Good morning, everyone, and welcome to this session organized by the AASLD Practice Guidelines Committee. This session will highlight four new AASLD guidances and guidelines that have just been completed or are in the process of being completed as we speak. My name is George Ioannou, and I'm very pleased to introduce this session as Chair of the AASLD Practice Guidelines Committee. Today you will hear concise presentations from the authors of four AASLD guidelines and guidances. They have been tasked with summarizing for us primarily what is new in these guidelines relative to the prior ones and what are some outstanding challenges in their field. The first guideline is autoimmune hepatitis presented by Dr. David Assis. The second guidance is a completely new topic of reproductive health and liver disease presented by Dr. Monica Sarkar. The third guidance is ascites and kidney injury in cirrhosis presented by Dr. Ray Kim. And the last one is an epic guidance on vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease presented by Dr. Patrick Northup. If you're confused by the terms guidance versus guideline, you're not alone. The AASLD has adopted a precise terminology for guidelines versus guidances that is also supported by the National Academy of Medicine. A guideline is a recommendation document that is supported by systematic reviews of the literature, usually synthesized in evidence tables and leading to a quantitative meta-analysis if feasible. Guidelines pose specific PICO questions and conduct a systematic review for each PICO question. PICO questions are formulated to specify precisely the patient, the intervention, the comparison, and the outcome. Finally, guidelines use the GRADE approach to summarize the strength of the recommendation and the quality of the evidence. In contrast, guidances are documents that do not require systematic review. Instead, the guidance statements are formulated by an expert panel based on their formal review of the literature. The guidance statements are not graded in terms of the strength and quality of the evidence. The AASLD will choose to do guidelines only for topics that are supported by a large number of randomized controlled trials or comparative studies in the case of diagnostic tests. The AASLD's mechanism for developing guidelines provides for checks and balances to ensure transparency, to avoid bias, and to limit the impact of any conflicts of interest on our guidelines and guidances. A writing group of experts is carefully selected by the Practice Guidelines Committee with approval by the Governing Board. The writing group drafts the guideline. Systematic reviews are performed independently if needed by the Mayo Evidence-Based Medicine Writing Group. The AASLD Practice Guidelines Committee acts as an independent reviewer body and goes through multiple rounds of revisions back and forth with the writing group throughout the development of the guideline. The AASLD Ethics Committee oversees both the Practice Guidelines Committee and the writing group to ensure that they abide by the AASLD's Code of Conflicts of Interest. Finally, the Governing Board oversees the Practice Guidelines Committee and also provides final approval for all AASLD guidelines and guidances. We currently maintain 22 AASLD guidelines. They are all available full-text for free on our website. So please bookmark our website, download these guidelines, and use them. I want to finish by saying a big thank you to all the members of the Practice Guidelines Committee who work tirelessly to ensure high-quality, unbiased guidelines. I also want to say a big thank you to our AASLD staff liaisons, Audrey and Linnae, who organize and supervise everything. And without further ado, I would like to hand it over next to Dr. David Assis, who will present the new autoimmune hepatitis guideline. Hello and welcome to an update on autoimmune hepatitis. From the 2019 AASLD Practice Guidance and Guidelines. My name is David Assis, and I'm an assistant professor of medicine at Yale School of Medicine and a member of the writing group for the updated guidance. I have no relevant disclosures for this presentation. And I'd like to start by giving a bit of the background for this document. It constitutes a revision of the 2010 AASLD guidelines on autoimmune hepatitis. The current effort was co-chaired by Drs. Kara Mack and Albert Chaya, who shepherded a group deftly through this undertaking. The document contains both guidance statements, in which there was not a sufficient number of trials available to justify a systematic review and meta-analysis, as well as more formal guideline recommendations through the GRADE system, for which systematic reviews and meta-analyses were performed with the assistance of the Mayo Clinic Evidence-Based Practice Center. Both the guidance and guideline document, as well as the methodological paper on the systematic review and meta-analyses, were published this year in Hepatology. Let's start with some key definitions in autoimmune hepatitis, a field for which heterogeneity in definitions has been prevalent over the years. Autoimmune hepatitis itself, as we're well aware, is a characteristic histologic abnormality typically characterized by lymphoplasmicytic interface hepatitis, along with AST, ALT elevations, and total IgG, as well as the presence of at least one, if not more, characteristic autoantibodies. More recently, there has been an increased attention paid to a subphenotype of autoimmune hepatitis, which is acute severe autoimmune hepatitis, characterized by hepatocellular jaundice, elevated INR, the lack of hepatic encephalopathy, and no previously recognized liver disease. I'll also call to your attention some of the definitions used, such as biochemical remission, which is normal AST, ALT, and IgG, as well as definitions of treatment failure, incomplete response, relapse, and treatment intolerance at the beginning of the document. Let's start with the epidemiology of autoimmune hepatitis. Since the last update of these guidelines, it has been quite clear that there's been a nearly 50% increase in the incidence of autoimmune hepatitis over the last few decades. This study from Denmark shows that over a 20-year period, there's been a significant rise in the incidence of new cases of autoimmune hepatitis in that country, which has been seen around the world. Furthermore, there is clearly now an increasingly recognized second peak of new diagnoses of patients, particularly in the elderly, as exemplified in the graph to the right. The etiology of autoimmune hepatitis remains a bit mysterious, but is clearly a combination of genetics and environment. A GWAS study from 2014 clearly showed that loci for the HLA region, as well as lesser risk from non-HLA regions in the genome, is relevant, although with a modest impact on the risk for the disease. Furthermore, there is a contribution from environmental triggers, clearly in the case of medications, but also increasing evidence of potential prior viral infections. The pathogenesis of autoimmune hepatitis clearly is complicated and a complex pathophysiologic mechanism. There is a nice discussion in the document, which I don't have time to fully review, about the step-by-step disease process. Clearly a loss of tolerance, both centrally and peripherally, is to play a big role, as well as subtle changes in the microenvironment within the liver cytokine profile. The involvement of CD8 and CD4 T-cells has been well recognized, and there is an increasing recognition of the potential therapeutic value in addressing and stopping certain pathophysiologic mechanisms for B-cells and plasma cells in this disease. Furthermore, there is a more recent recognition of the plasticity of CD4 T-cell subsets in this disease, whereby regulatory T-cells can be converted to Th17 pathogenic effector T-cells. The clinical presentation of autoimmune hepatitis is quite heterogeneous. Most patients present with mild symptoms that are chronic over time, although a sizable percentage of patients will be fully asymptomatic and, interestingly, have a potential more difficult time in achieving biochemical remission, as well as trends for reduced 10-year survival. Some patients, up to a quarter or more patients, will have acute symptoms, and this includes the acute severe category of autoimmune hepatitis, as well as overt acute liver failure, which is a minority. The diagnosis of autoimmune hepatitis is complex in that there is not a single marker of disease. It is a clinical diagnosis based on the right clinical suspicion. This algorithm in the guidelines highlights that, and the patient for whom autoimmune hepatitis is suspected, the concurrence of a typical liver biopsy, such as shown in the graph to the right, with interface hepatitis by lymphocytes and plasma cells, as well as typical autoantibodies, type 1, characterized by ANA and SMA, and in pediatrics, predominantly LKM1, which would be type 2 autoimmune hepatitis, can lead, then, to the diagnosis of autoimmune hepatitis. Although, as you can see in this algorithm, there is also a substantial percentage of patients who likely have antibody-negative autoimmune hepatitis and tend to have similar clinical course and outcomes as to the antibody-positive patients. Overlap syndromes, always a diagnostic and management challenge, need to be fully addressed, especially in patients with either large duct abnormalities or small duct changes on liver biopsy. Increasingly, in this epidemic of fatty liver disease, there is not only the concurrence, but management challenges for those with steatohepatitis from NAFLD. In this regard, the updated guidelines do highlight the increasing diagnostic dilemma posed by this. It is well known that in patients with NAFLD, without any autoimmune hepatitis, there is a low positive autoantibody rate, such as ANA, in up to 17% of patients. And