Welcome to the clinical hepatology debrief. My name is Tamara Taddy. I'm Associate Professor of Medicine in the Section of Digestive Diseases at Yale School of Medicine and I direct the liver cancer program at the VA Connecticut Health Care System. I want to thank the ASLD for inviting me to give the clinical debrief. I have no disclosures. Just like the cells in this liver, there were thousands of presentations this year. 197 oral presentations and 1,769 poster presentations. That was a daunting task to choose from so I didn't do it myself. I enlisted the help of my colleagues Sylvia Villarino, Simona Jacob, and Ariel Jaffe. We met frequently by Zoom, email, and text to compare notes on the best papers and I'm grateful for their support and assistance in putting this debrief together. Because of the incredible amount of great science at this year's meeting, we focused on papers that addressed fundamental questions in the practice of hepatology and papers that may change or call into question our clinical practice. We chose papers that had the highest level of evidence such as randomized controlled trials, controlled studies, and large data sets and some small data sets too. Given the other debriefs, we excluded papers on NAFLD and NASH, viral hepatitis, and all non-human studies. We strove to provide the bottom line bread-and-butter takeaway messages, understanding that much of the content, including oral sessions, will be available on demand. For ease of presentation, I ordered papers thematically so these slides will serve as an anchor as I move from topic to topic. So we'll start with cirrhosis and portal hypertension. This study, number 661, Opportunities for Early Diagnosis of Unrecognized Cirrhosis in the Department of Veterans Affairs by Best et al. seeks to address the problem of how we improve detection of cirrhosis and early intervention. The prevalence of unrecognized cirrhosis is largely unknown and the authors aim to assess the prevalence of liver disease, risk factors, and rates of subsequent testing and cirrhosis diagnosis in the Veterans Health Administration system. The authors evaluated patients under VHA care in 2018 with no prior cirrhosis diagnosis who had at least one risk factor for cirrhosis. So of 6 million patients, about 50% had some risk factor for cirrhosis and in those 50% they reviewed the proportion of liver related testing in the preceding two years including things like imaging, transient elastography, and Fib4 score and that was done in about 75% of patients. 5% of patients screened positive for potential cirrhosis with a liver stiffness of greater than or equal to 12 kilopascals or a Fib4 score greater than or equal to 3.25 but of those patients numbering 133,000 only 10% were recognized as having a diagnosis of cirrhosis in the chart and of those patients 33% experienced a decompensating event from 2018 to 2019. This paper underscores the importance of population level screening in uncovering unrecognized cirrhosis enabling intervention earlier in the course of disease. Abstract number 91 external validation of the vocal pen cirrhosis surgical risk score by Fricker and colleagues addresses the problem of preoperative risk stratification. The vocal pen risk score was published in hepatology in 2020 and this VA study looking at over 4,000 veterans with cirrhosis who underwent over 5,000 surgeries shows that the Mayo cirrhosis surgical risk score is declining in calibration over time. In this study they aim to externally validate these novel cirrhosis surgical risk models to improve prognostication for a range of common surgeries. The vocal pen score is available on the web and includes nine biochemical and clinical variables including type of surgery and whether the surgery is emergent. In this validation study in 383 cirrhosis patients who underwent major surgeries the vocal pen score showed excellent performance most notably for 90-day mortality. While these models are not a substitute for clinical acumen they certainly improve our surgical risk prediction in patients with cirrhosis a very common question in consultative hepatology validation in a larger group is underway. Several notable abstracts deserve mention here because they address key problems such as is it safe to do a TEE in a patient with cirrhosis without screening for varices first or should non-selective beta blockers be continued in patients with refractory ascites common questions we encounter every day in practice. In the study by SAC regardless of absence or presence of varices no patients of the 119 study met the primary outcome of overt gastrointestinal bleeding suggesting routine pre-procedure EGD is of no utility. Non-selective beta blockers are thought to reduce intestinal permeability. Jensen and colleagues examined the data from 1,198 cirrhosis patients with ascites recruited for the randomized trials of satavaptan. Non-selective beta blockers decrease the risk of sepsis by 50% independent of dose. Further evidence for the utility of non-selective beta blockade in patients with decompensated cirrhosis comes from Tran and colleagues who showed in 163 patients that non-selective beta blocker use in patients with cirrhosis and refractory ascites improves long-term survival. As we move from decompensated cirrhosis to end-stage liver disease this paper by Uferi et al entitled randomized control trial of an advanced care planning video decision support tool for transplant ineligible patients with end-stage liver disease addresses the problem of patients with end-stage liver disease who are not candidates for liver transplantation