinary approach to addressing the multiple psychosocial, physical and spiritual needs of patients and their caregivers, and it is associated with improved health outcomes in chronic illnesses, including cirrhosis. However, it is highly underutilized in patients with decompensated cirrhosis. We encourage all members of the hepatology care team to consider providing palliative care to address multiple needs of our patients and their caregivers. These core principles of palliative care are clearly aligned with high-quality value-based hepatology care. Future research is needed to identify the optimal approaches to train medical staff in providing primary palliative care and finding out when are the best opportunities for engagement of specialty palliative care and identifying innovative models that successfully blend these currently distinct disciplines. But more important, the most important point is that palliative care should be offered earlier and to more patient-based services. Thank you very much. Hello, this concludes our ASLD practice guidelines update. My name is Elizabeth Verna. I'm currently the vice chair of this committee and have the honor of becoming the committee chair in 2022. I'd like to thank all of our speakers for their fantastic presentations today, as well as all of the members of the five writing groups for lending their tremendous efforts and expertise in the creation of these outstanding new documents. Before we conclude, I'd like to preview the year to come. I'm proud to announce that an additional five documents are currently in process, and we anticipate they will all be published in 2022. The topics of these documents include interventional approaches to gastroesophageal varices, portal hypertension, drug and supplement-induced liver injury, hepatocellular carcinoma, and ACLF and ICU care. In addition, we'll convene writing groups for eight additional documents that will kick off in 2022, including all aspects of adult and pediatric liver transplantation. A new initiative for our committee is to create companion documents for our guidelines and guidances specifically written for patients. So look out for these new patient resources in the year to come as well. As a reminder, all of our ASLD guidelines and guidances are available to both members and non-members on our website, which you can see here below. And finally, I'd like to thank the fantastic ASLD staff who make our committee work possible, as well as all of the hardworking members of our Practice Guidelines Committee. And a very special thank you to our leader for the last four years, George Iwanu. George, as all of you know, is a professor of medicine and an expert in hepatology and epidemiology. He has served in this committee since 2017 and has been the committee chair since March of 2018. When he concludes his almost four-year term at the end of this year, he will have overseen the expansion of our committee membership, successfully steered us to continue our important work throughout the pandemic, and has overseen the development of a total of 16 new guidance documents, six of which were brand new topics for the ASLD. So on behalf of the Practice Guidelines Committee, the ASLD membership, and all of the clinicians who rely on these documents to provide the highest quality of care for our patients, we thank you, George, for your leadership, your knowledge, your hard work, and your outstanding dedication. Thank you everyone for your attention and I hope you enjoyed the session.

ASOD Practice Guidelines Workshop

Liver diseases

Assessments

Nutrition

Wilson disease

Primary sclerosing cholangitis

Palliative care

Non-invasive liver disease assessments

Early diagnosis

Frailty in cirrhosis patients

Disease prevention framework

Multidisciplinary approach