furthermore, patients with histological findings of NAFLD or NASH can be found in patients who truly have autoimmune hepatitis. In one study of 73 patients with autoimmune hepatitis, up to 16% of these patients had concurrence of both diseases. And as you can see, there was an increased risk of liver-related mortality and adverse outcomes. There is a clear need for larger and multicenter studies to confirm and expand these findings and how these patients are characterized and also managed over time. Drug-induced autoimmune hepatitis is well known, and I would recommend to you a very thorough discussion and tables in the guideline documents for the most common medications. One highlight that is not fully addressed in great detail because it is a separate disease, but clinically relevant, is the increasing frequency of immune checkpoint inhibitors that have a similar presentation to autoimmune hepatitis. It is known that this condition does not behave in a similar way to autoimmune hepatitis, particularly over time. And for this, I would highlight a very comprehensive recent review in hepatology and some of the following differences. There is not a typical female predominance in patients with checkpoint inhibitor-induced hepatotoxicity. Although ANA positivity can occur, it is not nearly as frequent and mostly not found in patients with checkpoint inhibitor hepatotoxicity, in contrast to autoimmune hepatitis. Plasma cells, furthermore, are not typically found in the biopsy of these patients. And lastly, there is not a predisposition to recurrence or relapse after withdrawal of the immunosuppression following treatment. Overlap syndromes, as I mentioned, remain a dilemma for clinicians oftentimes. The guideline committee felt that these remain clinical descriptions and not validated pathological entities whose value truly is to identify individuals who may not respond to more conventional treatments for autoimmune hepatitis. The PARIS criteria, which while I will not have time to review in depth, can be used for the delineation of autoimmune hepatitis and PBC overlap. And it is also worth highlighting the fact that a sizable percentage of patients with autoimmune hepatitis will also have ulcerative colitis. And of these, 40 to 50% of patients may have cholangiographic findings of PSC. Therefore, some of the guidance and recommendations are that there should be consideration for ursodioxycholic acid in patients who have true overlap. And lastly, although we will not have time to discuss this, scoring systems for autoimmune hepatitis do not have much utility in assessing for overlap syndromes. Acute severe autoimmune hepatitis, which I had highlighted earlier, remains a management dilemma for many patients and clinicians. There is, of course, an increased risk of progression to acute liver failure. ANA antibodies may be less present, as well as IgG may be normal in these patients. Biopsy features may be harder to interpret. And the group felt that close assessment and response to treatment, particularly at seven to 14 days, is critical to know who is recovering and who needs a more urgent transplant evaluation. For more information on this increasingly recognized topic, I would refer to you a very recent and comprehensive review in J-HEP reports on this topic. We don't have time to discuss in detail all of the guidance recommendations for management. I would just point to the fact that due to the increased concurrence of celiac disease and thyroid disease, all patients should be screened for this who are diagnosed with autoimmune hepatitis. And there are further management guidance statements on vaccinations, mineral bone density management, and transient elastography for autoimmune hepatitis. Let's get to the treatment of autoimmune hepatitis, which comprises two out of the three systematic reviews. The first is regarding first-line treatment, where the recommendation is for glucocorticoids and azathioprine. And you can see here in this slide that the question for a PICO question and systematic review and meta-analysis was whether there's a difference for prednisone versus budesonide. For second-line therapy, the question became whether mycophenolate or MMF versus calcineurin inhibitors, predominantly tacro, although cyclosporine has also been studied, has any incremental benefit for these patients. The first systematic review then evaluated whether new patients diagnosed with autoimmune hepatitis have any difference in respect to likelihood or remission, interval to remission, and side effects as to whether they are treated with prednisolone or prednisone in combination with azathioprine or budesonide in combination with azathioprine. Because there's only one randomized controlled trial on this topic, we should spend a minute discussing the findings since it is the predominantly weighted study for this recommendation. Study published in 2010 evaluated over a six-month period budesonide versus prednisone along with azathioprine in each arm with the primary endpoint of normal AST, ALT, at six months without specified steroid adverse effects. You can see in the slide that there was an increased percentage of patients in the budesonide arm who achieved that primary endpoint as compared to prednisone. Furthermore, there was an absence of steroid-specific side effects in 72% of patients on budesonide versus only 46.6% of patients on prednisone. And patients who were initially given prednisone and then converted in the open-label period to budesonide has substantial decrease in their steroid-specific side effects. Budesonide, as we know, has a high first-pass metabolism and therefore predisposes to less systemic side effects. The first systematic review then evaluated that randomized controlled trial and also one non-randomized controlled trial, finding overall few qualified studies to answer this question, but given the weight and the methodological strengths of the study that I quoted from 2010, there was an odds ratio favoring budesonide and azathioprine for patients with a new diagnosis. The committee then evaluated this, finding that from a steroid side effect profile, budesonide would have certain benefits over systemic steroids in the case of prednisone. However, it should be noted that due to the high cost and copay for many patients, which makes it difficult to obtain budesonide, that needs to be taken into account. The first guideline recommendation then is that the ASLD suggests that budesonide and azathioprine or prednisolone or prednisone and azathioprine can be used as first-line treatments. This is a change from the 2010 guidelines in which budesonide was not featured. However, it's very important to be aware that for children and adults who have cirrhosis or who have acute severe autoimmune hepatitis, budesonide should not be used. In the case of cirrhosis, this is because of increasing reports of portal vein thrombosis in patients treated with budesonide. In the case of acute severe autoimmune hepatitis, budesonide has not been studied and is perhaps unlikely to be helpful because its onset of action may be more slow compared to systemic steroids. A word on azathioprine. The recent guidelines make it much more clear that there is a benefit and a statement of recommendation to test for TPMT activity. We know that about 0.5% of individuals have absent or near absent thiopurine methyltransferase activity, and even though it may not be cost effective, strictly speaking, to test all patients with a new diagnosis, the severity of the bone marrow toxicity makes this warranted. So therefore, we should consider screening patients with AIH for TPMT activity prior to the initiation of azathioprine. Which leads us to one of the central first-line treatment figures in the guideline document. Autoimmune hepatitis patients who do not have cirrhosis or acute severe autoimmune hepatitis can be treated with prednisone or budesonide along with azathioprine following TPMT testing with frequent laboratory monitoring during the induction phase. If there is biochemical response, the frequency of liver test monitoring can decrease along with the taper. Once biochemical remission is achieved, further spacing out of labs can be contemplated. And after 24 months of therapy, an immunosuppression withdrawal can be considered. In children, a biopsy should be performed. In adults, that may not be mandatory, but certainly should be considered. And lastly, during a phase of prolonged biochemical remission, a steroid withdrawal while continuing azathioprine could be an initial step. In patients with cirrhosis, some key differences are that budesonide should not be used, as previously mentioned. And in the case of decompensated cirrhotics, azathioprine should also not be used, lest it risk some complications with drug-induced cholestatic damage. But aside from that, the treatment algorithm is relatively similar to those without cirrhosis. Some differences exist in acute severe autoimmune hepatitis, such that budesonide and azathioprine should be avoided. And higher doses of steroids, either orally or IV, should be administered with very frequent liver test monitoring. An early referral for transplant evaluation is mandatory if hepatic encephalopathy develops or if there is not a sign of a response within 7 to 14 days. If there is a response, one key clinical point is that a withdrawal of immunosuppression should not be offered to these patients due to the high risk of a severe relapse in this patient population. Second line treatments, then, for autoimmune hepatitis in patients who have treatment failure, incomplete response, or drug intolerance. We queried whether MMF or calcineurin inhibitors would have any difference with respect to the likelihood of achieving remission. There were two retrospective studies. Unfortunately, no randomized controlled studies in this topic. And there really was not any