often receiving intensive medical care at the end of life. Uferi and colleagues assess patients knowledge and preferences for end-of-life care, life prolonging care, life limiting care, or comfort care after an educational intervention using either a five-minute ACP video decision support tool or a verbal narrative. In comparing the verbal arms versus the video arms for pre and post intervention CPR preferences and pre and post intervention intubation preferences although preferences changed in both the verbal and video arms the degree of change in the video arm was substantially higher than in the verbal arm. The takeaway from the study is that this ACP video decision support tool was feasible acceptable to patients and improve their knowledge about end-of-life care. More patients in the video arm opted against CPR or intubation. This suggests to me that we ought to be thinking about multimodal approaches to education and this study is of critical importance during COVID-19 when we may not be able to connect with our patients as readily. Moving on to alcohol-related liver disease. Study number 232, early alcohol relapse after an episode of alcohol-induced hepatitis, prevalence, impact of liver function, genetic and non-genetic factors, and identification of distinct risk profiles by Clemente et al. is an interesting study that addresses alcoholic hepatitis which is the most severe manifestation of alcohol-related liver disease and carries a very high mortality rate. Alcohol relapse we know negatively influences long-term survival in alcoholic hepatitis but the incidence predictors and impact of early relapse are poorly defined. This study aims to determine the prevalence of early alcohol relapse which is defined as resumption within three months of presentation with alcoholic hepatitis. In this paper the authors looked at 478 patients from the STOPA trial and validated their findings in 194 patients from the end team consortium. They looked at three classes of latent class regression to model high-risk profiles, intermediate risk profiles, and low-risk profiles. They found that high-risk patients were younger, unemployed, and without a stable relationship. Intermediate risk were middle-aged, employed, and in a stable relationship, and low-risk profiles were older with known cirrhosis. They were mostly retired and in a stable relationship. Non-genetic factors predict early relapse and these distinct profiles were identified and may allow personalization of treatment strategies. Study number seven, fecal microbiota transplant improves long-term outcomes in patients with alcohol use disorder, by Bajaj and colleagues, is intriguing and may change the way we think about cravings. This study addresses the problem of alcohol use disorder which is associated with an altered gut-brain access that can potentially propagate addiction and end organ damage. Fecal microbial transplant has led to short-term reduction in alcohol cravings but the long-term benefits are unknown. The aim was to define long-term safety and impact of FMT compared to placebo in patients with alcohol use disorder and cirrhosis in a randomized clinical trial. In this phase one study, patients who received FMT were noted to have reduced cravings compared to patients in the placebo arm. It's important to know that this is a small study with 10 patients randomized to placebo and 10 patients randomized to FMT. Patients were followed for six months and patients actually showed a trend towards greater total abstinence at six months but this was not statistically significant. What is interesting was that not only was FMT safe and well tolerated but there were reduced AUD related side effects in the FMT group with only one patient having an AUD related serious adverse event compared to seven in the placebo arm. Future trials should be performed to determine the impact of FMT on altering the gut-brain axis in patients with AUD. Moving on now to transplantation, we look at the study on early liver transplantation for severe alcoholic hepatitis not responding to medical treatment results of the French-Belgian prospective study QuickTrans presented by Lovette and colleagues. The problems addressed in this study are the fact that limited therapies exist for severe alcoholic hepatitis. Early transplant for select patients has demonstrated excellent outcomes but controlled prospective trials on the outcomes of these patients have been lacking. The aim of this study was to assess in a controlled fashion the non-inferiority of alcohol relapse among patients with severe alcoholic hepatitis selected for early liver transplantation to candidates for transplantation for alcohol-related cirrhosis with at least six months of abstinence. Patients were selected for transplant based on a dedicated algorithm for eligibility. 