Rejection in Liver Transplantation Recipients.

Rejection following liver transplantation continues to impact transplant recipients although rates have decreased over time with advances in immunosuppression management. The diagnosis of rejection remains challenging with liver biopsy remaining the reference standard for diagnosis. Proper classification of rejection type and severity is imperative as this guides management and ultimately graft preservation. Future areas of promise include non-invasive testing for detection of rejection to reduce the morbidity associated with invasive testing and further advances in immunosuppression management to reduce toxicities associated with immunosuppression while minimizing rejection related morbidity.

Patients With Acute-on-Chronic Liver Failure Have Greater Healthcare Resource Utilization After Liver Transplantation.

BACKGROUND & AIMS: Although liver transplantation (LT) has been demonstrated to provide survival benefit for patients with acute-on-chronic liver failure (ACLF), data are lacking regarding resource utilization for this population after LT. METHODS: We retrospectively reviewed data from 10 centers in North America of patients transplanted between 2018 and 2019. ACLF was identified by using the European Association for the Study of the Liver-Chronic Liver Failure criteria. RESULTS: We studied 318 patients of whom 106 patients (33.3%) had no ACLF, 61 (19.1%) had ACLF-1, 74 (23.2%) had ACLF-2, and 77 (24.2%) had ACLF-3 at transplantation. Healthcare resource utilization after LT was greater among recipients with ACLF compared with patients without ACLF regarding median post-LT length of hospital stay (LOS) (P < .001), length of post-LT dialysis (P < .001), discharge to a rehabilitation center (P < .001), and 30-day readmission rates (P = .042). Multivariable negative binomial regression analysis demonstrated a significantly longer LOS for patients with ACLF-1 (1.9 days; 95% confidence interval [CI], 0.82-7.51), ACLF-2 (6.7 days; 95% CI, 2.5-24.3), and ACLF-3 (19.3 days; 95% CI, 1.2-39.7), compared with recipients without ACLF. Presence of ACLF-3 at LT was also associated with longer length of dialysis after LT (9.7 days; 95% CI, 4.6-48.8) relative to lower grades. Multivariable logistic regression analysis revealed greater likelihood of discharge to a rehabilitation center among recipients with ACLF-1 (odds ratio [OR], 1.79; 95% CI, 1.09-4.54), ACLF-2 (OR, 2.23; 95% CI, 1.12-5.01), and ACLF-3 (OR, 2.23; 95% CI, 1.40-5.73). Development of bacterial infection after LT also predicted LOS (20.9 days; 95% CI, 6.1-38.5) and 30-day readmissions (OR, 1.39; 95% CI, 1.17-2.25). CONCLUSIONS: Patients with ACLF at LT, particularly ACLF-3, have greater post-transplant healthcare resource utilization.

Living Liver Donation Does not Significantly Affect Long-Term Life, Disability, or Medical Insurability.

INTRODUCTION: The growing practice of living liver donation requires comprehensive understanding of the financial implications for living liver donors. While obtaining and maintaining insurance is important to financial health, little is known about the impact of liver donation on future insurability. RESEARCH QUESTIONS: The purpose of this study was to evaluate the donors' experiences with insurance following donation and identify the insurance provider-driven factors that contribute to donor insurability. DESIGN: A two center cohort of living donors with donation between January 2000 and December 2018 (N = 442) were surveyed about postdonation insurance experiences. To understand insurance provider practices towards liver donors, life (n = 11) and disability (n = 4) insurance underwriters were asked to provide policy quotes for a standardized living liver donor profile. RESULTS: Responses (N = 101) were received by August 2020 (response rate = 22.9%). Living liver donors reported owning life (58%), disability (35%), and medical (87%) insurance at rates comparable to the general population with low proportions reporting difficulty obtaining these insurance types (9%, 9%, 4%, respectively). Post-donation life insurance ownership was associated with post-donation employment (P = 0.01). Underwriter responses indicate life and disability insurability were adversely affected up to 12 months following donation. CONCLUSIONS: Living liver donors did not have difficulty maintaining insurance in the long-term but should be counseled to purchase insurance prior to surgery as short-term insurability may be affected. Perception of difficulty obtaining insurance following donation remains of significant concern among living donors. Further collaboration between the transplant community and insurance companies is warranted.