favorable data one way or the other to suggest a difference. The odds ratio were at 1.95, but the confidence interval clearly crossed 1 with few qualified studies and with heterogeneous test results. The group, then, had to discuss the benefits and the downsides of MMF versus calcineurin inhibitors such as Tacro. Certainly, there is an ease of use for microventilator MMF given the lack of a need for trough values and monitoring, which is needed for tacrolimus. On the other hand, it's clearly the case that MMF should not be used in the context of pregnancy. The guideline recommendations, then, for this topic is that the ASLD suggests the use of MMF or tacro to achieve and maintain biochemical remission in those who have not been able to achieve remission with first-line agents. And based on a superior ease of use and side effect profile, the ASLD suggests the trial of MMF over tacro as the initial second-line agent in patients with autoimmune hepatitis. This is a nice segue to some of the cautionary items regarding autoimmune hepatitis in pregnancy, and I would highlight a much more robust discussion of autoimmune hepatitis in pregnancy in the current guideline document. The live birth rate is 73% in mothers with autoimmune hepatitis, which is similar for that of women with other chronic diseases. Historically, there had been some hesitation to use azathioprine. However, more recent data from systematic reviews, including the IBD literature, shows no increase in birth defects or low birth weight, although there is a slightly higher rate of premature birth. So the guidance statements address pregnancy in a more robust way for autoimmune hepatitis compared to the prior guidelines. Specifically, that maintenance of glucocorticoids and azathioprine can be continued throughout pregnancy. MMF is highly contraindicated during pregnancy due to teratogenicity, and this needs to be addressed very early during the preconception and family planning discussions. And lastly, women with autoimmune hepatitis should be monitored more closely in the first six months following delivery because this is a period of time in which there's an increased risk of a clinical relapse. Salvage therapies, there are an increasing number of case reports of anti-TNF agents and anti-B cell or CD20 agents being used for refractory disease. The group did not find sufficient numbers of studies to make a recommendation one way or the other for their use, and this is certainly an area in need of better studies moving forward. Let's conclude then with liver transplantation in autoimmune hepatitis. Fortunately, this disease does not represent a high burden in the total number of transplants and the five-year patient and graft survivals are relatively robust in autoimmune hepatitis in America. However, there is a risk of late acute rejection, chronic rejection, as well as recurrence of autoimmune hepatitis, which leads one to wonder on a clinical basis whether there is a utility or a benefit to long-term steroids post-transplant to prevent these complications. Therefore, the third systematic review and PICO question was to evaluate whether there is any benefit to maintenance versus withdrawal of glucocorticoids in patients post-liver transplant. There were two retrospective studies and only one randomized control study on this topic. There was not a meaningful difference given the data available for review between withdrawal or continuation of steroids. Once again, there were few qualified studies with heterogeneous test results and low quality of evidence. The group then weighed the benefits and the downsides of continuation or withdrawal of steroids. Clearly, from a patient perspective, avoiding steroid side effects is beneficial, and from a cost perspective, prednisone, although cheap, is something that would favor discontinuation. Given the lack of any data to suggest a net benefit of continuing indefinite steroids, the ASLD suggests that a gradual withdrawal of glucocorticoids can be considered after liver transplantation. Clearly, though, it's important to keep in mind that for patients with suspected or diagnosed recurrent autoimmune hepatitis, they should be clearly given steroids along with azathioprine, perhaps in conjunction or instead of calcinear inhibitors, to achieve biochemical remission. And we will not have time to discuss in detail de novo autoimmune hepatitis, which is in patients transplanted for other etiologies. But similarly, a workup for autoimmune hepatitis should proceed in patients who have any features of AIH following liver transplant. Lastly, unmet needs in autoimmune hepatitis. It probably is abundantly clear through this presentation that there is an urgent need for randomized control trials of first line, second line, and salvage therapies in this disease. We need better immune biomarkers of disease activity and predictors of relapse. And there is a very nice discussion and table which I would recommend to you on emerging therapeutic options for this disease, including multiple modalities of points in which we could intervene with more targeted therapies. So key takeaways. AIH, autoimmune hepatitis, is a complex disease affecting all ages. And with the widely heterogeneous clinical presentation, there's an urgent need for better and larger studies to inform these clinical recommendations. For first line treatment, prednisone or budesonide plus azathioprine can be considered, but not in cirrhotics and not in patients with severe acute AIH. For second line treatment, MMF or Tacro can be used. Due to ease of use, MMF could be considered first, although clearly not in the setting of pregnancy. And lastly, for post-transplant patients, there is now a recommendation to consider a gradual withdrawal of steroids in these patients. Lastly, I'd like to thank the entire writing group who worked so well together, and it was a pleasure and an honor to present this data on their behalf, as well as I'd like to thank the Practice Guidelines Committee. On behalf of my co-authors, I'm delighted to discuss our inaugural guidance document on reproductive health and liver disease. I'm a transplant hepatologist at UCSF and chair-elect of the ASLD Women's Initiatives Committee. I'm an NIH-funded investigator with a lifelong goal of improving the care of women at the intersection of reproductive health and liver disease. These are my disclosures. This guidance document is intended to be a comprehensive reference on adolescents and adults with chronic liver disease. It addresses the management of reproductive health in women and men from puberty to senescence. It also summarizes the natural history, evaluation, and optimal management of liver diseases during pregnancy and after delivery. But it should not replace clinical judgment for a unique patient, but instead provide general guidance to optimize the care of most. As our guidance document is quite extensive, I've listed a few topics that we'll discuss today. These represent either more controversial issues or topics that have not been previously addressed in prior ASLD guidelines or guidance documents. These include sexual function, fertility, and contraception, reproductive health considerations in NAFLD, hepatocellular adenomas and variceal screening and management in pregnancy, as well as intrapartic cholestasis of pregnancy. We'll start by discussing sexual function, fertility, and contraception. It is well known that there's altered hormonal signaling along the hypothalamic-pituitary-gonadal axis in both men and women with advanced liver disease. There's also increase in the peripheral conversion of androgens to estrogens, which is particularly problematic from a clinical standpoint for men. These hormonal derangements result in sexual dysfunction, including impaired sex drive, erectile dysfunction, and decreased fertility in women. Thus, sexual dysfunction is common in chronic liver disease and clinicians should routinely inquire about these symptoms, which are important quality of life metrics for our patients. When identified, a referral to a specialist may be needed for subsequent evaluation and treatment. While fertility is impaired in many women who have advanced liver disease, pregnancy in the setting of cirrhosis has been increasing over time. In this study, it was found that childbirth in women with cirrhosis has increased more than sevenfold over the past 20 years. Thus, women who wish to avoid pregnancy should be educated and encouraged to use the most highly effective and safe contraception in the context of their chronic liver disease. One contraceptive category of particular importance to our patient population are those that contain estrogen. Options include the combined hormonal contraceptive pills, the patch and the ring as shown below. Failure rates are around 9% and these agents are associated with an increased risk of hypertension, venous thromboembolism, and rarely risk a stroke. They also increase the risk of hepatocellular adenoma growth and can induce P450 and lead to some drug-drug interactions. They are metabolized by the liver but are deemed acceptable or safe for use in women who have cirrhosis with compensated disease as well as women who've had a prior liver transplant in the absence of graft failure. However, these agents are not considered safe for women who have decompensated cirrhosis, Bud Kiari syndrome, hepatocellular adenomas, or prior transplant that has progressed to graft failure. Another important contraceptive category for our patient population are long-acting reversible contraceptives or LARCs. LARCs include IUDs, both the hormonal and the copper, as well as the subcutaneous implant inserted in the superficial skin on the arm as shown below. These all have the lowest failure rate as compared to any other hormonal contraceptive agent of less than 1%. As compared to women with no chronic liver disease, they're