78 patients with severe alcoholic hepatitis were selected for transplantation of whom 68 received transplant. In the alcohol and sobriety group 129 were selected of whom 93 underwent transplant. When comparing first alcohol relapse 33.8% of severe alcoholic hepatitis patients relapsed and 24.7% of alcohol and sobriety relapsed. Using a pre-specified non-inferiority margin of 10% non-inferiority their primary outcome could not be shown. However the two-year survival in groups A and B those with severe alcoholic hepatitis and those with alcohol who achieved six months of sobriety were identical and excellent. The two-year survival from non-response in the group with severe alcoholic hepatitis selected for liver transplant versus those with severe alcoholic hepatitis who were not selected for transplant shows a significant difference of 82.8% probability of survival in those selected for transplant and 28.2% probability of survival in those not selected for transplant. Despite not meeting their endpoint, they showed no significant difference in relapse rates between groups. Heavy drinking was more frequently seen in patients who underwent early liver transplant. Perhaps most important is that studies in this population can be conducted in a controlled fashion across centers with reproducible transplant eligibility algorithms. Abstract number one entitled Paradigm Change in Liver Transplant Practice for Patients with Kidney Dysfunction After the Implementation of the New Liver-Kidney Allocation Policy presented by Suzuki et al. addressed this policy change and its effect on patients. The number of simultaneous liver-kidney transplants had been steadily increasing and indications for simultaneous liver-kidney transplant varied between centers and this prompted a policy change. Standardized criteria for simultaneous liver-kidney transplant and a safety net granting liver transplant patients with kidney dysfunction priority on the kidney transplant list were created in 2017. The effects of this new policy in patients with kidney dysfunction are not yet known. The study aimed to assess how the new simultaneous liver-kidney transplant policy affected access to simultaneous liver-kidney transplant, post-liver transplant along renal failure rates, and need for kidney transplant after liver transplant. UNOS OPTN data from 2015 to 2019 were examined in a pre- and post-policy change cohort and the cohorts were compared to one another. It's important to note that there were no effects of this policy change on liver transplant alone waitlist outcomes. Not surprisingly, there was a significant increase in kidney transplant listing after liver transplant, especially in patients on hemodialysis at the time of transplant listing. Patients who underwent liver transplant and had severe kidney dysfunction had a significantly higher probability of kidney transplant in the post-policy era and significantly reduced kidney transplant waitlist mortality in the post-policy era as well. There's much more on this policy and its effect on patients and I would point you in the direction of Dr. Asrani's abstract number 50 in which he takes a closer look at gender disparities. We'll now move from transplant to autoimmune and cholestatic diseases. This late-breaking oral presentation, number 11, is the enhanced study, the safety and efficacy of Celadelpar in patients with primary biliary cholangitis presented by Hirschfeld and colleagues. One in a thousand women over 40 years of age live with PBC and we know that PBC leads to impaired quantity and quality of life with debilitating fatigue and pruritus. Bursodeoxycholic acid remains the mainstay of therapy but there are positive treatments for non-responders. The original aim of this phase 3 randomized control trial was to evaluate the efficacy, safety, and tolerability of Celadelpar, a PPAR delta agonist, during one year of treatment in patients with PBC. The study was halted due to an adverse event ultimately deemed unrelated, so this trial evaluated the composite responder rate at month 3. The key takeaway from this study is that at the 10 milligram dosage of Celadelpar, 78% of patients met composite endpoint, 27% of patients normalized their alkaline phosphatase, and 50% normalized their ALT. There was a significant improvement in pruritus. Overall, Celadelpar was generally safe and well-tolerated. A 52-week phase 3 global registration study called the response trial will begin enrolling patients in quarter 1 of 2021. Study number 66 entitled Pediatric PSC is associated with poor outcomes in racial and ethnic minorities was presented by Hochberg and colleagues. They addressed the problem of the paucity of data regarding differences in PSC between children of different racial and ethnic groups. They aim to assess whether PSC disease type, severity, concomitant comorbidities, and natural history differ based on race or ethnicity in pediatric patients. The authors studied patients from the Pediatric PSC Consortium recruiting from 54 centers globally. They studied 1,091 patients with race and ethnicity data. The starkest differences were among Black patients who tended to present at older ages and with more severe fibrosis or cirrhosis. In this study, they showed that Black and Hispanic patients have clinically worse outcomes compared to White and Asian patients. They're more likely to be diagnosed with PSC at an advanced stage with extensive fibrosis. This may represent a delay in diagnosis, a more aggressive disease phenotype, or both. Studies are needed to better understand phenotypic variations by race and ethnicity. We often struggle to counsel our patients with autoimmune hepatitis who become pregnant. Paper number 97, Autoimmune Hepatitis in Pregnancy, a Systematic Review and Meta-Analysis of Maternal and Fetal Outcomes, presented by Jamali and colleagues, sheds light on these issues. We know that autoimmune hepatitis disproportionately affects young women who often become pregnant, and robust data are needed to help counsel women on pregnancy-related outcomes. The aim of this study was to assess maternal and fetal outcomes by meta-analysis of 12 studies that included over 500,000 pregnancies and 485 autoimmune hepatitis patients, with a total of 546 gestations. The key takeaways from this paper are that autoimmune hepatitis is associated with an increased risk of gestational diabetes, premature