Artificial intelligence to identify harmful alcohol use after early liver transplant for alcohol-associated hepatitis.

Early liver transplantation (LT) for alcohol-associated hepatitis (AH) is the fastest growing indication for LT, but prediction of harmful alcohol use post-LT remains limited. Among 10 ACCELERATE-AH centers, we examined psychosocial evaluations from consecutive LT recipients for AH from 2006 to 2017. A multidisciplinary panel used content analysis to develop a maximal list of psychosocial variables. We developed an artificial intelligence model to predict post-LT harmful alcohol use. The cohort included training (N = 91 among 8 centers) and external validation (N = 25 among 2 centers) sets, with median follow-up of 4.4 (IQR 3.0-6.0) years post-LT. In the training set, AUC was 0.930 (95%CI 0.862-0.998) with positive predictive value of 0.891 (95%CI 0.620-1.000), internally validated through fivefold cross-validation. In the external validation set, AUC was 0.692 (95%CI 0.666-0.718) with positive predictive value of 0.82 (95%CI 0.625-1.000). The model identified specific variables related to social support and substance use as highly important to predict post-LT harmful alcohol use. We retrospectively developed and validated a model that identified psychosocial profiles at LT predicting harmful alcohol use post-LT for AH. This preliminary model may inform selection and post-LT management for AH and warrants prospective evaluation in larger studies among all alcohol-associated liver disease being considered for early LT.

Patterns of Alcohol Use After Early Liver Transplantation for Alcoholic Hepatitis.

BACKGROUND & AIMS: Early liver transplantation (LT) for alcoholic hepatitis (AH) is lifesaving but concerns regarding return to harmful alcohol use remain. We sought to identify distinct patterns of alcohol use post-LT to inform pre-LT candidate selection and post-LT addiction care. METHODS: Detailed post-LT alcohol use data was gathered retrospectively from consecutive patients with severe AH at 11 ACCELERATE-AH sites from 2006-2018. Latent class analysis identified longitudinal patterns of alcohol use post-LT. Logistic and Cox regression evaluated associations between patterns of alcohol use with pre-LT variables and post-LT survival. A microsimulation model estimated the effect of selection criteria on overall outcomes. RESULTS: Of 153 LT recipients, 1-, 3-, and 5-year survival were 95%, 88% and 82%. Of 146 LT recipients surviving to home discharge, 4 distinct longitudinal patterns of post-LT alcohol use were identified: Pattern 1 [abstinent](n = 103; 71%), pattern 2 [late/non-heavy](n = 9; 6.2%), pattern 3 [early/non-heavy](n = 22; 15%), pattern 4 [early/heavy](n = 12; 8.2%). One-year survival was similar among the 4 patterns (100%), but patients with early post-LT alcohol use had lower 5-year survival (62% and 53%) compared to abstinent and late/non-heavy patterns (95% and 100%). Early alcohol use patterns were associated with younger age, multiple prior rehabilitation attempts, and overt encephalopathy. In simulation models, the pattern of post-LT alcohol use changed the average life-expectancy after early LT for AH. CONCLUSIONS: A significant majority of LT recipients for AH maintain longer-term abstinence, but there are distinct patterns of alcohol use associated with higher risk of 3- and 5-year mortality. Pre-LT characteristics are associated with post-LT alcohol use patterns and may inform candidate selection and post-LT addiction care.

Avatrombopag Use in Patient With Thromboembolic Risks Listed for Combined Coronary Artery Bypass Grafting and Liver Transplant: A Case Report.

Thrombocytopenia commonly occurs in patients with advanced liver disease and can be a contraindication in patients needing combined coronary artery bypass grafting (CABG) and liver transplant (LT). Thrombopoietin receptor agonists, including avatrombopag, are part of a novel drug class and stimulate platelet production. Avatrombopag is indicated in the perioperative setting to avoid platelet transfusions, which carry several disadvantages. Avatrombopag was shown to be safe and effective in patients with chronic liver disease. This study describes the successful use of avatrombopag in a patient with thromboembolic risks in preparation for a combined CABG and LT. Larger clinical trials are necessary to validate our results.

Current Therapies for Alcohol-Associated Hepatitis.