not associated with a greater risk of pelvic inflammatory disease or impaired efficacy. Importantly, they don't rely on patient compliance. And once placed, they can be left in and effective for up to 10 years depending on the particular agent selected. As you can see, these are also safe to use across all forms of chronic liver disease, including women with decompensated cirrhosis as well as those with a prior liver transplant and graft failure. For sexual function, fertility, and contraception, clinicians should routinely inquire about sexual activity and pregnancy intentions in all reproductive age adolescents and women with chronic liver disease or liver transplant. Adolescents have an increased risk of unplanned pregnancy. So long-acting reversible contraceptives have particular advantages in this population. Estrogen-containing agents should be avoided in patients with deep liver disease Estrogen-containing agents should be avoided in patients with decompensated cirrhosis, those with Budghiari syndrome, hepatocellular adenomas, or prior transplants that has progressed to graft failure. Patients using agents other than LARCS are encouraged to combine these with a barrier method as all of those other contraceptive options do have higher failure rates. We'll now discuss reproductive considerations in women with NAFLD. The incidence of NAFLD has recently increased more than seven-fold in young adults. And among those with NAFLD, women have also been shown to have a greater risk of NASH as well as advanced fibrosis. The growing number of women and young adults with NAFLD has important clinical implications on their reproductive health. One particular at-risk group are women with polycystic ovary syndrome or PCOS. Approximately 10% of all premenopausal women have PCOS, which is typically marked by insulin resistance, obesity, and high androgen levels, such as elevated testosterone. More than 50% of women with PCOS have NAFLD on imaging. And PCOS has also been shown to increase the risk of more severe NASH as well as NASH fibrosis on biopsy. Clinical signs of PCOS include irregular menses and or hirsutism or excess hair growth, which is a sign of androgen excess. Thus, in reproductive age adolescents and women with NAFLD, evaluation for these symptoms of PCOS is recommended as PCOS may influence their risk for NAFLD progression. And these patients should be referred to a specialist for non-liver related PCOS management. With the rising numbers of young adults with NAFLD, we too are seeing a rise in pregnancies affected by NAFLD with rates that have nearly tripled over the past 10 years. In this recent US-based study, we found a more than threefold higher risk of hypertensive complications, such as preeclampsia, eclampsia, or HELP syndrome in pregnancies affected by NAFLD. We also found an increased risk of postpartum hemorrhage as well as preterm birth, all of which were independent of preexisting metabolic comorbidities. Breastfeeding should be encouraged in women with NAFLD in pregnancy due to its known benefits on metabolic health. In women without NAFLD, breastfeeding is protective against their future NAFLD risk. In obese mothers, breastfeeding also decreases the risk of NAFLD in their offspring. Breastfeeding has also been shown to help with more rapid weight reduction following delivery and also helps to improve insulin sensitivity in mothers. Thus preconception counseling should include review of maternal and fetal risks and the benefits of optimizing weight and metabolic comorbidities prior to conception. Optimal gestational weight gain through healthy diet and appropriate exercise should be emphasized. Monitoring of liver tests is similar to the non-pregnant patient and breastfeeding is encouraged. We'll now discuss hepatocellular adenomas in pregnancy. Hepatocellular adenomas are largely benign lesions, though do have malignant potential. Rupture risk can occur with larger lesions and estrogen has been shown to promote their growth. In the first and only prospective study of HCAs in pregnancy, women with lesions of less than five centimeters on pre-pregnancy MRI were included. They underwent an ultrasound every six weeks during pregnancy with significant growth defined as a greater than 20% increase. This occurred in just over 25% of all participants. One patient had a prophylactic embolization of a lesion that grew to greater than seven centimeters. Although there was no report of tumor rupture or hemorrhage, nor were there any adverse events for the fetus. These data support favorable maternal and fetal outcomes for smaller HCA lesions in pregnancy. In our guidance document, we propose the following approach to HCAs in pregnancy. For HCA lesions of less than five centimeters prior to conception, ultrasound monitoring during each trimester and up to 12 weeks postpartum is reasonable. For HCA lesions less than five centimeters in pregnancy, no intervention is needed. For HCA lesions that grow to greater than or equal to five centimeters in pregnancy, bland embolization can be considered. For women with HCAs of greater than or equal to five centimeters prior to pregnancy, prophylactic bland embolization can be considered. And if the HCA is eradicated, no follow-up during pregnancy is required. For lesions that are reduced to a size less than five centimeters but still present, ultrasound monitoring during each trimester and up to 12 weeks postpartum is reasonable. And for those women who do undergo resection prior to pregnancy, no follow-up during pregnancy is required. Women with HCA should be counseled about the possibility of adenoma growth and rupture in pregnancy. Ultrasound monitoring during each trimester of pregnancy and up to three months postpartum is reasonable. Pregnancy with HCA lesions of less than five centimeters is not contraindicated. And for women who have HCAs of greater than or equal to five centimeters, prophylactic embolization or resection should be considered prior to conception. We'll now discuss variceal screening and management in women with cirrhosis. There are notable physiologic changes of pregnancy that increase the risk of variceal growth and bleeding. These include an increase in circulating blood volume, increase in collateral flow, increase in portal flow with subsequent increase in intra-hepatic resistance. There's also decrease in systemic vascular resistance and increase in peripheral vasodilation with associated increase in cardiac output. The clinical consequences of these physiologic changes include increase in the risk of developing varices, having growth in the size of varices and subsequent variceal hemorrhage. Variceal bleeding carries up to 20% maternal mortality in pregnancy. Although the incidence has fallen in the past 20 years from up to 33% to now less than 10%. The greatest risk of variceal bleeding occurs in the second trimester when intravascular volume expansion is the greatest, as well as during delivery when there's IVC compression from an enlarged uterus and with repeated Valsalva maneuvers for women undergoing a vaginal delivery. Non-selective beta blockers can help to reduce this risk and include Natalol and Propranolol, both of which are compatible with pregnancy and lactation. For pregnancy, there have been rare reports of intrauterine growth restriction, neonatal respiratory depression and infant hypoglycemia, although the benefits outweigh these uncommon risks. For lactation, Natalol is associated with a greater excretion to breast milk that Propranolol is favored. There's inadequate data during pregnancy or lactation for Carvedolol, thus Propranolol is the favored agent. All of these agents have historical FDA category C, although the FDA has gotten rid of this alphabetized system and instead advises that clinicians weigh the risks and the benefits of individual medication based on a patient's clinical indication for medication use during pregnancy. The following algorithm should be used to stratify and manage varices in women with cirrhosis, depending on whether they'd had an upper endoscopy within one year prior to conception and what that upper endoscopy showed. For women without varices on their preconception upper endoscopy, no treatment is indicated during pregnancy, as shown on the left. For women with small varices, you should consider initiation of a non-selective beta blocker. For medium or large varices, women should be initiated on a non-selective beta blocker or undergo band ligation until variceal obliteration, with band ligation favored if there's evidence of high-risk bleeding stigmata. For women without a recent upper endoscopy, EGD should be performed in the early second trimester. And again, if small varices, you should consider initiation of a non-selective beta blocker. And for medium or large varices, initiate a non-selective beta blocker or perform band ligation. Transient elastography is a useful tool in the general population with compensated cirrhosis to help identify patients who have a low risk for clinically significant varices based on a liver stiffness and platelet count. This can help to identify the population who can avoid the need for screening upper endoscopy. However, this strategy is not appropriate for determining the need for screening upper endoscopy in either the preconception or pregnancy periods, as it can miss up to 30% of patients with small varices for whom we would advise consideration of a non-selective beta blocker to lower their risk for variceal bleeding in pregnancy. There's also physiologic changes of pregnancy that may alter liver stiffness, and there's inadequate safety data, thus transient elastography is not FDA approved for use in pregnancy at this time. Our guidance statements on varices in pregnancy, endoscopy does require preoperative consultation with maternal fetal medicine specialists to coordinate fetal monitoring and maternal