births, small for gestational age, and low birth weight babies, as is seen with outcome and odds ratio on the bottom right. Pregnant women should be monitored closely before, during, and after pregnancy. It's important to note that in the prevalence data, flares are most prevalent postpartum at 41%. These findings will help us counsel our patients with autoimmune hepatitis who become pregnant. Similar findings were reported by Wang et al. in abstract number 99. Moving on to Drug-Induced Liver Injury. Paper number 116, entitled, Outcomes Following Resumption of Immune Checkpoint Inhibitor Therapy After High-Grade Immune-Mediated Hepatitis, was presented by Lee and colleagues. We know that immune checkpoint inhibitors are increasingly used for treatment of a broad spectrum of malignancies. Current guidelines by ASCO and ESMO recommend permanent discontinuation of immune checkpoint inhibitor therapy after grade 3 to 4 immune checkpoint inhibitor therapy. The aim of this study was to examine clinical outcomes following immune checkpoint inhibitor re-challenge in melanoma patients with resolved high-grade 3 or higher immune checkpoint inhibitor hepatitis. In this study of 102 melanoma patients who developed high-grade immune checkpoint inhibitor hepatitis, 31 were re-challenged, and of those 31, 4 or 13% developed recurrence of grade 2 or greater immune checkpoint inhibitor hepatitis. 15 of the 31, or 48%, developed any immune-related adverse event after re-challenge. Six required discontinuation, and that was 19%, inclusive of the four who developed hepatitis. Nine were not severe enough to require discontinuation. There was no difference in time to death in those re-challenged, as shown in the Kaplan-Meier curve, and this is important. There is a poster by Fontana and colleagues that goes over the histopathology of immune checkpoint inhibitor hepatitis, and they note that patients who develop immune checkpoint inhibitor hepatitis don't usually die of acute liver failure. They usually die of progression of cancer. Immune-related liver toxicity that requires discontinuation after re-challenge is overall uncommon, and high-grade immune checkpoint inhibitor hepatitis should be reconsidered as an absolute contraindication for immune checkpoint inhibitor re-challenge, thereby keeping options open for our patients with cancer. Moving on now to neoplasia. Trends in liver cancer are evolving rapidly. In this paper, number 136, The Striking Rural-Urban Disparities in Hepatocellular Carcinoma Trends in the United States from 1995 to 2016, Ganey and colleagues look at rural-urban disparities in HCC incidence trends. We know that HCC is the fastest-growing cancer in the U.S., and while rural-urban disparities have been studied in other cancers, there are little data on differences in HCC incidence trends. The aim of this study was to compare trends in age-adjusted incidence rates of HCC in rural and urban areas in the U.S. over 20 years, stratified by race, ethnicity, and other factors. The authors studied the North American Association for Central Cancer Registry's data, which covers 93% of the U.S. population using a preset rural-urban variable based on USDA and census data. This was last released in 2013. They show that the rate of increase in HCC is significantly higher in rural than urban areas. Hispanics have the highest age-adjusted incidence rate of all racial ethnic groups, 14.9 per 100,000 people. Rural whites and blacks have high average annual percentage changes, 5.67 and 5.38, respectively. If you look at the increase from 1995 at baseline age-adjusted incidence rate, you can see that the rural rates have gone up by 227% for HCC. There's striking rural and urban disparities in HCC, which have been growing over time and underscore health inequities that deserve further study. We'll end with COVID-19. Understanding that there was plenty of coverage of COVID-19 and liver disease-related topics at the meeting, I just wanted to focus on one paper. Abstract number nine, entitled, Predictors of Outcomes of COVID-19 in Patients with Chronic Liver Disease, the COLD Study, was a U.S. multicenter study presented by Adneji and colleagues. Chronic liver disease is a risk factor for severe COVID-19 and COVID-19-related mortality. The authors aim to better understand the clinical course of COVID-19 in patients with This study spanned 23 centers in the United States and recruited 978 patients. It started on a Twitter chat, which is a testament to our virtual existence. Of the 978 patients recruited, 868 had chronic liver disease and only 1% had chronic liver disease. The study was Of the 978 patients recruited, 868 had chronic liver disease and 110 were liver transplant recipients. Patients with chronic liver disease were noted to have high mortality rates at 14%. Alcoholic liver disease, decompensated cirrhosis, and HCC were liver-specific risk factors for increased COVID-19 mortality, as is shown in the Kaplan-Meier curves. The authors recommend to emphasize telemedicine to prioritize chronic liver disease patients for vaccination and also to include these patients in prospective studies and drug trials. For final takeaways, I want to thank the presenters for their hard work and resilience in these difficult times, and I hope to see everybody next year in Anaheim. I also want to once again thank my colleagues who helped me with this debrief, Drs. Sylvia Villarino, Simona Jacob, and Ariel Jaffe. Thank you.

Dr. Tamara Taddy

Clinical Hepatology Debrief

ASLD conference

liver-related topics

cirrhosis detection

autoimmune hepatitis pregnancies