Alcohol-associated hepatitis is associated with poor outcomes, especially when severe. Despite extensive study with a plethora of potential therapeutic agents, treatment options remain limited, with the current standard of therapy being corticosteroids. Granulocyte colony-stimulating factor is an alternate agent that seems promising, although further study in a more heterogenous patient population is needed before implementation. Adjuncts to therapy that are often overlooked are alcohol abstinence and adequate optimization of nutrition to improve outcomes. In select patients, early liver transplantation may be an option or enrollment in clinical trials.

TIPS for Adults Without Cirrhosis With Chronic Mesenteric Venous Thrombosis and EHPVO Refractory to Standard-of-Care Therapy.

BACKGROUND AND AIMS: Extrahepatic portal vein occlusion (EHPVO) from portal vein thrombosis is a rare condition associated with substantial morbidity and mortality. The purpose of this study is to investigate the efficacy of transjugular intrahepatic portosystemic shunts (TIPS) for the treatment of chronic EHPVO, cavernomatosis, and mesenteric venous thrombosis in adults without cirrhosis who are refractory to standard-of-care therapy. APPROACH AND RESULTS: Thirty-nine patients with chronic EHPVO received TIPS. Laboratory parameters and follow-up were assessed at 1, 3, 6, 12, and 24 months, and every 6 months thereafter. Two hepatologists adjudicated symptom improvement attributable to mesenteric thrombosis and EHPVO before/after TIPS. Kaplan-Meier was used to assess primary and overall TIPS patency, assessing procedural success. Adverse events, radiation exposure, hospital length-of-stay and patency were recorded. Cavernoma was present in 100%, with TIPS being successful in all cases using splenic, mesenteric, and transhepatic approaches. Symptom improvement was noted in 26 of 30 (87%) at 6-month follow-up. Twelve patients (31%) experienced TIPS thrombosis. There were no significant long-term laboratory adverse events or deaths. At 36 months, freedom from primary TIPS thrombosis was 63%; following secondary interventions, overall patency was increased to 81%. CONCLUSIONS: TIPS in chronic, noncirrhotic EHPVO with cavernomas and mesenteric venous thrombosis is technically feasible and does not adversely affect liver function. Most patients demonstrate subjective and objective benefit from TIPS. Improvement in patency rates are needed with proper timing of adjuvant anticoagulation.

ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury.

Idiosyncratic drug-induced liver injury (DILI) is common in gastroenterology and hepatology practices, and it can have multiple presentations, ranging from asymptomatic elevations in liver biochemistries to hepatocellular or cholestatic jaundice, liver failure, or chronic hepatitis. Antimicrobials, herbal and dietary supplements, and anticancer therapeutics (e.g., tyrosine kinase inhibitors or immune-checkpoint inhibitors) are the most common classes of agents to cause DILI in the Western world. DILI is a diagnosis of exclusion, and thus, careful assessment for other etiologies of liver disease should be undertaken before establishing a diagnosis of DILI. Model for end-stage liver disease score and comorbidity burden are important determinants of mortality in patients presenting with suspected DILI. DILI carries a mortality rate up to 10% when hepatocellular jaundice is present. Patients with DILI who develop progressive jaundice with or without coagulopathy should be referred to a tertiary care center for specialized care, including consideration for potential liver transplantation. The role of systemic corticosteroids is controversial, but they may be administered when a liver injury event cannot be distinguished between autoimmune hepatitis or DILI or when a DILI event presents with prominent autoimmune hepatitis features.

Comparing Real World, Personalized, Multidisciplinary Tumor Board Recommendations with BCLC Algorithm: 321-Patient Analysis.

PURPOSE: To evaluate hepatocellular carcinoma (HCC) treatment allocation, deviation from BCLC first-treatment recommendation, and outcomes following multidisciplinary, individualized approach. METHODS: Treatment-naïve HCC discussed at multidisciplinary tumor board (MDT) between 2010 and 2013 were included to allow minimum 5 years of follow-up. MDT first-treatment recommendation (resection, transplant, ablation, transarterial radioembolization (Y90), transarterial chemoembolization, sorafenib, palliation) was documented, as were subsequent treatments. Overall survival (OS) analyses were performed on an intention-to-treat (ITT) basis, stratified by BCLC stage. RESULTS: Three hundred and twenty-one patients were treated in the 4-year period. Median age was 62 years, predominantly male (73%), hepatitis C (41%), and Y90 initial treatment (52%). There was a 76% rate of BCLC-discordant first-treatment. Median OS was not reached (57% alive at 10 years), 51.0 months, 25.4 months and 13.4 months for BCLC stages A, B, C and D, respectively. CONCLUSION: Deviation from BCLC guidelines was very common when individualized, MDT treatment recommendations were made. This approach yielded expected OS in BCLC A, and exceeded general guideline expectations for BCLC B, C and D. These results suggest that while guidelines are helpful, implementing a more personalized approach that incorporates center expertise, patient-specific characteristics, and the known multi-directional treatment allocation process, improves patient outcomes.