sedation. In women with cirrhosis, pre-pregnancy upper endoscopy is recommended with screening in the early second trimester if not previously performed within one year prior to conception, or if there's evidence of ongoing liver injury or decompensation occurs that may further increase the risk of variceal development and bleeding. Meparidine, midazolam, propofol, and fentanyl may all be used in pregnancy with efforts to minimize the duration of anesthesia. If small gastroesophageal varices are identified, primary prophylaxis using non-selected beta blocker should be considered. For medium or large varices, primary prophylaxis can include either band ligation until obliteration or non-selected beta blocker, with propranolol being the favored non-selected beta blocker in pregnancy and lactation. For acute variceal hemorrhage, the management is the same as the non-pregnant population, although antibiotic therapy should preferentially use cephalosporins, which are safe in pregnancy, and turlopressin should be avoided as it can induce uterine contractions and decrease uterine blood flow. Mode of delivery should be guided only by obstetric indications in women with cirrhosis, as cirrhosis alone is not an indication to pursue a cesarean delivery. We'll now discuss intra-hepatic cholestasis of pregnancy. The prevalence of ICP in pregnancy varies between 0.4 and 10%, depending on the particular population studied. Risk factors include advanced maternal age, multi-parity and metabolic syndrome, as well as HCV infection. The link between hepatitis C and ICP has not been fully elucidated, although hepatitis C is thought to have a direct cytopathic effect on biliary epithelial cells and predisposing to ICP in HCV-infected mothers. Personal or family history of ICP also increases the risk, as do the presence of certain genetic variants that are associated with cholestasis. The clinical presentation of ICP is classically itching, most notably of the palms and the soles, without an associated rash. ICP typically develops during the second and third trimesters, although for all liver diseases that are unique to pregnancy, the onset can occur outside of the typical gestational age, with ICP reported as early as the first trimester, particularly in women who do have genetic variants of cholestasis. Liver enzymes in ICP can be as high as 30 times the upper limits of normal. Total bile acid levels should be greater than 10 and can be measured in a fasting or non-fasting state. Maternal risks are minimal, although the genetic variants do increase the risk for benign recurrent intrapartic cholestasis and progressive familial intrapartic cholestasis. Fetal risks are of greatest concern and include preterm birth, neonatal respiratory depression and asphyxia, as well as intrauterine fetal demise. These risks are highest with bile acid levels greater than 100 and ursodeoxycholic acid has been shown to lower bile acid levels. Interestingly, recent randomized control data that assessed UDCA versus placebo failed to show a difference between groups on a composite risk of perinatal death, preterm delivery or prolonged neonatal unit admission. Thus, pruritus in the second and third trimesters plus a total bile acid level of greater than 10 without other causes of pruritus is diagnostic of ICP. Elevation of liver enzymes is frequent but not required for the diagnosis. Women with ICP should be tested for hepatitis C and pruritus management includes UDCA as a first-line therapy. And though data are limited, there are many other options for the treatment of refractory pruritus in pregnancy, including antihistamines, colostyramine, rifampin and SAMe. UDCA is safe in pregnancy and does reduce bile acid levels, although data supporting its benefit on reducing fetal risks, including IUFD are lacking. Vitamin K should be supplemented when PT, INR are prolonged and women with persistent symptoms or elevated liver tests or bile acids after delivery should be evaluated for other causes of chronic liver diseases, including genetic variants that are associated with cholestasis. As our key takeaways, chronic liver disease commonly affects reproductive and sexual health. Clinicians should routinely inquire about sexual activity and function in women and men, as well as contraceptive use and pregnancy intentions in adolescents and reproductive age women. While pregnancy with liver disease is higher risk, pregnancy planning allows us to perform the necessary liver-related evaluation prior to conception and to transition our patients off of teratogenic medications while helping to optimize their liver disease prior to pregnancy. Liver disease and pregnancy does require a multidisciplinary approach with close collaboration with our obstetric colleagues in an effort to achieve optimal maternal and infant outcomes. Thank you for your attention, and I'd be happy to address any questions at the end of our session. It is my pleasure to discuss the new guidance, ascites and kidney injury in cirrhosis. I'd like to acknowledge a few people here, including the eight members of the writing group and PGC review leaders and Audrey from ASLD staff. Thank you. I have nothing to disclose. Ascites in a cirrhotic patient represents an important landmark in the progression of disease. It is exemplified in the CTP score, where obviously it is one of the components in constituting the score. It is a reminder that these patients should be considered for liver transplant evaluation. I also would like to acknowledge Professor Roger Williams, who is a senior author already in 1973, who just passed away this summer. The pathophysiology leading to ascites and other complications related to ascites is summarized on this slide. The key event here is splanchnic vasodilatation, as well as portal hypertension and bacterial translocation. Splanchnic vasodilatation leads to arterial underfilling, sodium retention, and plasma volume expansion, which in conjunction with increased lymph formation as a result of portal hypertension lead to ascites formation. Other events such as hyponatremia, hepatorenal syndrome, spontaneous infections, all are related to the cascade of events shown on this slide. In patients who present with new onset ascites, diagnostic parasynthesis is an important initial investigation. We recommend getting cell count and differential count for PMN enumeration. Total protein and albumin quantitation with or without cultures as appropriate for the setting. We also need serum albumin to calculate serum ascites albumin gradient, or SAG. If SAG is 1.1 or higher and the total protein is less than 2.5, that indicates cirrhotic ascites, whereas total protein greater than 2.5 will point to post sinusoidal ascites such as heart failure or butt carry syndrome. SAG less than 1.1, you should consider peritoneal disease such as malignancy or tuberculosis. We classify ascites into three grades. Grade one is ascites that is only detected by ultrasound, whereas grade three is marked tense distension of the abdomen, and grade two is ascites in between those two categories. We do not recommend treatment for grade one ascites. Grade two ascites is treated by sodium restriction two grams per day or less, diuretics including spironolactone with or without furosemide. We need to monitor weight and electrolytes in these patients with a goal of losing one kilogram per day in patients with edema or 0.5 without. Grade three ascites is initially treated with large volume prosthesis followed by medical management including salt restriction and diuretics. A few tips on medical management of cirrhotic patients with ascites. We should absolutely avoid nephrotoxic drugs such as NSAID, angiotensin-converting enzyme inhibitors, angiotensin receptor blockades, and aminoglycosides. Muscle cramps are frequent occurrences in patients with cirrhosis that have significant impact on their quality of life. Treatment that has been shown to be effective include albumin, calcium, quinidine, and some of the muscle relaxants. Long-term albumin have been tested in recent studies and yet the data are not conclusive enough that we don't recommend using it in our practice. The first study that showed benefit is multistandard Italian randomized control study, open-label 431 patients. These were cirrhotic patients with ascites treated with diuretics, meld of 16. The patients were given albumin 40 grams weekly for 18 weeks versus standard care. The endpoint was survival, and the survival graph shows that patients who received albumin did significantly better than just standard care alone. But that data was not supported by another study which was a Spanish randomized control trial, a bit smaller study with 196 patients comparing midodrine and albumin versus standard care for 12 months, which it did not show survival benefit. So again, at this point, long-term albumin is not recommended yet. Refractory ascites is defined as ascites that cannot be mobilized or recurs early and that that cannot be prevented. Diuretic-resistant ascites is lack of response as shown here at the bottom of the slide to dietary sodium restriction and maximal doses of diuretics. Diuretic-intractable ascites is when patients develop diuretic-induced complications even before they reach the maximum doses of diuretics. Here is the definition for recurrent ascites as well as early recurrence of ascites we can reference in our management algorithm which is shown in the next slide. In patients with grade three ascites while on diuretics, there are three things to check. The first is dietary history to assess for sodium restriction. The second is urine sodium measurement and third is assessment for diuretic response and complications. If the patient is compliant with sodium restriction and the patient has minimum urinary sodium excretion while the patient has no response to the maximum doses diuretics or patient develops complications before they reach the maximum doses, that satisfies the definition for refractory ascites. When these conditions are met, the management options are two. The first is large volume paracentesis with albumin which needs to be combined with monitoring for post-paracentesis circulatory dysfunction. If these patients have liver dysfunction, they are candidates for liver transplantation. In patients who are doing better, they may be candidates for TIPS procedure and the criteria for successful TIPS candidate is shown here. Other complications of ascites may include hyponatremia, hydrothorax or abdominal hernias. Hyponatremia may be graded into asymptomatic mild hyponatremia greater than 125 milligrams per liter, which we do not treat. We just monitor these patients. Moderate hyponatremia, 120 to 125. We try to restrict water to one liter per day. For patients with severe hyponatremia less than 120, water restriction the same amount plus the albumin is recommended. Vasopressin receptor antagonists or so-called VAPTINs may raise serum sodium levels during treatment. However, they need to be used with caution for a short period of time, less than 30 days. If we need to correct hyponatremia with hypertonic saline, there needs to be a specified goal and the goal rate should to increase should be to increase the sodium level by four to six milliequivalents per liter over a 24-hour period, not to exceed eight milliequivalents per liter over that 24-hour period. Osmotic demyelination syndrome is a relevant concern in patients undergoing liver transplantation. The risk can be mitigated with multidisciplinary coordinated care for transplant candidates. However, liver transplantation and therefore, liver transplantation should not be prohibited by hyponatremia alone. Hepatic hydrothorax is first treated with dietary sodium restriction and diuretics and thoracentesis as required. Second line treatment will be tips. Chest tube should not be inserted whereas indwelling tunneled catheters may be considered in carefully selected patients who are not transplant candidates. Abdominal hernia repair has a high risk. It is best for the patient to wait for transplantation if he or she is a candidate. Elective repair may be considered with multidisciplinary care after ascites and other conditions have been optimized. In patients who have refractory ascites, tips can be a useful tool to control the ascites to allow hernia repair. Spontaneous infections is a common complication in patients with cirrhotic ascites. About 50% of spontaneous infections are community acquired, which is detected at or less than 48 hours of admission. The remaining 50% of half of them are nosocomial, which means greater than 48 hours of admission or healthcare associated, which is a patient that is exposed to healthcare less than 90 days. The distinction of this is important because the response to the third generation cephalosporins that we're used to using is different depending on the setting. For community acquired, it's about 80%. For nosocomial, it's as low as 40%. Healthcare associated is somewhere in between. Once you diagnose SPP with polymorphonuclear leukocyte greater than 250, the next question to ask is whether the infection is nosocomial or hospital acquired, whether there has been a recent exposure to antibiotics or the patient presented with septic shock. If the answer to these is yes, then we should apply broad spectrum coverage such as paparacilin, broad spectrum coverage such as paparacilin and tazovectin. And if there is a MRSA present as well at vancomycin, if VR is present at daptomycin. In patients who are of a more benign condition, we can go back to third generation cephalosporin such as ceftriaxone. Other aspects of medical management, we recommend repeat TAP two days after empirical antibiotic treatment to confirm response. And the response is defined as PMN decreasing to greater than 25%. So less than 25% would indicate lack of response. We should give albumin, especially in patients with AKI and or jaundice. In patients who recover from SPP, secondary prophylaxis may be recommended. The best evidence comes from long-term prophylaxis with daily norfloxacin, which is not available in the US today. We consider ciprofloxacin as an acceptable alternative to norfloxacin in this setting. Upper GI bleeding patients should receive a short-term antibiotic coverage such as ceftriaxone one gram over 24 hours. Primary prophylaxis against SPP is a little bit controversial, but using ciprofloxacin for that indication may be considered in patients with low protein, less than 1.5 grams per liter of ascites, or in patients with renal dysfunction or liver failure as specified on this slide. The last section is acute kidney injury and hepatorenal syndrome. AKI acute kidney injury can be staged into three. AKI stage one is increase of creatinine of 0.3 or greater up to two times the baseline value. AKI stage two is creatinine two to three times baseline. AKI stage three is greater than three times the baseline or absolute value greater than four or initiation of renal replacement therapy. Contrast this against the previous HRS definitions, which are no longer used, creatinine of 2.5 for HRS-1 and 1.5 for HRS-2. The diagnosis of HRS-AKI, or somewhat similar to HRS-1, includes the following, cirrhosis with ascites, meeting AKI criteria as shown here on the left side, absence of shock, no nephrotoxic drug exposure, no signs of structural kidney injury, and no response after two consecutive days of diuretic withdrawal and plasma volume expansion with albumin, which is further amplified in this slide, which shows diagnosis and management of AKI and cirrhosis. Acute rise in creatinine by 0.3 or greater needs to be followed with clinical assessment, including urinary sediment and biomarker measurements. If specific diagnosis is made, such as ATN, acute interstitial nephritis, urinary tract infection, the patient needs individualized nephrology care. Most patients, however, will not have those, and then the next question we ask is whether the creatinine doubled from baseline. If the answer is yes, the patient has AKI stage 2 or 3, the next step is risk factor management, as shown on the left side of that slide, including reduction or withdrawal of diuretics, volume replacement, withdrawal of nephrotoxic drugs, and detection and treatment of infections. Do that, and then immediately start giving albumin one gram per kilogram for two days. In patients who don't have AKI stage 2 or 3, meaning AKI stage 1, the next step is, again, employing this risk factor management. If the patient improves, then we go back to the monitoring mode. If the patient is watched for up to 48 hours and there's no resolution of the AKI, then we start giving albumin. If the patient does not respond and actually the creatinine keeps rising despite risk factor management, without delay, the patient needs to go to albumin infusion for volume expansion. If the patient responds to the volume expansion, then again, then we go to the monitoring mode. If not, then that defines HRS AKI. These patients need to be considered for vasoconstrictor treatment. If they are a candidate, go to vasoconstrictor therapy. If they are not vasoconstrictor treatment, then we need help from our nephrology colleague. Medical management of HRS AKI, the treatment choice is vasoconstrictor plus albumin. When and if terlipressin is available, which can be given as IV bolus or continuous infusion, is the first line. Norepinephrine is a reasonable alternative to terlipressin. Thirdly, midodrine and octretide combination may be considered. Response criteria can be determined up to 14 days, and it consists of creatinine decreasing to 1.5 milligrams per deciliter, or it returning to within 0.3 of baseline. Futility is defined by creatinine increasing to pretreatment level up to four days, or after maximum tolerate doses for a defined duration. HRS AKI may recur after treatment discontinuation, which can be retreated with the same regimen. We need to be careful about side effects of vasoconstrictor therapy, which includes ischemic complications, as well as pulmonary edema from the albumin infusion. Liver transplantation is an appropriate consideration for patients with HRS AKI. They need urgent liver transplant evaluation. Renal replacement therapy is an adjunct in that setting. It needs to be initiated with a clear endpoint. It must not be delayed, waiting for response to vasoconstrictor. Multidisciplinary care is useful in this setting, consisting of hepatology, nephrology, critical care, transplant surgery, and so forth. Simultaneous liver-kidney transplantation is recommended when criteria are met. Non-selected beta blocker has been a bit controversial. In patients with refractory ascites and SBP, patients are not necessarily contraindicated in this setting, but they should be withheld if hypotensive, as shown here, or hyponatremic, or they have AKI. Beta blockers may be reintroduced if these circulatory dysfunctions improve. Among patients with AKI, discontinuing beta blocker should be considered as a part of risk factor management. Children with cirrhotic ascites are managed similarly as adults. First, they need to be considered for referral for liver transplantation. Diagnostic parasympathesis is performed if there's fever, abdominal pain, or clinical deterioration. In asymptomatic patients, it's a judgment call. Initial management consists of sodium restriction and diuretics, as shown in this slide. Large volume parasympathesis is used in grade three in refractory ascites with albumin infusion. The indication risks and benefits in children of these maneuvers remain to be defined. In patients with proven or suspected SBP, broad-spectrum antibody coverage is recommended, whereas there is insufficient data how to treat children with HRS-AKI, so more research is needed. There