Liver Transplantation Following Yttrium-90 Radioembolization: 15-Year Experience in 207-Patient Cohort.

BACKGROUND AND AIMS: Radioembolization (yttrium-90 [Y90]) is used in hepatocellular carcinoma (HCC) as a bridging as well as downstaging liver-directed therapy to curative liver transplantation (LT). In this study, we report long-term outcomes of LT for patients with HCC who were bridged/downstaged by Y90. APPROACH AND RESULTS: Patients undergoing LT following Y90 between 2004 and 2018 were included, with staging by United Network for Organ Sharing (UNOS) tumor-node-metastasis criteria at baseline pre-Y90 and pre-LT. Post-Y90 toxicities were recorded. Histopathological data of HCC at explant were recorded. Long-term outcomes, including overall survival (OS), recurrence-free survival (RFS), disease-specific mortality (DSM), and time-to-recurrence, were reported. Time-to-endpoint analyses were estimated using Kaplan-Meier. Univariate and multivariate analyses were performed using a log-rank test and Cox proportional-hazards model, respectively. During the 15-year period, 207 patients underwent LT after Y90. OS from LT was 12.5 years, with a median time to LT of 7.5 months [interquartile range, 4.4-10.3]. A total of 169 patients were bridged, whereas 38 were downstaged to LT. Respectively, 94 (45%), 60 (29%), and 53 (26%) patients showed complete, extensive, and partial tumor necrosis on histopathology. Three-year, 5-year, and 10-year OS rates were 84%, 77%, and 60%, respectively. Twenty-four patients developed recurrence, with a median RFS of 120 (95% confidence interval, 69-150) months. DSM at 3, 5, and 10 years was 6%, 11%, and 16%, respectively. There were no differences in OS/RFS for patients who were bridged or downstaged. RFS was higher in patients with complete/extensive versus partial tumor necrosis (P < 0.0001). For patients with UNOS T2 treated during the study period, 5.2% dropped out because of disease progression. CONCLUSIONS: Y90 is an effective treatment for HCC in the setting of bridging/downstaging to LT. Patients who achieved extensive or complete necrosis had better RFS, supporting the practice of neoadjuvant treatment before LT.

Safety and Efficacy of Segmental Yttrium-90 Radioembolization for Hepatocellular Carcinoma after Transjugular Intrahepatic Portosystemic Shunt Creation.

PURPOSE: To evaluate safety and efficacy of segmental yttrium-90 (Y90) radioembolization for hepatocellular carcinoma (HCC) after transjugular intrahepatic portosystemic shunt (TIPS) placement. The hypothesis was liver sparing segmental Y90 for HCC after TIPS would provide high antitumor response with a tolerable safety profile. MATERIALS AND METHODS: This single-arm retrospective study included 39 patients (16 women, 23 men) with ages 49-81 years old who were treated with Y90. Child-Pugh A/B liver dysfunction was present in 72% (28/39) with a median Model for End-stage Liver Disease score of 18 (95% confidence interval, 16.4-19.4). Primary outcomes were clinical and biochemical toxicities and antitumor imaging response by World Health Organization (WHO) and European Association for the Study of the Liver (EASL) criteria. Secondary outcomes were orthotopic liver transplantation (OLT), time to progression (TTP), and overall survival (OS) estimates by the Kaplan-Meier method. RESULTS: The 30-day mortality was 0%. Grade 3+ clinical adverse events and grade 3+ hyperbilirubinemia occurred in 5% (2/39) and 0% (0/39), respectively. Imaging response was achieved in 58% (22/38, WHO criteria) and 74% (28/38, EASL criteria), respectively. Median TTP was 16.1 months for any cause and 27.5 months for primary index lesions. OLT was completed in 88% (21/24) of listed patients at a median time of 6.1 months (range, 0.9-11.7 months). Median OS was 31.6 months and 62.9 months censored and uncensored to OLT, respectively. CONCLUSIONS: Segmental Y90 for HCC appears safe and efficacious in patients after TIPS. Preserved transplant eligibility suggests that Y90 is a useful tool for bridging these patients to liver transplantation.

Highlights From the AASLD/EASL ALD Endpoints Conference 2019.

Watch a video presentation of this article Watch an interview with the author.

Alcohol and Liver Function in Women.

Alcohol-related liver disease generally has been ascribed to men because men reportedly consume alcohol at an increased rate and quantity as compared to women. Recent literature has reported, however, that rates of liver disease attributed to alcohol use by women have increased, largely due, in part, to the increased number of women who consume alcohol regularly. This increase is a paramount concern, as women are more susceptible than men to the effects of alcohol-related liver injury. Health care providers should make efforts to counsel women on the risks of excess alcohol consumption to prevent further increase in alcohol-related liver disease and its associated complications.

A Case of Drug-Induced Liver Injury Secondary to Natalizumab.

A 33-year-old Caucasian female with relapsing-remitting multiple sclerosis presented with abdominal pain, nausea, and vomiting and was found to have acute liver injury. After thorough investigation, she was diagnosed with drug-induced liver injury (DILI) thought secondary to redosing of Natalizumab therapy.

Isolated Elevated Bilirubin.

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-4-reading-shroff-maddur a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-4-interview-shroff-maddur an interview with the author https://www.wileyhealthlearning.com/Activity/7088613/disclaimerspopup.aspx questions and earn CME.

Streamlining radioembolization in UNOS T1/T2 hepatocellular carcinoma by eliminating lung shunt estimation.

BACKGROUND & AIMS: Pre-treatment Tc-99m macroaggregated albumin (MAA) scans are routinely performed prior to transarterial radioembolization (TARE) to estimate lung shunt fraction (LSF) and lung dose. In this study, we investigate LSF observed in early hepatocellular carcinoma (HCC) and provide the scientific rationale for eliminating this step from routine practice. METHODS: Patients with HCC who underwent Y90 from 2004 to 2018 were reviewed. Inclusion criteria were early stage HCC (UNOS T1/T2/Milan criteria: solitary ≤5 cm, 3 nodules ≤3 cm). LSF was determined using MAA in all patients. Associations between LSF and baseline characteristics were investigated. A "no-MAA" paradigm was then proposed based on a homogenous group that expressed very low LSF. RESULTS: Of 1,175 patients with HCC treated with TARE, 448 patients met inclusion criteria. Mean age was 65.6 years and 303 (68%) were males. A total of 352 (79%) had solitary lesions and 406 (91%) unilobar disease. Two-hundred and forty-three (54%), 178 (40%) and 27 (6%) patients were Child-Pugh class A, B and C, respectively. Median LSF was 3.9% (IQR 2.4-6%). Median administered activity was 0.9 GBq (IQR 0.6-1.4), for a median segmental volume of 170 cm3 (range: 60-530). Median lung dose was 1.9 Gy (IQR: 1.0-3.3). The presence of a transjugular intrahepatic portosystemic shunt (TIPS; n = 38) was associated with LSF >10% (odds ratio 12.2; 95% CI 5.2-28.6; p <0.001). Median LSF was 3.8% (IQR: 2.4-5.7%) and 6% (IQR: 3.8-15.3%) in no-TIPS vs. TIPS patients (p <0.001). CONCLUSION: LSF is clinically negligible in patients with UNOS T1/T2 HCC without TIPS. When segmental injections are planned, this step can be eliminated, thereby reducing time-to-treatment, number of procedures, and improving convenience for patients traveling from faraway. LAY SUMMARY: Transarterial radioembolization is a microembolic transarterial treatment for hepatocellular carcinoma. In our study, we found that early stage patients, where segmental injections are planned, exhibited low lung shunting, effectively eliminating the risk of radiation pneumonitis. We propose that the lung shunt study be eliminated in this subgroup, thus leading to fewer procedures, a cost reduction and improved convenience for patients.