are a few things new with this guideline, such as grading of ascites, definition of refractory ascites and hyponatremia. We emphasize the significance of MDRO in spontaneous infection in cirrhotic patients. We present new algorithms for AKI and HRS-AKI. Whether terliprastine and when, it will be available remains to be seen. We try to align our guidelines with transplant guidelines as well. There are some things that we can recommend for future directions. Multidisciplinary care for cirrhotic patients with ascites can be standardized. Optimal use of albumin for long-term needs to be clarified. Timing for tips for refractory ascites, early, late, has been debated. Proper role of VAPTINs needs to be studied. Optimal window for non-selective beta blocker use can be better defined. Antibiotic stewardship to prevent MDRO need to be optimized. We need better understanding of biomarkers for renal injury and recovery, as well as transplant allocation after vasoconstrictor treatment. There needs to be a lot more research to be done in pediatric patients with ascites. Thank you very much for your attention. Hello, my name is Patrick Northup. I'm from the University of Virginia in Charlottesville, Virginia. It's my distinct honor to present the 2020 AASLD practice guidance on vascular liver disorders, portal vein thrombosis, and procedural bleeding in patients with liver disease on behalf of the practice guidance writing group. I have nothing to disclose about this presentation. It really has been an honor to lead this distinguished writing group over the past year of this project. Members of this group are world experts in vascular liver diseases and hemostasis and cirrhosis, and I'm proud to have been associated with this group. We've worked very hard on this project, and while we've not always agreed on the issues, we've come together with a consensus document that explores new areas not covered in prior guidance documents and helps define future research directions in the field. I'd like to personally thank all of them for the hard work, and it's truly been an honor to lead this distinguished group. We were given a very specific task by the AASLD to completely rewrite a practice guidance that was last updated in 2009. We had to add coverage of procedural bleeding and quote coagulopathy, end quote, as a vascular complication of liver disease, and we had to cover extensive new knowledge about an important topic, portal vein thrombosis. The challenges were severe with this project. First, the data was sparse and very low level, and we had to develop an expert panel opinion practice guidance. There were eight writing group members, seven time zones. That equaled a lot of Zoom trouble, and these meetings happened late in the evening for some and early in the morning for others. We had to summarize several varied and loosely related disease processes with tight word and reference restrictions, and then finally, none of us anticipated the global pandemic, which ravaged Europe and the United States in the middle of this project and at key times moving forward. We think the final product is excellent in our opinion. We developed an expert opinion consensus document with literature review and focus on actionable recommendations. Final document is a beast. It's 15,000 words, 184 double-spaced typewritten pages, 10 tables, 5 figures, 355 references. Truly a mammoth work. Document is planned for publication in hepatology in early 2021 and in an online enhanced format like some other guidance documents that the ASLD has available publicly. I want to caution the listener that there is weak data on many of the topics we covered, and the literature is sparse. Our recommendations are based on the data that we could find and expert opinion. The reference lists in the document itself are not exhaustive, and they focus on recent literature published since the last guidance document was published in 2009. And let me remind everyone, a practice guidance is not the same as a practice guideline. This document should guide clinical decisions and point future research efforts, but is not by any means be considered a standard of care. Content covered in the new guidance document is broad. We cover coagulation and hemostasis in cirrhosis patients. Procedural bleeding risk assessment and prevention. We spend a lot of characters covering in-depth detail in portal vein thrombosis management in cirrhosis patients and in patients without cirrhosis. Hepatic vein thrombosis, Bud Kiari syndrome are covered extensively. We cover sinusoidal obstruction syndrome, liver vascular malformations and hereditary hemorrhagic telangiectasia, idiopathic non-cirrhotic portal hypertension and portosinusoidal vascular disorder, hepatic and splenic artery aneurysms, which has not been covered in major documents in the past, and issues specific to children and congenital disorders. First, in talking about coagulation and hemostasis, it's important to understand the rebalance of hemostasis and cirrhosis. There are entire weekend-long symposia dedicated to this topic, and I don't have the time to cover it in this 20-minute talk, but coagulopathy is a term that is now an anachronism. Because it ignores the other processes that happen in liver disease that compensate for the obvious factor deficiencies that we see in cirrhosis. Bleeding risk in cirrhosis patients is not accurately predicted by laboratory values, especially the INR. There is no interventional prospective studies with adequate controls and well-defined bleeding endpoints in cirrhosis patients in relation to procedural bleeding complications. I want to remind the viewers that not all bleeding is due to hemostatic failure or coagulation disorders. Bleeding due to portal hypertension, especially esophageal varices, is not prevented by manipulation of coagulation factors. It's directly related to portal pressures. Similarly, vessel rupture by puncture or injury, whether trauma or surgical bleeding, is not related to deficits in coagulation disorders. There is bleeding due to hemostatic failure. Typically, we see that with gastropathy or dental extraction bleeding, and those bleeding sources may benefit from a coagulation intervention. However, that is far from proven in the literature. After consideration of the literature, the writing group came to the following conclusions regarding pre-procedure testing for bleeding risk. Global tests of hemostasis, such as thrombin generation or whole blood viscoelastic tests, better capture the general hemostatic stasis of a patient with cirrhosis, but have not been clinically validated with bleeding endpoints. Due to conflicting data in the literature, current guideline recommendations from the ASLD do not suggest a specific ion or platelet cutoff where procedural bleeding risk is reliably increased. Therefore, given the low bleeding risk of many common procedures, the potential risks of platelet transfusion, the lack of evidence that elevating the platelet count reduces bleeding risk, and the ability to use effective interventions, including transfusion in the case of bleeding, it is reasonable to perform both high and low risk procedures without prophylactically correcting the platelet count. Similarly, with the INR, the INR should not be used to gauge procedural bleeding risk in patients with cirrhosis who are not taking vitamin K antagonists. Measures aimed at reducing the INR are not recommended prior to procedures in patients with cirrhosis who are not taking vitamin K antagonists. Finally, fresh frozen plasma transfusion prior to procedures is associated with risks and has no proven proven evidence of platelet count. Fresh frozen plasma transfusion prior to procedures is associated with risks and has no proven benefits in patients with cirrhosis. We understand that these recommendations conflict with other societal recommendations. Despite that, we have surveyed the evidence and we find no data to support the argument for routine pre-procedure correction of either platelet count, INR, or fibrinogen levels. Listed here is the table 4 from the document that also documents the other societal recommendations based on the same data we have evaluated. Portal vein thrombosis is a hot research topic in an area that troubles clinicians every day in the clinics. We've surveyed their literature on portal vein thrombosis, and we think there are important factors to consider in this disease process other than just the presence of portal vein thrombosis. All PVTs are not equal. The location matters. Intra-hepatic versus large extra-hepatic clot burden versus mesenteric. The percent of the lumen of the main portal vein occluded is important in determining the severity of the portal vein thrombosis. Finally, malignant invasion of the portal vein by tumor should not be considered a thrombotic event. Clinically, it should be treated differently, and as a research topic, it should also be separately considered. We can now reconstruct the portal venous system with imaging in great detail. It's important to use future technologies to better characterize portal vein thrombosis and obstruction to flow in the portal system. Because of the explosion in research and public health data, we have to be careful about the Because of the explosion in research and publications in portal vein thrombosis over the last decade, in the document, we summarize the strengths and weaknesses of the published classification schemes in our Table 6, if you're referring to the document after publication. We also bring forward a simplified but standardized terminology for time course, percent of main portal vein occlusion, and site of thrombosis. This is shown in Table 5 of the document. In the guidance document, we discuss portal vein thrombosis in patients with and without cirrhosis, nearly as separate diseases. In the cirrhosis patient, there's no need for routine thrombophilic condition evaluation unless something in the history raises a question. Treatment goals in patients with cirrhosis and portal vein thrombosis are uncertain. Allowing anatomic portal vein anastomosis at the time of transplant shows benefit, and prevention of extension is a possible benefit of treatment in these patients. However, those are both unproven in well-designed studies. In patients without cirrhosis, a full investigation for myeloproliferative disorders or other thrombophilic conditions is warranted. A complete description of the workup and testing protocols for patients without cirrhosis is shown in Table 8 in the document. The goal of treatment in those patients without cirrhosis is to prevent ischemia and portal hypertension complications, and to prevent the chronic complications of cavernoma and cavernous transformation. Specifically in regards to patients with cirrhosis, the writing group recommended those who have recent thrombosis of small intrapadic subbranches of the portal vein or minimally occlusive, less than 50 percent obstruction of the lumen thrombosis of the main portal vein, be observed with serial imaging every three months without therapy if it's thought to be reasonable in the clinical scenario. If regression is seen, then treatment can be considered at that time. In patients with cirrhosis and recently occlusive or partially occlusive, greater than 50 percent obstruction of the lumen thrombosis of the main portal vein or mesenteric vein involvement, antithrombotic therapy should be strongly considered to avoid progression and obstruction to future liver transplantation. In patients with chronic complete occlusion of the main portal vein or cavernous transformation with established collaterals, there's no established benefit of anticoagulant therapy in this population, and treatment should be targeted at management of the portal hypertension complication. I don't have time to cover today, but in the document, we talk extensively about specific medical therapies, including the DOACs. Also in the document in our figure 5, a treatment algorithm for cirrhosis patients experiencing portal vein thrombosis is presented. We cover hepatic vein thrombosis, or Bud Chiari syndrome, at length in the document. We have a full review of the latest data on management strategies for this disorder, including stepwise medical therapy, vascular decompression techniques, including TIPS, and directly inserted intrahepatic cortosystemic shunts. We talk about management of liver lesions, and patients with chronic Bud Chiari syndrome, and HCC screening. Finally, we cover the literature and recommendations on liver transplantation for this difficult topic. Hepatic and splenic artery aneurysms have not been covered extensively in prior guidance documents, and in fact, the area is not well covered in some of the other documents. We also have a number of other areas not well covered in societal recommendations, including the surgical literature. In fact, the literature is sparse with primary data. There's more review articles than there are primary data articles on this topic, and the area is really devoid of randomized trials. Many current management recommendations are not evidence-based. We extensively reviewed the literature on this topic. For recently diagnosed hepatic artery or splenic artery aneurysms of less than 2 centimeters in size, we recommend performing early follow-up imaging at 3 and 12 months to assess for spontaneous growth rate. If any significant growth of an aneurysm on serial imaging is found, it should prompt consideration of intervention in consultation with other experts. In patients with pregnancy plans or liver transplant candidates, consider elective interventions in those patients with hepatic artery or splenic artery aneurysms. In other patients, intervention has not been proven superior to expectant management. We spend quite a bit of time in the document covering sinusoidal obstruction syndrome, otherwise known as veno-occlusive disorder. We also cover liver vascular malformations, especially in the setting of hereditary hemorrhagic telangiectasia. Regarding SOS, we review the diagnostic criteria and classification systems. We assess special risk in patients with pre-existing liver disease. And finally, we discuss data supporting UDCA use and defibrotide indications. Regarding liver vascular malformations, we talk about the pitfalls of diagnosis and management of this disorder. We discuss the various complications associated with the vascular shunting of this disease, and that's shown in figure 5 in the document. We review established and newer treatments, including bevacizumab. There are separate sections on idiopathic non-serotic portal hypertension and portosinusoidal vascular disorder, as well as childhood and congenital disorders. Regarding non-serotic portal hypertension, we talk about risk factors and diagnostic criteria. We also introduce the overarching entity called portosinusoidal vascular disorder, which also encompasses similar histologic findings without portal hypertension. Regarding childhood and congenital disorders, we reinforce early referral to specialized centers with potential early intervention in extra-hepatic portal vein obstruction in children to prevent long-term complications. We also emphasize the use of beta blockers in infantile hemangiomata with glutathione expression based on the literature. So in this brief time, I've summarized a large document. The key takeaways are that there's a new practice guidance covering broad areas of hemostasis and liver disease, portal vein thrombosis, and vascular liver diseases. Look for publication both online and in print over the next three to four months after the digital liver meeting. We present new actionable guidance statements and treatment protocols that will help clinicians in the day-to-day management of patients, but we also review the literature and provide an emphasis on scientific deficits that will help researchers focus on new areas of exploration. I'd like to give a special thanks to Georgianou, David Goldberg, and the rest of the Practice Guideline Committee in helping guide us through this and in picking us to write this document. Also, a special thanks to Audrey Davis-Oweno and Lynnae Sanders, the ASLD staff, that have really helped us through this process and done a lot of the logistical work. I'd like to give a special nod to Kristen Johnson, the illustrator who works for the ASLD, who has given us professional and beautiful diagrams for the print and online versions. Finally, a thanks to all the writing group members and Dominique Valla with some arm-twisting who accepted the position to be the senior author on this document. I thank the working group for putting up with the frequent Zoom calls, the odd hours, the Google Docs sharing, and the five-plus revisions of this massive document, and I thank them once again. Finally, I've started the initial paperwork to add an AASLD special interest group, a SIG, specific to vascular liver disorders and hemostasis. This area really isn't well covered in the current SIG format, and I think there's plenty of interest from the community in participating and stay tuned for that. So, thank you for listening. I've crammed a 180-page document into 20 minutes. I look forward to answering questions in the chat group right after this presentation. My email is also on the slideshow. If you'd like to email me with specific questions, I'd be more than happy to answer. Good morning. This concludes our session on the new AASLD guidelines from this year. My name is Elizabeth Verna, and it is my great honor to be the Vice Chair of our Current Practice Guidelines Committee. I'd like to thank all of our speakers today for their fantastic presentations, as well as all of the members of the four writing groups for lending their tremendous efforts and expertise to the creation of these four outstanding new documents. Before we conclude, I'd like to preview some of the work to come for this year. I'm proud to announce that we have at least three guideline and guidance documents that are in the drafting process, and we anticipate will be published in the first quarter of next year. These include the Noninvasive Liver Disease Assessment Guideline and its companion meta analyses, the Wilson's Disease Guidance, and a new Nutrition Sarcopenia, Frailty, and Chronic Liver Disease Guidance document. In addition, we are in various stages of convening writing groups for eight additional guidance documents that we hope to kick off in the next year. These include an update on PSC and cholangiocarcinoma, on TIPS, BRTO, BATO, and CARTO for gastroesophageal varices, a new guidance document on palliative care and symptom-based management and end-stage liver disease, an update on hemochromatosis, an update on acute and chronic liver failure, portal hypertension and cirrhosis, acute liver failure, and long-term management of liver transplant recipients. Finally, a new initiative for our committee in the next year will be to create companion documents for our guidelines and guidances, specifically written for patients. So look out for these new patient resources coming in the next year. As a reminder, all of the ASLD guidelines and guidances are available to both members and non-members on our website at the link below. And finally, I'd like to give another big thank you to everybody involved in this committee, including the ASLD staff that allow our committee work to proceed, as well as all of the hardworking members of the Practice Guidelines Committee. Thank you for your attention, and I hope you enjoy the rest of the meeting.

autoimmune hepatitis

guidelines

epidemiology

diagnosis challenges

treatment options

personalized care

overlap syndromes

liver disease

pregnancy

cirrhosis

intrahepatic cholestasis

ascites

kidney injury